WHO DRUG
INFORMATION
VOLUME 22 NUMBER 1 2008
RECOMMENDED INN LIST 59 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES
WORLD HEALTH ORGANIZATION GENEVA WHO Drug Information Vol 22, No. 1, 2008 World Health Organization
WHO Drug Information
Contents
Challenges in Biotherapeutics Miglustat: withdrawal by manufacturer 21 Regulatory pathways for biosimilar Voluntary withdrawal of clobutinol cough products 3 syrup 22 Pharmacovigilance Focus Current Topics WHO Programme for International Drug Proposed harmonized requirements: Monitoring: annual meeting 6 licensing vaccines in the Americas 23 Sixteen types of counterfeit artesunate Safety and Efficacy Issues circulating in South-east Asia 24 Eastern Mediterranean Ministers tackle Recall of heparin products extended 10 high medicines prices 24 Contaminated heparin products recalled 10 DacartTM development terminated and LapdapTM recalled 11 ATC/DDD Classification Varenicline and suicide attempts 11 ATC/DDD Classification (temporary) 26 Norelgestromin-ethynil estradiol: infarction ATC/DDD Classification (final) 28 and thromboembolism 12 Emerging cardiovascular concerns with Consultation Document rosiglitazone 12 Disclosure of transdermal patches 13 International Pharmacopoeia Statement on safety of HPV vaccine 13 Cycloserine 30 IVIG: myocardial infarction, stroke and Cycloserine capsules 33 thrombosis 14 Erythropoietins: lower haemoglobin levels 15 Recent Publications, Erythropoietin-stimulating agents 15 Pregabalin: hypersensitivity reactions 16 Information and Events Cefepime: increased mortality? 16 Assessing the quality of herbal medicines: Mycophenolic acid: pregnancy loss and contaminants and residues 36 congenital malformation 17 Launch of procurement and supply Carbamazepine and skin reactions 17 management website 36 Canada Vigilance: a new name and data- Malaria research collection published 36 base 18 New pricing bulletin 37 Desmopressin and hyponatraemia 18 How to improve the use of medicines by consumers 37 Regulatory Action and News Model quality assurance system for procurement agencies 38 Influenza virus vaccines: northern Training courses in management and hemisphere winter 19 supply 38 Lumiracoxib-containing medicines: Pharmacists work to improve use of withdrawal 19 generics 39 Thalidomide approved for multiple myeloma 19 New genetic test for breast cancer 20 Recommended International Natalizumab for moderate-to-severe Nonproprietary Names: Crohn disease 20 41 First test to detect and identify 12 res- List 59 piratory viruses 21
1 WHO Drug Information Vol 22, No. 1, 2008
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2 WHO Drug Information Vol 22, No. 1, 2008
Challenges in Biotherapeutics
Regulatory pathways for challenges in evaluating the quality, safety and efficacy of these products. biosimilar products It was soon realized that marked differ- Innovative biotherapeutic products such ences exist in the definitions and regula- as insulin, human growth hormone and tory pathways for biosimilar products in erythropoietin offer promise for treating many countries. For example, in some many of the life threatening chronic Asian countries, a number of biosimilar diseases that present major challenges to products such as interleukins, interferons, public health programmes in both devel- erythropoetins, growth factors, hormones, oped and developing countries. enzymes and even monoclonal antibod- ies, are available on the market. How- Until now, the high cost of biotherapeutics ever, they are not defined as a class nor has often limited their use, particularly in are they approved within a distinct regula- low income countries. However, many of tory framework. In the European Union the current patents on these products are (EU), a few biosimilar products have been now expiring, offering an opportunity to approved so far through the European manufacturers to produce and market Medicines Agency (EMEA), which has the “generic” products. This will improve most well developed regulatory frame- availability and contribute to increased work for biosimilars so far and which is access at a more affordable price. De- supported by specific guidelines (1Ð3). pending on the jurisdiction, biotherapeutic products produced and marketed in this The existence of divergent approaches to way are referred to as ‘similar biological the regulatory oversight of biosimilars in medicinal products (bio-similars)’, ‘follow- different countries has revealed a need on protein products’, ‘subsequent-entry for defining globally acceptable regulatory products’ or ‘biogenerics’. expectations for these products. It was Worldwide, varying degrees of regulatory agreed that WHO should develop a global preparedness exist for the approval of regulatory guideline for biosimilar prod- biosimilars. In order to consolidate ucts to help WHO Member States meet thinking on the current situation, a WHO the challenge of establishing appropriate informal consultation was organized in national oversight (4). April 2007 by the Quality, Safety and Standards Team of the WHO Department Consequently, a drafting group has been of Immunization, Vaccines and Biologi- organized and is developing a WHO cals. The consultation was attended by guideline on Biosimilar/Follow-on protein/ national regulatory authorities from Subsequent-entry products. A number of developing and developed countries, key issues for future discussion were also innovator and generic biopharmaceutical highlighted during the meeting. industries, and academia. The objectives of the meeting were to discuss the current Terminology status of so-called “similar” biological Terminology currently used is not consist- medicinal products — biosimilars — and ent between the various countries and to review regulatory pathways and jurisdictions. In the EU, the term ‘similar
3 Challenges in Biotherapeutics WHO Drug Information Vol 22, No. 1, 2008
biological medicinal products’, commonly requires a thorough comparability exer- referred to as ‘biosimilars, is defined in cise to generate evidence substantiating the legislation. EU terminology and the the similar nature, in terms of quality, EMEA regulatory guidelines for bio- safety and efficacy, of the new biosimilar similars have been adopted in Australia product and the chosen reference or also. In the USA, biosimilars are termed comparator product. ‘follow-on protein products’, and in Japan ‘follow-on biologicals’. In Canada they are The second scenario considers that a referred to as ‘subsequent entry bio- thorough comparability exercise may not logics’. In India and Iran, they are usually be required but rather reliance on publicly referred to as biogenerics. WHO aims to available information coupled with addi- establish globally acceptable terminology. tional non-clinical and clinical studies to This issue is the starting point for defining demonstrate similarity could be used. In the ‘scope’ of the international guideline, the second approach, reliance on the therefore, it will hopefully be resolved reference product may not be as essen- during the development of the draft. For tial and a new biosimilar product ap- convenience, the term ‘biosimilars’ is proved with this approach would not be used in this document. granted all the indications of the refer- ence product. At the current time, it is Concept of biosimilars considered that further clarity and real The term ‘generic medicines’ refers to examples are needed to assist in devel- chemically-derived products which are opment of this second scenario as a therapeutically equivalent to the agreed regulatory pathway. reference or originator product. For such generics, demonstration of bioequiva- Proof of similarity lence with the originator product is usually In general, a biosimilar product may be appropriate to infer therapeutic equiva- approved following an abbreviated lence. However, it is unlikely that regulatory process based on the claim biotherapeutics can generally follow this that it is similar to an existing licensed standard approach for generics because product. The key issue to agree is how of their relatively large and complex much data are required to demonstrate molecular structures, which are more similarity. There was consensus in the difficult to adequately characterize in the WHO meeting that a comparability laboratory. programme should involve all aspects of development, with full analytical compara- Based on current analytical techniques, bility of quality, and abridged studies for two biologicals produced by different the non-clinical and clinical components manufacturing processes cannot be of a licence application. shown to be identical, but similar at best. For these reasons, the standard generic But there were clear differences between approach is scientifically not applicable to countries in the approach to non-clinical development of biosimilar products and and clinical studies for biosimilars. Al- additional non-clinical and clinical data though there was a strong view that are usually required. comparative studies remain central to an abbreviated regulatory process, in some Principally, two different strategies for countries non-clinical studies might be developing biosimilar products can be reduced to non-comparative studies for envisaged. The first scenario can be toxicity (single and/or repeat-dose), termed a ‘full comparability approach’ and where the goal is solely to establish the corresponds to the EU pathway, which non-clinical safety of biosimilars. For
4 WHO Drug Information Vol 22, No. 1, 2008 Challenges in Biotherapeutics
clinical assessment, there was agreement the use of publicly available information, that reduced studies compared to a full data provided by the manufacturers, and/ licence application for a biological medi- or information obtained by the NRA via cine or novel biotherapeutic would be information sharing with other NRAs. acceptable; however there was no clear However, this consideration may cause consensus on the details of a reduced legal problems unless careful approaches clinical assessment package. are made. Generally, confirmatory phase III studies All these issues will be discussed at the for safety and efficacy involving pharma- next WHO consultation on biosimilar in cokinetic and pharmacodynamic tests Seoul, Republic of Korea, May 2008. would be required, along with safe dose Progress in the development of the WHO ranging. However, views varied as to the guideline on biosimilar products will be extent to which these studies need to be reported to the Expert Committee on comparative or not. It was also unclear Biological Standardization (ECBS) at its whether the studies should demonstrate meeting in October 2008. non-inferiority or equivalence. It was also acknowledged that in some cases the References effort that would be required to perform the comparability study might be greater 1. EMEA guideline on similar biological than to seek licensure of the biothera- medicinal products. London, 2005 (CHMP/ peutic as a stand-alone medicinal prod- 437/04) uct. It would be the responsibility of the 2. EMEA guideline on similar biological sponsor of biosimilars to choose the medicinal products containing biotechnology- desired licensure pathway. derived proteins as active substance: Quality issues. London, 2006 (CHMP/BMWP/49348) The reference or comparator product A common feature in this process is the 3. EMEA guideline on similar biological reference or comparator product. Gener- medicinal products containing biotechnology- ally, countries expect this to be a locally derived proteins as active substance : non- registered product, but it has to be clinical and clinical issues. London, 2006 considered that a company might wish to (CHMP/BMWP/42832). register the biotherapeutic in a country 4. Meeting report available at http:// where the reference product is not (and is www.who.int/biologicals/areas/ unlikely ever to be) licensed. The option biological_therapeutics /Final Biosimilar of accepting reference products not meeting Report for web 13 September licensed by the national regulatory 2007.pdf. authority (NRA) would increase opportu- nities for access to alternatives to innova- 5. European Generic Medicines Association tor biologics and/or entry of biosimilars to (EGA) Handbook on Biosimilar Medicines. some markets. Brussels, 2007 6. United States Food and Drug Administra- It is conceivable that scientific issues that tion, Office of Generic Drugs, http:// limit their use could be addressed through www.fda.gov/cder/ogd/index.htm#Introduction
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Pharmacovigilance Focus
WHO Programme for individual/organization requesting the data. It was important for data privacy to International Drug be rigorously preserved in accordance Monitoring: annual meeting with national legislation, and it was recommended that rules and procedures The annual meeting of representatives be established to deal with third party from national centres participating in the requests. A caveat should also be created WHO Programme for International Drug to set out the basic principles applicable Monitoring was recently convened in to the practice of sharing information. To Buenos Aires, Argentina. Working groups maintain data privacy, narratives should were set up during the meeting to discuss never be given to third parties, but may points of immediate interest and to be given to the market authorization provide recommendations. A summary of holder. Alternatively, a third party can be the proceedings is set out below. asked what specific fields they would need, while physicians often prefer WHO adverse drug reactions data- summaries. base: public access Requests for information are received at The Netherlands National Centre has all twelve national centres represented already opened its database to the in the working group but not all have general public and was able to offer procedures available for dealing with useful feedback (www.lareb.nl). Fore such inquiries. example, information provided by the Centre is restricted to age groups rather Users of the data base have been identi- than specific ages since a specific age fied as physicians, researchers, epidemi- could be an identifier. ologists, lawyers, general public and patient organizations or the general Extending open access public, media, and politicians. Queries to the signal document range from very basic information A signal document is a publication of (number of reports; number of fatal potentially interesting pharmacovigilance cases) to more detailed information, e.g. signals drawn from the WHO global for specific rare adverse drug reactions, individual case safety reports (ICSR) signals, or comparative data. National database, Vigibase. Signals are noted by Centres need to improve their capacity to the Uppsala Monitoring Centre Review respond and to be more transparent by Panel and distributed to a restricted allowing the public access to decision- audience of national pharmacovigilance making processes. Such access would authorities. strengthen public trust. There are many advantages to providing There was no objection to information open access to the signal document: from the adverse drug reactions (ADR) information will reach a wider audience, data bases being provided to interested will provide greater transparency, in- third parties, but it was felt that the crease public confidence in pharma- responses should be tailored to the covigilance, contribute to scientific re-
6 WHO Drug Information Vol 22, No. 1, 2008 Pharmacovigilance Focus
search, and give feedback to the report- patients, it is hoped to improve compli- ers. Disadvantages include misinterpreta- ance, and by accepting patient reports tion of information and possible creation one gets a closer view of patient safety. of unnecessary concern. In providing Mechanisms for reporting by patients open access to the document, it would be must be suitable and user friendly. Em- useful to describe how the reports are powering patients by providing informa- collected, how a signal is detected and tion is an opportunity for national centres how the results should be interpreted. to improve their public health role. Con- sumer reports accepted by national In conclusion, it was proposed that all centres should be reported to the WHO signals should be published in the same adverse drug reactions database at the journal, that marketing authorization Uppsala Monitoring Centre. holders should be allowed to comment and that national centres should be Direct to consumer advertising notified of signals in advance in order to be prepared. Signals could be graded to With regard to direct-to-consumer adver- better assess impact, which may as- tising of pharmaceuticals, the group sessed by noting a change in number of unanimously recommended prohibiting reports or increased number of studies. direct-to-consumer advertising.
Exchange of information Risks in special populations: women and children It was agreed that there is a need to involve consumers and patients in phar- Few data are available on the safety of macovigilance practices. Concerns medicines used in pregnant and lactating regarding patient reporting include the women. Women may be inadvertently mixed quality of reports, incomplete exposed to unsafe products and there is information, which sources of information a particular lack of information, education are being used by patients, and patient and guidance in resource-limited settings. access to prescribers. Intensive monitoring systems could lead to creating pregnancy registries which International experience indicates that in would serve as a useful tool. “Congenital the majority of countries, patients are abnormalities” registers could also be advised to make a report to their physi- used to collect information on congenital cian or to go to a pharmacist. Some abnormalities, stillbirths, birth defects, etc. patients are allowed to report directly to national centres. Although many national In relation to medicines use in women of centres are not interested in accepting childbearing age there is an urgent need reports from patients/consumers, some to educate health professionals, the may accept reports from special interest general public and the media on safety groups. In developing countries, patients issues. Establishment of a medical need the assistance of a health profes- information centre would be desirable. sional to make a report. An Information Hotline is also available in some coun- Children are vulnerable because they tries. EudraVigilance, in the European have unique physiological features and Union, does not accept reports from handle medicines differently. Extrapola- patients because they require reports to tion of adult data to children is often not be medically confirmed. appropriate nor backed by solid evidence. In resource poor settings, children are Consumers/patients have rights and are often malnourished and conditions such acknowledged as end users. By involving as marasmus and kwashiorkor are
7 Pharmacovigilance Focus WHO Drug Information Vol 22, No. 1, 2008
common. Many medicines have not been ¥ the Uppsala Monitoring Centre should developed in paediatric doses and are develop a web-page for ME activities, used off-label, so that dosage in children with links to relevant information. is often inaccurate. Fortunately, clinical trials in children are now required in some ¥ a special ad-hoc meeting should take regions before marketing approval. place to review progress. Global networking and sharing of informa- ¥ co-operation should continue with the tion, or pooling of data could contribute to World Alliance for Patient Safety. better knowledge of the true extent of adverse drug reactions in children. Communication and Poison Centres are often a useful source crisis management of information for adverse drug reactions in children. Management of crises includes handling the impact of rumours, defining the role of WHO has published a booklet promoting the media, and managing the public safety of medicines in children and, at the perception of disasters. This is very next International Conference of Drug important where coincidental adverse Regulatory Authorities (ICDRA) in Swit- events following immunization occur or in zerland, a two-day satellite meeting will the event of premature withdrawal or focus on better medicines for children. suspension of a product. Patients and professionals need to interact on the Medication errors: expanding the interpretation of science. scope of pharmacovigilance centres National centres need to oversee proc- The role of pharmacovigilance centres in esses through guidelines, standard monitoring medication errors (ME) needs operating procedures and protocols to to be expanded and the ability to detect enable them to predict, prepare and plan cases increased. Existing systems are for future events. These protocols should limited by unharmonized terminology and identify communications priorities and unhelpful presentation of information. explain how to address a communications Pharmacovigilance centres are not yet crisis. Trusted opinion leaders could be responsive enough for root cause analy- identified and recruited to help manage sis and corrective action. the crisis, and communication materials should be designed to target the issues. A proposal for a combined ADR and ME Training should focus on process man- report form needs to be discussed further. agement and communication skills. There are areas which can be identified for focused analysis, or which may In dealing with potential groups that are concentrate on patients presenting with questioning the decisions of a public health authority, it is important to consider allergy due to ME. the context of culture and allow equal It was recommended that: opportunities for these groups to articu- late their concerns. When explaining the ¥ national centres interact with relevant facts of a crisis, compassion and empathy national bodies to ensure integration of were cited as critical components of a credible messenger. activities related to ME
¥ national centres complete and return Cohort Event Monitoring questionnaires to facilitate a compre- Cohort event monitoring (CEM) is a hensive overview of data. methodology which analyses cohorts by
8 WHO Drug Information Vol 22, No. 1, 2008 Pharmacovigilance Focus
various means based on prescription encouraging reporting of adverse drug records, public health programmes, and reactions to antiretrovirals. The objective other health records and is a discipline of this working group was to determine which should be included in pharmaco- whether SPR could be used as a method- vigilance training. CEM has many addi- ology to improve spontaneous adverse tional needs in the area of terminology drug reactions reporting. because CEM uses terms that are never reported or rarely used in spontaneous The general consensus was that SPR reporting. However, such terminology has was not a methodology per se, but could to be in the context of local culture and be used to encourage spontaneous programmes. A complete dictionary of reporting of adverse drug reactions. SPR ‘adverse events’ with a hierarchical could be used to suit country and/or structure should be developed. product specific needs, to encourage spontaneous reporting of adverse drug The working group proposed to map reactions, and to increase awareness and WHO-ART terminology and the events culture of reporting. It could be effective if dictionary developed by New Zealand’s used appropriately to complement exist- Intensive Medicines Monitoring Pro- ing pharmacovigilance activities/systems. gramme, to update WHO-ART corre- spondingly, with provisions on ongoing However, SPR does not necessarily maintenance in accordance with progress increase the quality of reporting, it can in medical sciences, and to have the limit reporters to reporting specified terminology available within a data adverse drug reactions only. It does not management tool such as the Vigiflow determine the incidence of adverse drug (see www.who-umc.org). The data reactions and may limit information for management tool should be adapted to signal generation. receive reports from CEM. Reference: Pharmaceuticals Newsletter, Stimulated passive reporting Number 6, 2007. http://www.who.int/medicines Stimulated passive reporting (SPR) has been used in South Africa as a way of
9 WHO Drug Information Vol 22, No. 1, 2008
Safety and Efficacy Issues
Recall of heparin 2. March 07, 2008 - Updated Questions and products extended Answers - FDA; February 28, 2008 - Public Health Update - FDA; February 28, 2008 - United States of America — On 11 Press Release - Baxter; February 11, 2008 - February 2008, the Food and Drug Public Health Advisory - FDA Updated 02/28/ 2008 ; February 11, 2008 - Questions and Administration (FDA) informed healthcare Answers - FDA; February 11, 2008 - News professionals of important warnings and Release - FDA. http://www.fda.gov/medwatch/ instructions for heparin sodium injection report/hcp.htm use. On 28 February 2008, the FDA issued an update to inform the public that Contaminated heparin the manufacturer has extended its recall products recalled of multi-dose vials of heparin sodium for injection to also include single-dose vials Canada — Health Canada testing of of heparin sodium for injection. heparin products marketed in Canada has identified a contaminant in products There have been reports of serious adverse events including allergic or from manufacturer B. Braun Medical Inc. hypersensitivity-type reactions, with The contaminant, oversulphated condroi- tin sulphate, has also been found in symptoms of oral swelling, nausea, vomiting, sweating, shortness of breath, heparin products in the United States and and cases of severe hypotension. Most Australia. events developed within minutes of heparin initiation although the possibility On 11 March 2008, Health Canada for a delayed response has not been requested that all suppliers of heparin for sale in Canada test their heparin products excluded. The reports have largely involved use of multiple-dose vials. using the same methodology that uncov- However, there have been several cases ered the contamination in the United States. Health Canada is continuing its in which products from multiple, single- dose vials have been combined to admin- testing of heparin products from all ister a bolus dose. Canadian companies and will continue to update Canadians as needed. Heparin sodium is an anticoagulant used in patients undergoing kidney dialysis, Health professionals should only use certain types of cardiac surgery, and heparin where it is medically essential treatment or prevention of other serious after careful weighing of the risks and medical conditions, including deep benefits for each individual patient. venous thrombosis and pulmonary Patients should be monitored during and emboli. immediately following heparin administra- tion for signs of allergy or anaphylactic References reaction. 1. FDA Public Health Update Recall of Heparin Sodium Injection and Heparin Lock Reference: Advisory 2008-49, dated 20 March Flush Solution (Baxter) 28 February 2008. 2008. http://www.hc-sc.gc.ca http://www.fda.gov/medwatch/report/hcp
10 WHO Drug Information Vol 22, No. 1, 2008 Safety and Efficacy Issues
Dacart™ development On the basis of these data, it has been terminated and Lapdap™ decided to terminate further development recalled of Dacartª. A product recall process has commenced at pharmacy level in Kenya, Data from two Phase III clinical trials for Lapdapª, this being the only market assessing use of the artemisinin-based with recent sales of the product. combination therapy Dacartª, a fixed- References dose combination of chlorproguanil, dapsone and artesunate, currently in 1. Press Release. Update on GSK’s malaria clinical development have shown disap- treatments: Dacartª and Lapdapª 29 pointing results. February 2008 at http://www.gsk.com. The first trial was primarily designed to 2. Medicines for Malaria Venture. http:// establish the efficacy of Dacartª versus www.mmv.org Coartemª (artemetherÐlumefantrine), 3. Review of the safety of chlorproguanil- currently the first-line antimalarial therapy dapsone in the treatment of uncomplicated in many endemic countries. The study, falciparum malaria in Africa. WHO/HTM/MAL/ carried out in 1372 patients showed 2005.1106 at http://www.who.int/malaria/docs/ statistical non-inferiority with 94% efficacy LapDap.pdf at 28 days for Dacartª and 97% for Coartemª. However, although the Varenicline and suicide efficacy of Dacartª was in line with attempts expectations, the reduction of haemo- globin observed in patients with glucose- European Union — The European 6-phosphate dehydrogenase (G6PD) Medicines Agency (EMEA) has concluded deficiency taking Dacartª, was greater that updated warnings to doctors and than that of Coartemª. patients are needed to increase aware- ness of cases of suicidal ideation and A reduction in haemoglobin can lead to anaemia which, in some severe suicide attempts reported in patients incidences, may require treatment with using varenicline (Champix¨), a medicine indicated for smoking cessation in adults. blood transfusions. G6PD deficiency is a hereditary enzyme disorder which is estimated to impact 10Ð25% of the At its December 2007 meeting, the Committee for Medicinal Products for population in sub-Saharan Africa. The G6PD enzyme is important for the normal Human Use (CHMP) concluded that there functioning of red blood cells and defi- is a need to update the product informa- tion for Champix¨ to warn doctors and ciency of the enzyme in certain individu- als can only be detected using a blood patients that depression has been re- test which is often not a practical option. ported. The symptoms of this depression may include suicidal ideation and suicide The second trial, in 892 patients, was attempt. designed to establish the efficacy of Dacartª versus Lapdapª (chlorpro- The CHMP has requested that the mar- guanil and dapsone), another anti- keting authorization holder submit a malarial product Glaxo SmithKline devel- variation to the marketing authorization oped in partnership with the Medicines for before 19 December 2007 to implement Malaria Venture (MMV). Significant these changes to the product information. reductions in haemoglobin levels of The EMEA will continue to keep this issue patients with G6PD deficiency were under close scrutiny and take appropriate observed for both products in this trial. actions if further concerns arise.
11 Safety and Efficacy Issues WHO Drug Information Vol 22, No. 1, 2008
Reference: Press Release, Doc. Ref. EMEA/ 3. Sidney S, Petitti DB, Soff GA, et al. Venous 595516/2007. 14 December 2007 www.emea. thromboembolic disease in users of low- europa.eu estrogen combined estrogen-progestin oral contraceptives. Contraception 2004;70:3-10.
Norelgestromin-ethinyl 4. Stein PD, Beemath A, Olson RE. Obesity as estradiol: infarction & a risk factor in venous thromboembolism. Am thromboembolism J Med 2005;118:978-80. [PubMed] Canada — Evra¨ is a transdermal 5. Evra¨ (ethynilestradiol, norelgestromin) hormonal contraceptive system contain- [product monograph]. Toronto: Janssen-Ortho ing 6 mg of norelgestromin and 0.6 mg of Inc; 2007. ethinyl estradiol per patch. Since its introduction on the Canadian market in 6. Abdollahi M, Cushman M, Rosendaal FR. Obesity: risk of venous thrombosis and the early 2004, 16 cases of thromboembolism interaction with coagulation factor levels and and 1 of myocardial infarction suspected oral contraceptive use. Thromb Haemost of being associated with the product have 2003;89:493-8. been reported to Health Canada. Two of the 17 patients died. 7. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboem- Hormonal contraception is a known risk bolism during pregnancy or postpartum: a 30- factor for venous thromboembolism year population-based study. Ann Intern Med (VTE). Others include prolonged immobil- 2005;143:697-706. ity, major surgery, family history of VTE, increasing age, smoking and obesity (1Ð Emerging cardiovascular 5). The risks may be cumulative if more concerns with rosiglitazone than one risk factor is present (1). An association between being overweight Australia — The Australian Adverse Drug and thrombosis has also been observed Reactions Advisory Committee (ADRAC) among women using oral contraceptives has drawn the attention of prescribers to (6) and the combined effect was greater an emerging concern about the cardio- than the expected risks based on their vascular safety of the thiazolidinedione individual effects (6). The risk of VTE is (TZD) drug rosiglitazone. also reported to be higher during the first 3 postpartum months than during preg- TZD drugs (rosiglitazone, pioglitazone) nancy (7). The product monograph states improve glycaemic control and are that women should be encouraged to use approved for the treatment of Type 2 a nonhormonal form of contraception in diabetes mellitus. Whether they have long the 3 months following delivery (5). term benefits in reducing the chronic Extracted from Canadian Adverse Reac- complications of Type 2 diabetes remains tion Newsletter, Volume 18(1), January an open question. It is well established 2008 at http://www.hc-sc.gc.ca that TZDs cause fluid retention and can exacerbate or precipitate cardiac failure. References 1. Hirsh J. Guidelines for antithrombotic Recently, three separate meta-analyses therapy. 5th ed. Hamilton (ON): BC Decker of data derived from pooled clinical trials Inc.; 2005. p. 64. of rosiglitazone have reported an in- creased risk of cardiac ischaemia (1Ð3), 2. Grimes DA, Shields WC. Family planning The product information for rosiglitazone for obese women: challenges and opportuni- (Avandia/Avandamet¨) has been ties. Contraception 2005;72:1-4.
12 WHO Drug Information Vol 22, No. 1, 2008 Safety and Efficacy Issues
amended to reflect these emerging 4. Home PD et al for the RECORD study results and the Therapeutic Goods Group. Rosiglitazone evaluated for cardiovas- Administration has now required the cular outcomes - An interim analysis. NEJM following boxed warning: “The use of 2007; 357: 28-38. Avandia/Avandamet¨ is not recom- mended in patients with known ischaemic Disclosure of heart disease, particularly in those taking transdermal patches nitrates. Avandia/Avandamet¨ has been shown to be associated with an increased Australia — The Therapeutic Goods risk of myocardial ischaemia (angina, Administration has received a report of an infarction) in pooled short-term clinical inadvertent overdose of opioid medicines studies, particularly in those who needed caused when subcutaneous morphine several antidiabetic drugs or nitrates.” was administered pre-operatively to a patient who was wearing a Norspan¨ The TGA has commissioned an additional transdermal patch, delivering buprenor- review of the information. Pending the phine 20 µg/hour. Despite a thorough outcome of this review, prescribers medical history, the patient omitted to tell should include this potential additional the anaesthetist and other medical staff risk in their consideration of appropriate that she was using Norspan patches, and drug therapy for Type 2 diabetes, taking she had applied a fresh patch on the day into account that rosiglitazone should not of surgery. Medical staff discovered the be prescribed for patients with known patch when the patient became comatose ischaemic heart disease or those consid- with significant respiratory depression ered to be at high risk for ischaemic heart after the conventional dose of morphine disease. was given. Extracted from Australian Adverse Drug Doctors are advised to remind their Reactions Bulletin, Volume 26, Number 6, patients to disclose use of all medica- December 2007. http://www.tga.gov.au tions, including those administered by non-conventional routes such as Reference transdermal patches and subcutaneous implants. Physical examinations should 1. Nissen SE & Wolski K. Effect of rosiglita- include a check for topically applied or zone on the risk of myocardial infarction and superficially implanted medicines. death from cardiovascular causes. NEJM 2007; 356: 2457-2471 (correction published in volume 357, p 100). Extracted from Australian Adverse Drug Reactions Bulletin, Volume 26, Number 6, 2. FDA Briefing Document (pdf,6.15Mb)* December 2007. http://www.tga.gov.au
13 Safety and Efficacy Issues WHO Drug Information Vol 22, No. 1, 2008
(EU). Gardasil¨ is a vaccine approved for Two patients received IVIG for common the prevention of cervical cancer and variable immune deficiency, and 17 were other diseases caused by human papillo- prescribed it off-label. Strokes resulted in mavirus (HPV) types 6, 11, 16 and 18. the most serious outcomes (1 death, 4 cases of persistent sequelae). The two European cases were reported as part of the continuous monitoring of Serum viscosity has been shown to the safety of medicines. One of the cases increase following IVIG administration (3). occurred in Austria and the other in Although several possible mechanisms Germany. In both cases, the cause of have been proposed (4), some authors death could not be identified. have postulated that the change in serum viscosity during IVIG administration Reference: Press Release, Doc. Ref. EMEA/ together with mild dehydration and other 37479/2008, 24 January 2008 at: http://www. risk factors (e.g., age, atherosclerosis) emea.europa.eu contribute to the development of a “threshold” facilitating the production of IVIG: myocardial infarction, thrombotic ARs (4). Five reports noted the stroke and thrombosis concomitant use of diuretics, which may have contributed to a rise in serum Canada — Use of intravenous immune viscosity. globulin (IVIG) is reported to have in- creased by approximately 115% over the Health care professionals are encouraged past 7Ð8 years, making Canada one of to report ARs suspected of being associ- the highest per capita users of IVIG in the ated with the use of IVIG and to include world (1). In this context of increasing any available information that could help use, it is important that health profession- characterize potential risk factors. als recognize the serious adverse reac- tions (ARs) suspected of being associ- Extracted from Canadian Adverse Reac- ated with the use of these products. tion Newsletter, Volume 18(1), January 2008 at http://www.hc-sc.gc.ca IVIG consists mostly of concentrated IgG manufactured from large pools of human References plasma. Health Canada has authorized the use of a number of commercial 1. Hume HA, Anderson DR. Guidelines for the brands for such indications as replace- use of intravenous immune globulin for hematologic and neurologic conditions. ment therapy for primary or secondary Transfus Med Rev 2007;21:S1-2. immunodeficiency syndromes and treat- ment of idiopathic thrombocytopenic 2. Constantine MM, Thomas W, Whitman L, et purpura. In addition, IVIG is often used al. Intravenous immunoglobulin utilization in off-label either as a passive immunizing the Canadian Atlantic provinces: a report of agent or as an immunomodulator for the the Atlantic Collaborative Intravenous Immune treatment of a growing number of condi- Globulin Utilization Working Group. Transfu- tions (2). sion 2007;47(11):2072-80. From October 1997 to July 2007, 10 3. Steinberger BA, Ford SM, Coleman TA. reports of stroke, 6 reports of thrombosis , Intravenous immunoglobulin therapy results in 4 reports of myocardial infarction (MI), 2 post-infusional hyperproteinemia, increased reports of pulmonary embolus and 1 serum viscosity and pseudohyponatremia. Am report of transient ischemic attack were J Hematol 2003;73(2):97-100. suspected of being associated with IVIG.
14 WHO Drug Information Vol 22, No. 1, 2008 Safety and Efficacy Issues
4. Alexandrescu DT, Dutcher JP, Hughes JT, References et al. Strokes after intravenous gamma globulin: Thrombotic phenomenon in patients 1. Singh AK, Szczech L, Tang KL, Barnhart H, with risk factors or just coincidence? Am J Sapp S, Wolfson M, Reddan. Correction of Hematol 2005;78(3):216-20. anemia with epoetin alfa in chronic kidney disease. NEJM 2006; 355: 2085-2098 Erythropoietins: lower 2. Drueke TB, Locatelli F, Clyne N, Eckardt haemoglobin levels KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A. Normalization of hemoglobin Australia — Dosage instructions for the level in patients with chronic kidney disease use of erythropoiesis-stimulating agents and anemia. NEJM 2006; 355: 2071-2084. (erythropoietins) in patients with chronic 3. Phrommintikul A, Haas SJ, Elsik M, Krum kidney disease have been updated in line H. Mortality and target haemoglobin concen- with evidence that higher haemoglobin trations in anaemic patients with chronic levels may be associated with an in- kidney disease treated with erythropoietin: a creased risk of morbidity and mortality. meta-analysis. Lancet 2007; 369: 381-388. Erythropoietins currently available in Australia are erythropoietin alfa, erythro- Erythropoiesis-stimulating poietin beta, and darbepoetin alfa, ap- agents proved for the treatment of anaemia associated with chronic renal failure and United States of America — On 8 with the treatment of certain malignan- November 2007, the Food and Drug cies. Administration (FDA) strengthened the warning sections for Epogen/Procrit¨ and Recent studies and a meta-analysis have Aranesp¨ following results of six studies compared outcomes in patients with showing decreased survival and/or chronic kidney disease treated with an tumour progression in patients with erythropoietin (1Ð3). The larger of the two cancer receiving an erythropoiesis- randomized studies showed a lower stimulating agent (ESA). incidence of adverse cardiovascular outcomes in the subnormal (113 g/L) Findings from two additional clinical compared to the normal (135 g/L) target studies (PREPARE and GOG-191) now haemoglobin group (1). The second study show an increase in mortality and shorter showed no difference in cardiovascular time to tumour progression in patients outcomes between the two groups, (2) with cancer receiving an ESA. This new and the meta-analysis of nine randomized infor-mation further underscores the trials showed a lower all-cause mortality safety concerns regarding use of ESAs in and lower incidence of arteriovenous patients with cancer. access thrombosis in patients in the lower target haemoglobin groups (3). On 30 November 2007, the manufacturer of epoetin alfa (Epogen¨ and Procrit¨) Product information documents for the and darbepoetin alfa (Aranesp¨) notified three erythropoietins have been amended FDA of findings from the PREPARE to indicate a target haemoglobin not (Preoperative Epirubicin Paclitaxel exceeding 120 g/L in patients with anae- Aranesp¨) study in patients with primary mia due to chronic kidney failure. breast cancer receiving chemotherapy Extracted from Australian Adverse Drug prior to surgery and randomly assigned to Reactions Bulletin, Volume 26, Number 6, a group that was to receive Aranesp¨ or December 2007. http://www.tga.gov.au no Aranesp¨.
15 Safety and Efficacy Issues WHO Drug Information Vol 22, No. 1, 2008
On 4 December 2007, the manufacturer reports in The Australian Adverse Drug notified FDA of the findings of GOG-191 Reactions Advisory Committee (ADRAC) (National Cancer Institute Gynecologic database, with a range of symptoms Oncology Group), a study in which 109 of reported in 22 individuals (14F:8M). a planned 460 patients with cervical Presentations have included anaphylaxis cancer treated with chemotherapy and and 7 reports of allergic skin rash. The radiation were randomly assigned to a others were angioedema of eyelids, group that was either to receive an ESA tongue, mouth, face, lips or upper airway, or transfusions. The GOG-191 study with breathing difficulty when severe and stopped enrolling patients because of a widespread. higher rate of potentially life-threatening blood clots occurring in the patients who Of the 22 cases, 6 women developed received an ESA. symptoms within hours of their first dose of pregabalin. In 14 of the cases, Both the PREPARE study in breast pregabalin was the sole suspected drug. cancer and the GOG-191 study in cervi- Four patients required emergency treat- cal cancer showed higher rates of death ment, including adrenaline and/or and or tumour progression in patients parenteral steroids and IM or oral antihis- who received an ESA compared to tamine. Three of the cases of skin reac- patients who did not receive an ESA. tion were confirmed by a positive dechallenge and subsequent rechallenge. FDA is currently reviewing this informa- There is insufficient information about the tion and will take additional actions as patients’ histories of atopy or other appropriate. FDA will hold another public allergies to comment on the predictive advisory committee meeting in early 2008 value of such a history. to reevaluate the risk and benefit balance of ESAs for the treatment of patients with The pregabalin Product Information chemotherapy-induced anemia. In the includes a contraindication for patients interim, healthcare professionals should who have demonstrated hypersensitivity consider the risks of tumour progression to pregabalin or to any of the excipients. and decreased survival observed when Pregabalin prescribers should be alert to ESAs are used as supportive care in the fact that acute allergic reactions may patients with cancer. These risks should present early after its introduction and be carefully weighed against the need for after any dose increases, and counsel and potential risks of red cell blood patients accordingly. transfusions. Extracted from Australian Adverse Drug Reference: FDA Medwatch. 3 January 2008 Reactions Bulletin, Volume 26, Number 6, http://www.fda.gov/medwatch/ December 2007. http://www.tga.gov.au
Pregabalin: hypersensitivity Cefepime: increased reactions mortality? Australia — Pregabalin (Lyrica¨) is approved for use in the treatment of United States of America — An article in a recent issue of The Lancet Infectious neuropathic pain in adults and as adjunc- tive therapy in adults with partial seizures Diseases has raised the question about with or without secondary generalisation. increased mortality with the use of cefepime. The Food and Drug Adminis- Post-marketing reports of hypersensitivity reactions to pregabalin comprise 13% of tration (FDA) is currently reviewing safety all the pregabalin adverse reaction data and has requested additional data to
16 WHO Drug Information Vol 22, No. 1, 2008 Safety and Efficacy Issues
further evaluate the risk of death in systemic mycophenolate mofetil (MMF) patients treated with cefepime. Cefepime during pregnancy. MMF is converted is a broad spectrum cephalosporin to MPA, the active ingredient in Myfortic¨, antibiotic currently approved for the following oral or IV administration. The treatment of a variety of infections due to prescribing information revisions are in susceptible strains of microorganisms. response to a Food and Drug Administra- tion (FDA) request sent to all marketed FDA is working with the manufacturer of MMF and MPA products. cefepime, to further evaluate the finding of increased mortality in patients who Reference: Communication from FDA at http:/ received cefepime. Until the evaluation is www.fda.gov/medwatch. completed, healthcare providers who are considering the use of cefepime should Carbamazepine and be aware of the risks and benefits de- skin reactions scribed in the prescribing information and the new information from this meta- United States of America — The Food analysis. and Drug Administration (FDA) has informed patients that dangerous or even References fatal skin reactions (Stevens Johnson syndrome and toxic epidermal necroly- 1. Yahav D, Paul M, Fraser A et al. Efficacy sis), that can be caused by carbama- and safety of cefepime: a systematic review zepine therapy, are significantly more and meta-analysis. Lancet Infect Dis 2007; 7: common in patients with a particular 338Ð48) human leukocyte antigen (HLA) allele, 2. FDA Medwatch, 14 November 2007. http:/ HLA-B*1502. www.fda.gov/medwatch This allele occurs almost exclusively in patients with ancestry across broad areas Mycophenolic acid: of Asia, including South Asian Indians. pregnancy loss and Genetic tests for HLA-B*1502 are already congenital malformation available. Patients with ancestry from areas in which HLA-B*1502 is present United States of America — The manu- should be screened for the HLA-B*1502 facturer has informed prescribers that use allele before starting treatment with of mycophenolic acid (MPA) (Myfortic¨) carbamazepine. If they test positive, during pregnancy is associated with carbamazepine should not be started increased risks of pregnancy loss and unless the expected benefit clearly congenital malformations. This new outweighs the increased risk of serious important safety information involves: skin reactions. Patients who have been Increased risk of first trimester pregnancy taking carbamazepine for more than a loss and increased risk of congenital few months without developing skin malformations, especially external ear reactions are at low risk of these events and facial abnormalities including cleft lip ever developing from carbamazepine. and palate, and anomalies of the distal This is true for patients of any ethnicity or limbs, heart, oesophagus, and kidney. genotype, including patients positive for HLA-B*1502. This new safety information This change is a result of postmarketing will be reflected in updated product data from the United States National labelling. Transplantation Pregnancy Registry (NTPR) and additional postmarketing Reference: FDA Alert, 12 December 2007 at http://www.fda.gov/medwatch/report/ data collected in women exposed to
17 Safety and Efficacy Issues WHO Drug Information Vol 22, No. 1, 2008
Canada Vigilance: a new name Desmopressin and and database hyponatraemia Health Canada is pleased to announce United States of America — The Food Canada Vigilance as the new name for and Drug Administration (FDA) has the Canadian Adverse Drug Reaction requested that prescribing information for Monitoring Program. The Program is also desmopressin includes important new implementing a new database that will information about severe hyponatraemia provide an enhanced capacity for the and seizures. postmarketing surveillance of adverse reactions (ARs). The Canada Vigilance Certain patients taking desmopressin are database will contribute to the ongoing at risk for developing severe hypo- assessment and communication of health natraemia that can result in seizures and product safety information. Health death. Children treated with desmo- Canada, through the Canada Vigilance pressin intranasal formulations for pri- Program, is responsible for the collection mary nocturnal enuresis (PNE) are and assessment of AR reports that have particularly susceptible to severe been submitted by health professionals or hyponatremia and seizures. As such, consumers, either directly or through desmopressin intranasal formulations are Market Authorization Holders. Since no longer indicated for the treatment of 1965, Health Canada has been gathering primary nocturnal enuresis and should information on suspected ARs to health not be used in hyponatraemic patients or products (pharmaceuticals, biologics patients with a history of hyponatremia. [e.g., fractionated blood products, and PNE treatment with desmopressin tablets therapeutic and diagnostic vaccines], should be interrupted during acute ill- natural health products and radiopharma- nesses that may lead to fluid and/or ceuticals). electrolyte imbalance. All desmopressin formulations should be used cautiously in Reference: Canadian Adverse Reaction patients at risk for water intoxication with Newsletter, Volume 18(1), January 2008 at hyponatremia. http://www.hc-sc.gc.ca Reference: FDA Alert, 4 December 2007 at http://www.fda.gov/medwatch/report
Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and unexpected adverse drug reactions. A signal is defined as "reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually, more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information". All signals must be validated before any regulatory decision can be made.
18 WHO Drug Information Vol 22, No. 1, 2008
Regulatory Action and News
Influenza virus vaccine: contraindicated for patients with potential northern hemisphere winter liver problems and advice to doctors that they should frequently monitor patients World Health Organzation — It is treated with lumiracoxib for liver reac- recommended that vaccines for use in the tions. More spontaneous reports of 2008-2009 influenza season (northern serious liver problems have been re- hemisphere winter) contain the ceived since then, which have increased following: the concerns regarding hepatic safety for lumiracoxib. ¥ an A/Brisbane/59/2007 (H1N1)-like virus. The CHMP’s opinion will now be for- warded to the European Commission for ¥ an A/Brisbane/10/2007 (H3N2)-like the adoption of a decision. virus. (A/Brisbane/10/2007 is a current southern hemisphere vaccine virus). Reference: Press Release. EMEA/CHMP/ 579301/2007 13 December 2007 ¥ a B/Florida/4/2006-like virus. (B/Florida/ www.emea.europa.eu 4/2006 and B/Brisbane/3/2007 are current southern hemisphere vaccine Thalidomide approved for viruses). multiple myeloma
Reference: Weekly Epidemiological Record, European Union — The European No. 9, 2008, 83, 77Ð88. http://www.who.int/ Medicines Agency (EMEA) has recom- wer mended the approval of thalidomide (Thalidomide Pharmion¨) for the treat- Lumiracoxib-containing ment of multiple myeloma, a rare cancer medicines: withdrawal of the bone marrow. The Committee for Medicinal Products for European Union — The European Human Use (CHMP) concluded that the Medicines Agency (EMEA) has recom- benefits of Thalidomide Pharmion¨ in mended withdrawal of the marketing combination with melphalan and pred- authorizations for all lumiracoxib-contain- nisone outweigh its risks for the first-line ing medicines, because of the risk of treatment of multiple myeloma for pa- serious side effects affecting the liver. tients over 65 years of age or those who cannot be treated with high-dose chemo- Lumiracoxib is a nonsteroidal anti- therapy. inflammatory drug (NSAID) that belongs to the group ‘COX-2 inhibitors’. It is used Clinical studies have shown that adding for symptomatic relief in the treatment of Thalidomide Pharmion¨ to melphalan osteoarthritis of the hip and knee. and prednisone can prolong survival time by about 18 months in newly-diagnosed The liver safety of lumiracoxib has been multiple myeloma patients over 65 years monitored continuously since its launch in of age, as compared to patients who 2005. In August 2007, the product was received conventional chemotherapy.
19 Regulatory Action and News WHO Drug Information Vol 22, No. 1, 2008
Thalidomide is teratogenic. Because of The test is suitable for breast cancer this, the CHMP consulted representatives patients who are premenopausal or for of thalidomide victims and myeloma whom tumor characteristics, such as patient groups from across the European tumor size or lymph node involvement, Union to develop measures that can suggest a higher likelihood of tumour effectively minimize the risk of foetal recurrence or decreased survival. exposure to thalidomide and has ap- proved a risk management plan. Reference: FDA News, 14 January 2008, http://www.fda.gov Subject to the granting of a marketing authorization by the European Commis- Natalizumab for moderate- sion, Thalidomide Pharmion¨ will only be available by prescription, and treatment to-severe Crohn disease will be initiated and monitored by a doctor United States of America — The Food who has experience in the treatment of and Drug Administration has approved multiple myeloma. natalizumab (Tysabri¨), currently ap- proved for use in treating some forms of Reference: Press Release. Doc. Ref. EMEA/ multiple sclerosis, for the treatment of 33024/2008, 24 January 2008. http://www. moderate-to-severe Crohn disease in emea.europa.eu patients with evidence of inflammation who have had an inadequate response New genetic test to, or are unable to tolerate, conventional for breast cancer Crohn disease therapies. Crohn disease patients using the drug must be enrolled United States of America — The Food in a special restricted distribution pro- and Drug Administration has approved a gram. test that helps in assessing the risk of tumour recurrence and long-term survival Natalizumab carries a boxed warning for for patients with relatively high-risk breast progressive multifocal leukoencephalo- cancer. The TOP2A FISH pharmDx¨ is pathy (PML), an opportunistic viral the first approved device to test for the infection that affects the brain and can TOP2A (topoisomerase 2 alpha) gene in lead to death or severe disability. cancer patients. Other serious adverse events that have The TOP2A gene plays a role in DNA occurred in patients include hypersensi- replication. The TOP2A FISH pharmDx tivity reactions, such as anaphylaxis and test uses fluorescently labelled DNA liver injury. Serious opportunistic and probes to detect or confirm gene or other atypical infections have been chromosome abnormalities, a technology observed in patients receiving immuno- known as fluorescent in situ hybridization suppressants while on Tysabri. Serious (FISH). herpes infections have also been ob- served. Common side effects include The recurrence of cancer depends partly headache, fatigue, infusion reactions, on certain genes whose activity may be urinary tract infections, joint and limb altered by changes in the number of gene pain, and rash. copies in the tumor. Changes in the TOP2A gene in breast cancer cells mean Reference: FDA News, 14 January 2008, there is an increased likelihood that the http://www.fda.gov tumor will recur or that long-term survival will be decreased.
20 WHO Drug Information Vol 22, No. 1, 2008 Regulatory Action and News
First test to detect and identify While the test is faster than conventional 12 respiratory viruses tests, it is specific to the dozen viruses listed and should be used with other United States of America — The Food diagnostics such as patient data, bacterial and Drug Administration has approved a or viral cultures and X-rays. Positive test that simultaneously detects and results do not rule out other infection or identifies 12 specific respiratory viruses. co-infection and the virus detected may not be the specific cause of the disease The test, called the xTAG Respiratory or patient symptoms. Viral Panel¨, is the first test for the detection and differentiation of influenza A Reference: FDA News, 3 January 2008 http:// subtypes H1 and H3. Influenza A is the www.fda.gov most severe form of influenza for hu- mans, and has been the cause of major Miglustat: withdrawal by epidemics. The new panel is also the first manufacturer test for human metapneumovirus (hMPV), newly identified in 2001. European Union — The European Medicines Agency (EMEA) has been The panel amplifies viral genetic material formally notified of the decision to with- found in secretions taken from the back of draw an application for an extension of the throat in patients with possible respi- indication for the centrally authorized ratory tract infections. In the test, specific medicine miglustat (Zavesca¨). beads, or microspheres, bind to the Miglustat was expected to be used for the amplified viral genetic material. The treatment of neurological manifestations beads are then sorted so that the specific in patients with Niemann Pick type C virus can be identified. Other viruses disease, a rare inherited neurodegene- identified by the panel: rative disease of childhood and adoles- cence. Zavesca is an orphan medicinal ¥ influenza B - one of three types of product. human influenza, less severe than influenza A Zavesca¨ is currently authorized for the oral treatment of mild to moderate type 1 ¥ respiratory syncytial virus subtype A and Gaucher disease and may be used only B (both are leading causes of infant in the treatment of patients for whom pneumonia and bronchiolitis and often enzyme replacement therapy is unsuit- contribute to the development of long- able. term pulmonary disease) The Committee for Medicinal Products for ¥ parainfluenza 1, 2 and 3 (all are leading Human Use (CHMP) had given a nega- factors in croup and the common cold) tive opinion recommending the refusal of the type II variation to extend the indica- ¥ rhinovirus (the most common viral tion on 18 October 2007. The company infective agent in humans and a cause has stated it will resubmit for this indica- of the common cold) tion in the near future with additional data. ¥ adenovirus (a cause of respiratory tract Reference: Press Release. Doc. Ref. EMEA/ infections often similar to strep throat or 95140/2008, 25 February 2008. http:/ tonsilitis). www.emea.europa.eu
21 Regulatory Action and News WHO Drug Information Vol 22, No. 1, 2008
Voluntary withdrawal of Preliminary findings from a recent clinical clobutinol cough syrup trial with clobutinol in adult healthy volunteers have shown a prolongation of Singapore —Clobutinol (Silomat®) was the QTc interval in the ECG. As clobutinol licenced in Singapore in 1999. It is an is indicated for a non-serious disease orally active non-opioid antitussive agent, condition and in view of the potentially and is indicated for the treatment of life-threatening adverse effects, HSA irritable, non-productive cough and agreed with the actions of the manufac- inflammatory disorders of the airways. turer to withdraw clobutinol from the worldwide market. In September 2007, the manufacturer voluntarily withdrew Silomat¨ from the A Dear Healthcare Professional Letter Singapore market as a precautionary (DHCPL) was issued by the company to measure due to concerns of a potential alert healthcare professionals to the increased risk of cardiac arrhythmias that findings and the decision to recall and could be associated with the active suspend the sales of Silomat¨. ingredient. Published experimental data have indicated the potential of clobutinol Reference: Adverse Drug Reaction News, December 2007, Vol.9 No.3, at http:// affecting the hERG (human ether-a-go-go www.hpp.moh.gov.sg. related gene) potassium channels.
22 WHO Drug Information Vol 22, No. 1, 2008
Current Topics
Proposed harmonized well as in English and French versions. requirements: licensing The information required is structured vaccines in the Americas using the International Conference on Harmonization (ICH) Common Technical A Vaccines Working Group of the Pan- Document (CTD), specifically adapted to American Network on Drug Regulatory the market authorization of vaccines, and Harmonization (PANDRH) was estab- complemented by Recommendations for lished in March 2005 to develop harmo- vaccines published in the World Health nized documents and approaches to the Organization’s Technical Report Series. licensing of vaccines in the Americas. Because of their special characteristics, vaccines should always be considered as At its first meeting, held in Panama, the new products for the purpose of market Working Group, made up of national authorization. regulatory authorities of seven countries The purpose of these documents is to (Argentina, Brazil, Canada, Chile, Cuba, achieve greater harmonization in the Mexico and Venezuela), proposed the information submitted in the application development of harmonized registration for market authorization of vaccines for requirements for vaccines for human use. human use. They apply to all vaccines to Information derived from a survey con- be registered, regardless of whether they ducted by the Pan-American Health are manufactured in the country of origin Organization (PAHO) of licensing require- or not. Since the same information should ments for vaccines in 16 countries of the be submitted to all countries in the region was reviewed in detail. Americas, the licensing process and A second meeting of the Working Group, ultimately the availability of vaccines held in December 2005 in Venezuela, should be facilitated. It is expected that proceeded to identify and agree upon the having a common document will also basic requirements and data which need benefit the region by making more effi- to be submitted by a manufacturer to a cient use of technical and financial National Regulatory Authority in support resources, as well as facilitating mutual of an application for licensing. At the recognition processes where appropriate. Group’s third meeting, held in Canada, the first draft of a document on harmo- These draft documents are posted on the nized requirements for the licensing of PAHO (http://www.paho.org) as well as vaccines in the region was reviewed and the Health Canada (http://www/hc- developed further, as was an accompany- sc.gc.ca) websites for the purpose of ing guideline on the preparation of appli- inviting comments and suggestions on cations. the proposals . Comments proposing modifications to the texts should be The two draft documents are: Proposed addressed to Dra Maria de los Angeles Harmonized Requirements for Licensing Cortes, Regional Advisor on Vaccines of Vaccines in the Americas, and an and Biologicals, THR/EV, Pan American accompanying attachment entitled Health Organization, 525 23rd St. NW. Guidelines for Preparation of Applica- Washington DC. 20037-2895 USA. tions. They are available in Spanish, as [email protected]
23 Current Topics WHO Drug Information Vol 22, No. 1, 2008
Sixteen types of counterfeit 6. USP (2005) Fake antimalarials found in Yunnan Province, China, 2004. Available at: artesunate circulating in http://www.uspdqi.org/pubs South-east Asia 7. AED-SATELLIFE. Center for Health Infor- In the late 1990s counterfeits of artesu- mation and Technology. http:// nate, a vital life-saving antimalarial drug, www.healthnet.org were discovered circulating in South-east Asia. Surveys have suggested that 38% Ð Eastern Mediterranean 53% of shop-bought artesunate in main- land South-east Asia are fake and have Ministers tackle high been reported from Cambodia, the medicines prices People’s Republic of China, Lao PDR, Medicines prices, availability, affordability Myanmar, Thai/Myanmar border, and and other component issues were re- Vietnam. The diversity of different types cently discussed by delegates at a of fake hologram have increased and now meeting of the Regional Committee for 16 are recognized. WHO’s Eastern Mediterranean Region, held in Cairo 20Ð23 October 2007. An article has recently been published in PLoS Medicine which includes an up- Results were presented from 11 surveys dated warning sheet describing these undertaken in the region using the WHO/ holograms and stickers Greater action by HAI medicine price measurement meth- governments and international organiza- odology. tions is strongly urged to combat this under-recognized and serious public Key findings showed: health problem. ¥ Substantial differences in government Reports of counterfeit artemisinin deriva- procurement prices across countries in tives and ACTs in Africa are also ex- the region. tremely alarming and could undermine the effectiveness of these medicines for ¥ Government purchasing of expensive malaria control in Africa. originator brands, as well as cheaper generics, in all but 3 countries. On References average, originator brands were about 3 1. A Collaborative Epidemiological Investiga- times more expensive than generics. tion into the Criminal Fake Artesunate Trade in Prices of generics were often high. South East Asia. PLoS Medicine e32 doi:10.1371/journal.pmed.0050032. http:// ¥ Availability in public sector facilities was medicine.plosjournals.org or: http:// very poor e.g. 16 of the 35 surveyed www.tropicalmedicine.ox.ac.uk medicines were not found in any outlet 3. The Pharmacy and Poisons Board, Repub- surveyed in Yemen, and 23 of 29 lic of Kenya Ministry of Health. 2007. Available medicines were not found in over 50% at: http://www.pharmacyboardkenya.org. of the outlets in Pakistan.
4. Fake antimalarials in Southeast Asia are a ¥ Excessive prices in the private sector for major impediment to malaria control: multina- originator brands and lowest priced tional cross-sectional survey on the preva- generics, e.g. Sudanese patients were lence of fake antimalarials. Trop Med Int paying 18 times international reference Hlth, 2004 9:1241Ð1246 prices for originator brands. Lowest priced generics were over 5 times the 5. Fake artesunate in southeast Asia. Lancet, 2001 357:1948Ð1950. reference prices in most countries.
24 WHO Drug Information Vol 22, No. 1, 2008 Current Topics
¥ Most treatments purchased in the A resolution was passed that featured the private sector were unaffordable (based establishment of a web-based medicines on the salary of the lowest paid un- prices hub in the region to share informa- skilled government worker). tion on medicine prices and pricing structures, as well as best practices in ¥ Some countries were applying taxes to medicine management. This innovative essential medicines. approach is welcomed as it will improve A lengthy discussion followed with com- price transparency and empower govern- ments from delegates of 16 countries. ments to negotiate for more favourable They acknowledged the many problems prices. The resolution also urged govern- related to medicines prices in both the ments to strengthen pricing policies public and private sectors. Many also (including public procurement of generics, noted that the TRIPS Agreement had and enhanced competition amongst contributed to rising prices and dimin- suppliers) and rationalize supply chain ished access to medicines, especially in costs in the private sector. WHO EMRO developing countries. resolved to support Members States in this work including the development of Various policy and programme options guidelines on pricing policies and sharing were mentioned including the increased information on best practices from other use of quality generics to improve afford- regions. ability, regressive mark-ups to encourage References the dispensing of lower priced generics, pooled procurement, greater transpar- 1. The resolution and the technical paper ency and the sharing of price information. Medicine prices and access to medicines in A number of options were proposed for the Eastern Mediterranean region is available countries to consider to reduce prices. on WHO EMRO’s website at http:// Countries were urged to develop, imple- www.emro.who.int/rc54/ ment and enforce sound evidence-based policies and programmes and monitor 2. Survey data is available on HAIs website: their impact, and to ensure medicines are http://www.haiweb.org/medicineprices affordable and available to all.
25 WHO Drug Information Vol 22, No. 1, 2008
ATC/DDD Classification
ATC/DDD Classification (temporary)
The following anatomical therapeutic chemical (ATC) classifications and defined daily doses (DDDs) were agreed by the WHO International Working Group for Drug Statistics Methodology in 24-25 October 2007. Comments or objections to the de- cisions from the meeting should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology at [email protected]. If no objections are received, the new ATC codes and DDDs will be considered final and included in the January 2009 issue of the ATC index.The inclusion of a substance in the lists does not imply any recommendation of use in medicine or pharmacy.
ATC level INN/Common name ATC code
New ATC level codes (other than 5th levels): Other cephalosporins J01DI Other diuretics C03X Vasopressin antagonists C03XA
New ATC 5th level codes: Alitretinoin D11AX19 Azacitidine L01BC07 Calcium acetate and mmagnesium carbonate V03AE04 Ceftobiprole medocaril J01DI01 Clevudine J05AF12 Combinations G03GA30 Conivaptan C03XA02 Eszopiclone N05CF04 Etravirine J05AG04 Fluorodopa (18F) V09IX05 Glycyrrhizic acid A05BA08 Hyaluronic acid R01AX09 Influenza, live attenuated J07BB03 Lubiprostone A06AX03 Metformin and vildagliptin A10BD08 Nicotinic acid, combinations C10AD52 Olmesartan medoxomil and amlodipine C09DB02 Paclitaxel poliglumex L01CD03 Pramlintide A10BX05 Rivaroxaban B01AX06 Romidepsin L01XX39 Satraplatin L01XA04
26 WHO Drug Information Vol 22, No. 1, 2008 ATC/DDD Classification
ATC level INN/Common name ATC code
Sugammadex V03AB35 Temsirolimus L01XE09 Terguride G02CB06 Tolvaptan C03XA01 Vorinostat L01XX38
INN/common name Previous ATC New ATC
ATC code changes: Benfluorex C10AX04 A10BX06 Bupropion N07BA02 N06AX12 Methoxyflurane N01AB03 N02BG09 Tedisamil C01EB12 C01BD06
New DDDs:
INN/common name DDD Unit Adm.R ATC code
Alfa1 antitrypsin 0.6 g P B02AB02 Aliskiren 0.15 g O C09XA02 Ambrisentan 7.5 mg O C02KX02 Apomorphine 20 mg P N04BC07 Aripiprazole 15 mg P N05AX12 Betaine 6 g O A16AA06 Darunavir 1.2 g O J05AE10 Fesoterodine 4 mg O G04BD11 Maraviroc 0.6 g O J05AX09 Melatonin 2 mg O N05CH01 Methoxy polyethylene glycol-epoetin beta 4 mcg P B03XA03 Paliperidone 6 mg O N05AX13 Paricalcitol 2 mcg O A11CC07 Prulifloxacin 0.6 g O J01MA17 Rufinamide 1.4 g O N03AF03 Sitagliptin 0.1 g O A10BH01 Stiripentol 1 g O N03AX17 Telbivudine 0.6 g O J05AF11
27 WHO Drug Information Vol 22, No. 1, 2008
ATC/DDD Classification
ATC/DDD Classification (final)
The following anatomical therapeutic chemical (ATC) classifications and defined daily doses (DDDs) were agreed by the WHO International Working Group for Drug Statistics Methodology in March 2007. They will be included in the January 2008 issue of the ATC index. The inclusion of a substance in the lists does not imply any recommendation of use in medicine or pharmacy. The WHO Collaborating Centre for Drug Statistics Methodology can be contacted at [email protected]
ATC level INN/Common name ATC code
New ATC level codes (other than 5th levels): Melatonin receptor agonists N05CH
New ATC 5th level codes: Aliskiren and hydrochloro thiazide C09XA52 Azithromycin S01AA26 Diphtheria-hemophilus influ- enzae B-pertussis-tetanus- hepatitis B-meningococcus A CJ07CA13 Lacosamide N03AX18 Maraviroc J05AX09 Nitazoxamide P01AX11 Raltegravir J05AX08 Ramelteon N05CH02 Risedronic acid, calcium and colecalciferol, sequential M05BB04 Sitimagene ceradenovec L01XX37 Tafluprost S01EE05
Change of ATC codes:
INN/common name Previous ATC New ATC
Melatonin N05CM17 N05CH01
28 WHO Drug Information Vol 22, No. 1, 2008 ATC/DDD Classification
New DDDs:
INN/common name DDD Unit Adm.R ATC code
Argatroban 0.2 g P B01AE03 Carbetocin 0.1 mg P H01BB03 Dexrazoxane 1.5 g P V03AF02 Exenatide 15 mcg P A10BX04 Levetiracetam 1.5 g P N03AX14 Lumiracoxib 0.1 g O M01AH06 Nitazoxanide 1 g O P01AX11 Phentolamine 1 mg P G04BE05 Risedronic acid, calcium and cole- calciferol, sequential 5 mg1 O M05BB04 Sitaxentan 0.1 g O C02KX03 Sodium phenyl- butyrate 20 g O A16AX03
1 refers to risedronic acid
29 WHO Drug Information Vol 22, No. 1, 2008
Consultation Document
The International Pharmacopoeia
CYCLOSERINUM CYCLOSERINE
Draft proposal for the International Pharmocopoeia (November 2007). Please address any comments to Quality Assurance and Safety: Medi- cines, PSM, World Health Organization, 1211 Geneva 27, Switzerand. Fax +4122 791 4730 or e-mail to [email protected]
O NH NH 2 H O
C3H6N2O2
Relative molecular mass. 102.1
Chemical name. (R)-(+)-4-Amino-3-isoxazolidinone; (R)-4-aminoisoxazolidin-3-one; CAS Reg. No. 68-41-7.
Other name. Orientomycin, PA-94, 106-7, Closina, Farmiserina, Micosetina, Oxamycin, Seromycin.
Description. A white or pale yellow, crystalline powder.
Solubility. Freely soluble in water; slightly soluble in methanol R and propylene glycol R; very slightly soluble in ethanol (~750 g/l) TS; practically insoluble in chloroform R and in ether R.
Category. Antibacterial drug.
Storage. Cycloserine should be kept at a temperature between 2 û and 8 ûC in a tightly closed container.
30 WHO Drug Information Vol 22, No. 1, 2008 Consultation Document
Additional information Cycloserine is slightly hygroscopic and deteriorates upon absorbing water. Its solution is dextrorotatory.
REQUIREMENTS Definition. Cycloserine is an analogue of the amino acid D-alanine with broad- spectrum antibiotic and glycinergic activities produced by Streptomyces garyphalus and S. orchidaceus or obtained by synthesis.
Cycloserine contains not less than 98.0% and not more than 100.5% of C3H6N2O2, calculated with reference to the dried substance.
Identity tests
Either test A, or tests B and C may be applied.
A. Carry out the examination as described under 1.7 Spectrophotometry in the infra- red region. The infrared absorption spectrum is concordant with the spectrum ob- tained from cycloserine RS or with the reference spectrum of cycloserine. B. Dissolve about 1 mg in 10 ml of sodium hydroxide (0.1 mol/l) VS. To 1 ml of result- ing solution add 3 ml of acetic acid (~60 g/l) TS and 1 ml of recently prepared mixture of equal volumes of a 40 mg/ml solution of sodium nitroprusside R and sodium hy- droxide (~200 g/l) TS; a blue colour is developed gradually. C. The absorption spectrum of a 25 µg/ml solution in hydrochloric acid (0.1mol/l) VS, when observed between 215 nm and 360 nm, exhibits a maximum at about 219 nm; 1% the specific absorbance (A1cm ) is between 327 and 361. Specific optical rotation. Use a 50 mg/ml solution in sodium hydroxide (~80 g/l) TS and calculate with reference to the dried substance; [á]D 20 ˚C = +108˚ to +114û.
Heavy metals. Use 2.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals content according to Method A; not more than 10 µg/g.
Sulfated ash. Not more than 5.0 mg/g.
Loss on drying. Dry at 60 ûC under reduced pressure (not exceeding 0.6 kPa or about 5mm of mercury) for 3 hours; it loses not more than 10 mg/g. pH value. pH of a 100 mg/ml solution in carbon-dioxide-free water R, 5.5-6.5.
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 base-deactivated octadecylsilyl silica gel for chromatography R (5 ìm).
Mobile phase A: 4 volumes of acetonitrile R, 70 volumes of 0.02 mol/l sodium octanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 16 volumes of purified water.
31 Consultation Document WHO Drug Information Vol 22, No. 1, 2008
Mobile phase B: 17 volumes of acetonitrile R, 70 volumes of 0.02 mol/l sodium octanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 3 volumes of purified water.
Prepare the sodium octanesulfonate solution by dissolving 4.7 g of sodium octanesulfonate R in 1000 ml of purified water.
Prepare the phosphate buffer pH 2.8 by dissolving 27.2 g of potassium dihydrogen phosphate R in 800 ml of purified water, adjust the pH to 2.8 by adding phosphoric acid (~20 g/l) TS and dilute to 1000 ml with purified water.
Use the following conditions for gradient elution:
Time Mobile phase A Mobile phase B Comments (min) (% v/v) (% v/v)
0 Ð 16 100 0 Isocratic 16 Ð 18 100 to 0 0 to 100 Linear gradient 18 Ð 22 0 100 Isocratic 22 Ð 24 0 to 100 100 to 0 Return to initial conditions 24 Ð 30 100 0 Isocratic re-equilibration
Prepare the following solutions using mobile phase A as diluent. For solution (1) use 0.5 mg of the test substance per ml. For solution (2) dilute a suitable volume of solu- tion (1) to obtain a concentration equivalent to 0.5 ìg of cycloserine per ml.
For the system suitability test: prepare solution (3) by diluting a suitable volume of solution (1) to obtain a concentration equivalent to 25 ìg of cycloserine per ml, heat carefully in a boiling water-bath for 30 minutes.
Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectro- photometer set at a wavelength of 219 nm.
Maintain the column temperature at 45 ûC.
Inject 50 ìl of resolution solution. The test is not valid unless the resolution between the principal peak and the large degradation peak with a relative retention of about 3.2 is not less than 35. If necessary adjust the amount of acetonitrile in mobile phase A.
Inject alternatively 50 µl each of solutions (1) and (2).
In the chromatogram obtained with solution (1), the area of any peak, other than the principal peak, is not greater than twice the area of the principal peak obtained with solution (2) (0.2%). The sum of the areas of all peaks, other than the principal peak, is not greater than five times the area of the principal peak obtained with solution (2) (0.5%). Disregard any peak with an area less than 0.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%).
32 WHO Drug Information Vol 22, No. 1, 2008 Consultation Document
Assay Dissolve about 0.1 g, accurately weighed, in 5 ml of water. Add 75 ml of 2-propanol R and titrate with carbonate-free sodium hydroxide (0.1 mol/l) VS using thymolphthalein/ ethanol TS as indicator. Perform a blanc determination and make any necessary correction.
Each ml of sodium hydroxide (0.1 mol/l) VS is equivalent to 10.21 mg of C3H6N2O2.
CYCLOSERINI CAPSULAE CYCLOSERINE CAPSULES
Draft proposal for the International Pharmocopoeia (November 2007). Please address any comments to Quality Assurance and Safety: Medi- cines, PSM, World Health Organization, 1211 Geneva 27, Switzerand. Fax +4122 791 4730 or e-mail to [email protected]
Category. Antibacterial drug.
Storage. Cycloserine capsules should be kept in a tightly closed container and stored at a temperature between 2û to 8ûC.
Additional information. Strength in the current WHO Model list of essential medi- cines: 250 mg.
REQUIREMENTS
Comply with the monograph for “Capsules”.
Definition. Cycloserine capsules contain Cycloserine. They contain not less than
90.0% and not more than 110.0% of the amount of C3H6N2O2.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 capsules. They ensure that, if tested, the contents of the capsules would comply with a loss on drying limit of not more than 20 mg/g when determined by drying a quantity of the capsules contain- ing 0.1 g of cycloserine for 3 hours under reduced pressure (not exceeding 0.6 kPa or about 5 mm of mercury) at 60 ûC.
Identity tests
Either tests A or tests B and C may be applied.
A. Examine the chromatograms obtained in the assay. The principal peak in the chromatogram obtained with the test solution is similar in retention time to the principal peak in the chromatogram obtained with the reference solution.
33 Consultation Document WHO Drug Information Vol 22, No. 1, 2008
B. Shake a quantity of the contents of the capsules equivalent to 10 mg of cycloserine with 100 ml of sodium hydroxide (~40 g/l) TS and filter. To 1 ml of the filtrate add 3 ml of acetic acid (~60 g/l) TS and 1 ml of recently prepared mixture of equal volumes of a 40 mg/ml solution of sodium nitroprusside R and sodium hydroxide (~200 g/l) TS; a blue colour is developed gradually.
C. The absorption spectrum of the solution obtained in the assay, when observed between 215 nm and 360 nm, exhibits a maximum at about 219 nm.
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 base-deactivated octadecylsilyl silica gel for chromatography R (5 ìm).
Mobile phase A: 4 volumes of acetonitrile R, 70 volumes of 0.02 mol/l sodium octanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 16 volumes of purified water.
Mobile phase B: 17 volumes of acetonitrile R, 70 volumes of 0.02 mol/l sodium octanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 3 volumes of purified water.
Prepare the sodium octanesulfonate solution by dissolving 4.7 g of sodium octanesulfonate R in 1000 ml of purified water.
Prepare the phosphate buffer pH 2.8 by dissolving 27.2 g of potassium dihydrogen phosphate R in 800 ml of purified water, adjust the pH to 2.8 by adding phosphoric acid (~20 g/l) TS and dilute to 1000 ml with purified water.
Use the following conditions for gradient elution:
Time Mobile phase A Mobile phase B Comments (min) (% v/v) (% v/v)
0 Ð 16 100 0 Isocratic 16 Ð 18 100 to 0 0 to 100 Linear gradient 18 Ð 22 0 100 Isocratic 22 Ð 24 0 to 100 100 to 0 Return to the initial conditions 24 Ð 30 100 0 Isocratic re-equilibration
Prepare the following solutions using mobile phase A as diluent. For solution (1) mix the contents of 20 capsules and transfer a quantity equivalent to about 50 mg of cycloserine, dissolve, dilute to 100 ml and filter. For solution (2) dilute a suitable volume of solution (1) to obtain a concentration equivalent to 0.5 ìg of cycloserine per ml. For the system suitability test: prepare solution (3) by diluting a suitable volume of solution (1) to obtain a concentration equivalent to 25 µg of cycloserine per ml, heat carefully in a boiling water-bath for 30 minutes.
34 WHO Drug Information Vol 22, No. 1, 2008 Consultation Document
Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectro- photometer set at a wavelength of 219 nm.
Maintain the column temperature at 45 ûC.
Inject 50 µl of solution (3). The test is not valid unless the resolution between the principal peak and the large degradation peak with a relative retention of about 3.2 is not less than 35. If necessary adjust the amount of acetonitrile in mobile phase A.
Inject alternatively 50 ìl each of solutions (1) and (2).
In the chromatogram obtained with solution (1), the area of any peak, other than the principal peak, is not greater than four times the area of the principal peak obtained with solution (2) (0.4%). The sum of the areas of all peaks, other than the principal peak, is not greater than ten times the area of the principal peak obtained with solution (2) (1.0%). Disregard any peak with an area less than 0.5 times the area of the princi- pal peak in the chromatogram obtained with solution (2) (0.05%).
Assay Either method A or method B may be applied.
A. Determine by High performance liquid chromatography as described in the test for related substances with the following modifications.
Prepare solutions as follows. For solution (1) mix the contents of 20 capsules and transfer a quantity equivalent to about 10 mg of cycloserine, dissolve, dilute to 100 ml and filter. For solution (2) dissolve cycloserine RS in mobile phase A to obtain a concentration of 0.1 mg/ml.
Inject alternatively 50 µl each of solutions (1) and (2).
Calculate the content of cycloserine (C3H6N2O2) from the declared content of C3H6N2O2in cycloserine RS. B. To a quantity of the mixed contents of 20 capsules equivalent to 0.250 g of cyclo- serine, accurately weighed, add sufficient hydrochloric acid (0.1mol/l) VS to produce 200 ml, shake for 10 minutes and filter. Dilute 2 ml of the filtrate to 100 ml with hydro- chloric acid (0.1mol/l) VS.
Measure the absorbance of this solution in a 1-cm layer at the maximum at about 219 nm against a solvent cell containing hydrochloric acid (0.1mol/l) VS. Calculate the percentage content of C3H6N2O2in the capsules, using the absorptivity value of 34.3 (A1cm 1% = 343). [Note from Secretariat: This has to be checked by WHO Collaborat- ing Centre, Sweden.]
Dissolution. Carry out the test as described under 5.5 Dissolution test for solid oral dosage forms.
35 WHO Drug Information Vol 22, No. 1, 2008 Recent Publications, Information and Events
Assessing the quality of or regional pharmacopoeias and in WHO herbal medicines: documents. contaminants and residues Reference: Assessing the quality of herbal medicines: with reference to contaminants and This WHO guideline Assessing the quality residues. http://www.who.int/medicines of herbal medicines: with reference to contaminants and residues presents a general overview of potentially hazardous Launch of procurement and contaminants and residues in herbal supply management website medicines and includes guiding principles The AIDS Medicines and Diagnostic for assessing the quality of herbal medi- Service (AMDS) of WHO and its partner cines in terms of major contaminants and organizations have initiated development residues. It also recommends analytical of a unique procurement and supply methods for qualitative and quantitative management website for HIV-related determination of such contaminants and health commodities: the PSM Toolbox. residues. The PSM Toolbox website features a Within the overall context of quality user-friendly search engine, regularly assurance, these guidelines are intended updated content, a forum to share tool to provide general technical guidance to use experiences and more. You are countries. The objectives of the guideline invited to submit tools via the website for are to provide: review by the project working group and possible inclusion on the website. ¥ guiding principles for assessing the quality and safety of herbal medicines, An offline, CD-ROM version of the PSM with specific reference to contaminants Toolbox is also available at cmorris@ and residues; idasolutions.org or [email protected].
¥ model criteria for identifying possible Reference: http://www.psmtoolbox.org/ contaminants and residues; Malaria research ¥ examples of methods and techniques; collection published and Leading research scientists, physicians, ¥ examples of practical technical proce- and public health specialists from around dures for controlling the quality of the world have published papers on new finished herbal products. insight into the international burden of malaria and how the global community The scope of these guidelines does not can best combat the disease. cover issues of adulteration of herbal medicines and/or counterfeit products. The collection of latest research is pre- sented in a 340-page supplement to the The annexes present several examples of American Journal of Tropical Medicine suitable methodologies found in national and Hygiene entitled “Defining and
36 WHO Drug Information Vol 22, No. 1, 2008 Recent Publications, Information and Events
Defeating the Intolerable Burden of documents, so each bulletin will only be 4 Malaria III: Progress and Perspectives.” pages long, and produced quarterly. The supplement contains 42 articles and features a diverse range of contributors, Reference: http://www.haiweb.org/ including epidemiologists, entomologists, medicineprices/ microbiologists, economists and social scientists. How to improve the use of medicines by consumers This publication is available free to scientists, researchers, and other inter- A revised version of the WHO guide How ested parties worldwide and describes to improve the use of medicines by the latest developments on a broad range consumers is now available on the WHO of malaria issues. Medicines website. Additional papers explore malaria advo- Influencing human behaviour is a com- cacy efforts and international cooperation, plex undertaking that requires careful examining the gains made by the Multilat- groundwork and carries responsibility for eral Initiative on Malaria and the Global improving public health. To develop an Fund, and making recommendations for a intervention capable of delivering measur- long-term vision for global malaria pre- able changes requires working with vention and control. communities to find the answers to eight basic questions: The third in a series, the new supplement contains data contributed by malaria 1. What is current medicine use? researchers from around the world, 2. What are the problems related to including many in malaria-endemic areas. current medicines use and what are Reference: Defining and Defeating the the critical factors underlying these Intolerable Burden of Malaria III: Progress and problems? Perspectives. http://www.fic.nih.gov/news/ press_releases/malaria_eradication1-08.htm 3. What practices put people most at risk and are a priority for an intervention? New pricing bulletin 4. What solutions are possible that will build on existing perceptions and Since publishing the WHO/HAI survey understandings to motivate changes in tool in mid-2003, over 50 surveys have individual and social behaviour? been conducted worldwide measuring medicine prices, availability, affordability, 5. Who needs to be addressed? and price components in the supply chain from manufacturer to patient. More 6. What channels of communication and surveys are planned for 2008. A number what materials/approaches are likely to of countries are considering policy be most effective? changes in response to survey 7. What other measures might be findings, and some are now regularly monitoring prices and availability. needed? The purpose of the pricing bulletin is to 8. How will the intervention be monitored inform on this work — survey results, and evaluated? workshops, advocacy campaigns, policy Having found appropriate answers, the changes, monitoring work, project activi- work then starts, with the people most ties and publications etc. It is appreciated affected, to put into practice an interven- that people lack time to read lengthy tion that will encourage rational use of
37 Recent Publications, Information and Events WHO Drug Information Vol 22, No. 1, 2008
medicines in the community to help information file. Annex 7, Technical Report everyone attain the best possible Series No. 917 (2003). http://whqlibdoc.who. level of health.” int/trs/WHO_TRS_917_annex7.pdf
Reference: How to improve the use of Training courses in medicines by consumers. http://www.who.int/ management and supply entity/medicines/publications/WHO_PSM_ PAR_2007.2.pdf Managing drug supply in developing countries Model quality assurance Managing drug supply in developing system for procurement countries is a training course covering the agencies complete drug management cycle. The course is run by IDA solutions and WHO The Model quality assurance system for and is designed to expose participants to procurement agencies was developed by modern management techniques of drug WHO through an extensive consultative supply systems and to teach them how to process. The final guide was endorsed by apply them to their own specific situation; the WHO Expert Committee on Specifica- to provide practical tools to decision tions for Pharmaceutical Preparations in makers in essential drugs programmes to 2005 and published as Annex 6 of the improve their level of performance; and to Technical Report Series Number 937 (1). encourage the exchange of views and experiences between senior officers and In 2003, the WHO Expert Committee also decision makers adopted a procedure (2) that allows the assessment of procurement agencies as Dates & Location 2008 well as guidelines for the preparation of a procurement agency information file (3). ¥ June 23 Ð July 5. The Netherlands. These texts are available on the web and (French) provide a basic tool to enable an official assessment process. ¥ October 6 Ð18. The Netherlands. (English) References: Supply chain management of HIV 1. WHO Expert Committee on Specifications for Pharmaceutical Preparations. A model and AIDS medicines and supplies quality assurance system for procurement This course covers the Drug Manage- agencies. Annex 6. Technical Report Series, ment Cycle with emphasis on HIV/AIDS No. 937 (2006). http://whqlibdoc.who.int/trs/ Project/Programme management WHO_TRS_937_eng.pdf#page=217 Course objectives: to expose participants to issues specific to planning the procure- 2. WHO Expert Committee on Specifications ment and distribution of ARVs - for Pharmaceutical Preparations. Procedure provide programme managers with skills for assessing the acceptability, in principle, of in programme planning and management procurement agencies for use by United - teach participants how to apply those Nations agencies. Annex 6. Technical Report skills in their own country - provide Series No. 917 (2003). http://whqlibdoc.who. int/trs/WHO_TRS_917_annex6.pdf practical tools to decision-makers in essential medicine programmes to 3. WHO Expert Committee on Specifications improve their level of performance - for Pharmaceutical Preparations. Guidelines exchange views and experiences be- for the preparation of a procurement agency tween senior decision-makers.
38 WHO Drug Information Vol 22, No. 1, 2008 Recent Publications, Information and Events
Dates & Location 2008 Pharmacists have also contributed articles on generic medicines to the ¥ November 24 Ð December 6. The CASE newsletter as well as to a weekly Netherlands. (French) supplement on healthcare in the national newspaper. Individual institutions too ¥ South-Africa (English) http:// have their own initiatives. www.aa4a.co.za There is also discussion on whether physicians should deliver a prescription ¥ In-country Lusophone version allowing the patient to choose where they would like to buy their medicines, and Reference: IDA Solutions. http://www. idasolutions. org whether to obtain generic or branded products. Currently, physicians are allowed to sell and dispense drugs from Pharmacists work to their clinics and they charge for a pre- improve use of generics scription when a patient requests one. Pharmacists in Singapore have linked References up with the Consumer Association, CASE, to educate and empower patients 1. http://www.pss.org.sg/main/content/view/ on generic products, and advocate 490/ generics as a cost-saving solution. Joint 2. CASE Public Forum. Know Your Medicine, initiatives have included public forums Understand Your Options. http://www.pss. and publication of drug prices. org.sg/main/content/view/502/ and http:// www.case.org.sg
39 World Health Organization WHO Drug Information Vol 22, No. 1, 2008
Announcement
The 13th International Conference of Drug Regulatory Authorities (ICDRA) will be hosted by the Swiss Agency for Therapeutic Products (Swissmedic) in collaboration with the World Health Organization
The ICDRA will take place in Berne, Switzerland from 16 to 19 September 2008
Updated information is availabel at: http://www.icdra.ch
or
http://www.who.int/medicines/icdra
40 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
International Nonproprietary Names for Pharmaceutical Substances (INN)
RECOMMENDED International Nonproprietary Names: List 59
Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances [Off. Rec. Wld Health Org., 1955, 60, 3 (Resolution EB15.R7); 1969, 173, 10 (Resolution EB43.R9)], the following names are selected as Recommended International Nonproprietary Names. The inclusion of a name in the lists of Recommended International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy. Lists of Proposed (1–96) and Recommended (1–57) International Nonproprietary Names can be found in Cumulative List No. 12, 2007 (available in CD-ROM only).
Dénominations communes internationales des Substances pharmaceutiques (DCI)
Dénominations communes internationales RECOMMANDÉES: Liste 59
Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org. mond. Santé, 1955, 60, 3 (résolution EB15.R7); 1969, 173, 10 (résolution EB43.R9)] les dénominations ci-dessous sont choisies par l’Organisation mondiale de la Santé en tant que dénominations communes internationales recommandées. L’inclusion d’une dénomination dans les listes de DCI recommandées n’implique aucune recommandation en vue de l’utilisation de la substance correspondante en médecine ou en pharmacie. On trouvera d’autres listes de Dénominations communes internationales proposées (1–96) et recommandées (1–57) dans la Liste récapitulative No. 12, 2007 (disponible sur CD-ROM seulement).
Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI)
Denominaciones Comunes Internacionales RECOMENDADAS: Lista 59
De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (Resolución EB15.R7); 1969, 173, 10 (Resolución EB43.R9)], se comunica por el presente anuncio que las denominaciones que a continuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas. La inclusión de una denominación en las listas de las Denominaciones Comunes Recomendadas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia. Las listas de Denominaciones Comunes Internacionales Propuestas (1–96) y Recomendadas (1–57) se encuentran reunidas en Cumulative List No. 12, 2007 (disponible sólo en CD-ROM).
41 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
Latin, English, French, Spanish: Recommended INN Chemical name or description; Molecular formula; Graphic formula
DCI Recommandée Nom chimique ou description; Formule brute; Formule développée
DCI Recomendada Nombre químico o descripción; Fórmula molecular; Fórmula desarrollada
alaninati brivanibum brivanib alaninate (2R)-1-({4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methylpyrrolo= [2,1-f][1,2,4]triazin-6-yl}oxy)propan-2-yl L-alaninate
alaninate de brivanib L-alaninate de (2R)-1-({4-[(4-fluoro-2-méthyl-1H-indol-5-yl)oxy]- 5-méthylpyrrolo[2,1-f][1,2,4]triazin-6-yl}oxy)propan-2-yle
alaninato de brivanib L-alaninato de (2R)-1-({4-[(4-fluoro-2-metil-1H-indol-5-il)oxi]- 5-metilpirrolo[2,1-f][1,2,4]triazin-6-il}oxi)propan-2-ilo
C22H24FN5O4
N N N HCH3 O H2N O O NH O H CH3 CH3 F CH3
albiglutidum* albiglutide ([8-glycine]human glucagon-like peptide 1-(7-36)-peptidyl) ([8-glycine]human glucagon-like peptide 1-(7-36)-peptidyl)(human serum albumin (585 residues))
albiglutide ([8-glycine]peptide 1 analogue au glucagon humain-(7-36)- peptidyl)([8-glycine]peptide 1 analogue au glucagon humain- (7-36)-peptidyl)(albumine sérique humaine (585 aminoacides))
albiglutida ([8-glicina]péptido1 análogo al glucagón humano-(7-36)-peptidil) ([8-glicina]péptido 1 análogo al glucagón humano-(7-36)- peptidil)(albumina séria humana (585 aminoácidos))
C3232H5032N864O979S41
HGEGTFTSDV SSYLEGQAAK EFIAWLVKGR HGEGTFTSDV SSYLEGQAAK 50 EFIAWLVKGR DAHKSEVAHR FKDLGEENFK ALVLIAFAQY LQQCPFEDHV 100 KLVNEVTEFA KTCVADESAE NCDKSLHTLF GDKLCTVATL RETYGEMADC 150 CAKQEPERNE CFLQHKDDNP NLPRLVRPEV DVMCTAFHDN EETFLKKYLY 200 EIARRHPYFY APELLFFAKR YKAAFTECCQ AADKAACLLP KLDELRDEGK 250 ASSAKQRLKC ASLQKFGERA FKAWAVARLS QRFPKAEFAE VSKLVTDLTK 300 VHTECCHGDL LECADDRADL AKYICENQDS ISSKLKECCE KPLLEKSHCI 350 AEVENDEMPA DLPSLAADFV ESKDVCKNYA EAKDVFLGMF LYEYARRHPD 400 YSVVLLLRLA KTYETTLEKC CAAADPHECY AKVFDEFKPL VEEPQNLIKQ 450 NCELFEQLGE YKFQNALLVR YTKKVPQVST PTLVEVSRNL GKVGSKCCKH 500 PEAKRMPCAE DYLSVVLNQL CVLHEKTPVS DRVTKCCTES LVNRRPCFSA 550 LEVDETYVPK EFNAETFTFH ADICTLSEKE RQIKKQTALV ELVKHKPKAT 600 KEQLKAVMDD FAAFVEKCCK ADDKETCFAE EGKKLVAASQ AALGL 645
Disulfide bridges location Position des ponts disulfure / Posiciones de los puentes disulfuro 113-122 135-151 150-161 184-229 228-237 260-306 305-313 325-339 338-349 376-421 420-429 452-498 497-508 521-537 536-547 574-619 618-627
42 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
albinterferonum alfa-2b* albinterferon alfa-2b human serum albumin (585 residues) fusion protein with human interferon α-2b (165 residues)
albinterféron alfa-2b protéine de fusion entre l’albumine sérique humaine (585 aminoacides) et l'interféron α-2b humain (165 aminoacides)
albinterferón alfa 2b proteína de fusión entre la albumina sérica humana (585 aminoácidos) y el interferón α-2b humano (165 aminoácidos)
C3796H5937N1015O1143S50
DAHKSEVAHR FKDLGEENFK ALVLIAFAQY LQQCPFEDHV KLVNEVTEFA 50 KTCVADESAE NCDKSLHTLF GDKLCTVATL RETYGEMADC CAKQEPERNE 100 CFLQHKDDNP NLPRLVRPEV DVMCTAFHDN EETFLKKYLY EIARRHPYFY 150 APELLFFAKR YKAAFTECCQ AADKAACLLP KLDELRDEGK ASSAKQRLKC 200 ASLQKFGERA FKAWAVARLS QRFPKAEFAE VSKLVTDLTK VHTECCHGDL 250 LECADDRADL AKYICENQDS ISSKLKECCE KPLLEKSHCI AEVENDEMPA 300 DLPSLAADFV ESKDVCKNYA EAKDVFLGMF LYEYARRHPD YSVVLLLRLA 350 KTYETTLEKC CAAADPHECY AKVFDEFKPL VEEPQNLIKQ NCELFEQLGE 400 YKFQNALLVR YTKKVPQVST PTLVEVSRNL GKVGSKCCKH PEAKRMPCAE 450 DYLSVVLNQL CVLHEKTPVS DRVTKCCTES LVNRRPCFSA LEVDETYVPK 500 EFNAETFTFH ADICTLSEKE RQIKKQTALV ELVKHKPKAT KEQLKAVMDD 550 FAAFVEKCCK ADDKETCFAE EGKKLVAASQ AALGLCDLPQ THSLGSRRTL 600 MLLAQMRRIS LFSCLKDRHD FGFPQEEFGN QFQKAETIPV LHEMIQQIFN 650 LFSTKDSSAA WDETLLDKFY TELYQQLNDL EACVIQGVGV TETPLMKEDS 700 ILAVRKYFQR ITLYLKEKKY SPCAWEVVRA EIMRSFSLST NLQESLRSKE 750
Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro
53-62 75-91 90-101 124-169 168-177 200-246 245-253 265-279 278-289 316-361 360-369 392-438 437-448 461-477 476-487 514-559 558-567 586-683 614-723
Glycosylation sites : N-318 T-691
anamorelinum anamorelin (3R)-3-benzyl-N,N',N'-trimethyl-1-{2-methylalanyl-D-tryptophyl}= piperidine-3-carbohydrazide
anamoréline (3R)-3-benzyl-N,N',N'-triméthyl-1-(2-méthylalanyl-D-tryptophyl)= pipéridine-3-carbohydrazide
anamorelina (3R)-3-bencil-N,N',N'-trimetil-1-{2-metilalanil-D-triptofil}piperidina- 3-carbohidrazida
C31H42N6O3
H C CH O O CH3 3 3 H N N H2N N N CH3 H O CH3
HN
apremilastum apremilast N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methanesulfonyl)ethyl]- 1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
aprémilast N-{2-[(1S)-1-(3-éthoxy-4-méthoxyphényl)-2-(méthanesulfonyl)éthyl]- 1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acétamide
apremilast N-{2-[(1S)-1-(3-etoxi-4-metoxifenil)-2-(metansulfonil)etil]-1,3-dioxo- 2,3-dihidro-1H-isoindol-4-il}acetamida
43 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
C22H24N2O7S
OO O S CH3 H N
CH3 O O H3C NH
O OCH3
arbaclofenum placarbilum arbaclofen placarbil (3R)-3-(4-chlorophenyl)-4-[({(1S)-2-methyl-1-[(2-methylpropanoyl)= oxy]propoxy}carbonyl)amino]butanoic acid
arbaclofène placarbil acide (3R)-3-(4-chlorophényl)-4-[({(1S)-2-méthyl- 1-[(2-méthylpropanoyl)oxy]propoxy}carbonyl)amino]butanoïque
arbaclofeno placarbilo ácido (3R)-3-(4-clorofenil)-4-[({(1S)-2-metil-1-[(2-metilpropanoil)= oxi]propoxi}carbonil)amino]butanoico
C19H26ClNO6
H3C CH3 O O H H3C O O N CO2H H H CH3
Cl
arterolanum arterolane N-(2-amino-2-methylpropyl)-2-{cis-dispiro[adamantane- 2,3'-[1,2,4]trioxolane-5',1"-cyclohexan]-4"-yl}acetamide
artérolane N-(2-amino-2-methylpropyl)-2-{cis-dispiro[adamantane- 2,3'-[1,2,4]trioxolane-5',1"-cyclohexan]-4"-yl}acétamide
arterolano N-(2-amino-2-metilpropil)-2-{cis-dispiro[adamantano- 2,3'-[1,2,4]trioxolano-5',1"-ciclohexan]-4"-il}acetamida
C22H36N2O4
O O O H CH3 N O H H2NCH3
azilsartanum medoxomilum azilsartan medoxomil (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo- 4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,1'-biphenyl-4-yl]methyl}- 1H-benzimidazol-7-carboxylate
azilsartan médoxomil 2-éthoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,1'-biphényl-4-yl]méthyl}-1H-benzimidazole-7-carboxylate de (5-méthyl-2-oxo-1,3-dioxol-4-yl)méthyle
44 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
azilsartán medoxomilo 2-etoxi-1-{[2'-(5-oxo-4,5-dihidro-1,2,4-oxadiazol-3-il)-1,1'-bifenil- 4-il]metil}-1H-benzoimidazol-7-carboxilato de (5-metil-2-oxo- 1,3-dioxol-4-il)metilo
C30H24N4O8
O
OO
H3C O O O O HN N N
N O
CH3
azoximeri bromidum azoximer bromide poly{[1-(carboxymethyl)piperazin-1-ium-1,4-diyl bromide]ethylene- co-[(piperazin-1,4-diyl 1-oxide)ethylene]}
bromure d'azixomère poly{[bromure de 1-(carboxyméthyl)pipérazin-1-ium- 1,4-diyl]éthylène-co-[(1-oxyde de pipérazine-1,4-diyl)éthylène]}
bromuro de azoxímero poly{[bromuro de 1-(carboximetil)piperazin-1-io-1,4-diil]etileno- co-[(1-óxido de piperazin-1,4-diil)etileno]}
[[C8H15BrN2O2]x[C6H12N2O]y]n
CO2H
N+ N Br x N N O y n
begacestatum begacestat 5-chloro-N-[(2S)-4,4,4-trifluoro-1-hydroxy-3-(trifluoromethyl)butan- 2-yl]thiophene-2-sulfonamide
bégacestat 5-chloro-N-[(2S)-4,4,4-trifluoro-1-hydroxy-3-(trifluorométhyl)butan- 2-yl]thiophène-2-sulfonamide
begacestat 5-cloro-N-[(2S)-4,4,4-trifluoro-1-hidroxi-3-(trifluorometil)butan- 2-il]tiofeno-2-sulfonamida
C9H8ClF6NO3S2
OO H OH
S S CF3 N Cl H CF3
45 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
belataceptum belatacept [Tyr29,Glu104,Gln125,Ser130,Ser136,Ser139,Ser148](antigen CTLA-4 human-3-126]-peptide (fragment containing the human extracellular domain) fusion protein with immunoglobulin G1-[233 amino acids from the C-terminal of the heavy chain]-peptide (fragment containing the human monoclonal Fc domain), bimolecular (120→120')-disulfide
bélatacept (120→120')-disulfure bimoléculaire de [Tyr29,Glu104,Gln125,Ser130,Ser136,Ser139,Ser148](antigène CTLA-4 humain-[3-126]-peptide (fragment contenant le domaine extracellulaire) protéine de fusion avec l’immunoglobuline G1-[233 aminoacides C-terminaux de la chaîne lourde]-peptide (fragment contenant le domaine Fc de l’anticorps monoclonal humain))
belatacept (120→120')-disulfuro bimolecular de [Tyr29,Glu104,Gln125,Ser130,Ser136,Ser139,Ser148](antígeno CTLA-4 humano-[3-126]-péptido (fragmento que contiene el dominio extracelular) proteína de fusión con la inmunoglobulina G1-[233 aminoácidos C-terminales de la cadena pesada]-péptido (fragmento que contiene el dominio Fc del anticuerpo monoclonal humano))
C3508H5440N922O1096S32
MHVAQPAVVL ASSRGIASFV CEYASPGKYT EVRVTVLRQA DSQVTEVCAA TYMMGNELTF LDDSICTGTS SGNQVNLTIQ* GLRAMDTGLY ICKVELMYPP PYYEGIGNGT* QIYVIDPEPC PDSDQEPKSS** DKTHTSPPSP APELLGGSSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY* RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK 2
* glycosylation sites * sites de glycosylation * posiciónes de glicosilación
belinostatum belinostat N-hydroxy-3-[3-(N-phenylsulfamoyl)phenyl]prop-2-enamide
bélinostat N-hydroxy-3-[3-(phénylsulfamoyl)phényl]prop-2-ènamide
belinostat N-hidroxi-3-{3-[(fenilsulfamoil]fenil}prop-2-enamida
46 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
C15H14N2O4S
O H OH N N S H OO
boceprevirum boceprevir (1R,2S,5S)-N-[(2Ξ)-4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)]- 3-{(2S)-2-[(tert-butylcarbamoyl)amino]-3,3-dimethylbutanoyl}- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
bocéprévir (1R,2S,5S)-N-[(2Ξ)-4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)]- 3-{(2S)-2-[(tert-butylcarbamoyl)amino]-3,3-diméthylbutanoyl}- 6,6-diméthyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
boceprevir (1R,2S,5S)-N-[(2Ξ)-4-amino-1-ciclobutil-3,4-dioxobutan-2-il)]- 3-{(2S)-2-[(terc-butilcarbamoil)amino]-3,3-dimetilbutanoil}-6,6-dimetil- 3-azabiciclo[3.1.0]hexano-2-carboxamida
C27H45N5O5
CH3 CH H3C H 3 CH3 CH3 H C CH O 3 3 H O N H H H3C N N N NH2 H H O H O H O
canakinumabum* canakinumab immunoglobulin G1, anti-[Homo sapiens interleukin 1, beta (IL1B)] human monoclonal ACZ885; gamma1 heavy chain (Homo sapiens VH-IGHG1*03) (221-214’)-disulfide with kappa light chain (Homo sapiens V-KAPPA-IGKC*01); (227-227’’:230-230’’)-bisdisulfide dimer
canakinumab immunoglobuline G1, anti-[Homo sapiens interleukine 1, beta (IL1B)] anticorps monoclonal humain ACZ885; chaîne lourde gamma1 (Homo sapiens VH-IGHG1*03) (221-214’)-disulfure avec la chaîne légère kappa (Homo sapiens V-KAPPA-IGKC*01); dimère (227- 227’’:230-230’’)-bisdisulfure
canakinumab inmunoglobulina G1, anticuerpo monoclonal humano ACZ885 anti-[ interleukina 1 de Homo sapiens, beta (IL1B)]; cadena pesada gamma1 (Homo sapiens VH-IGHG1*03) (221-214’)-disulfuro con la cadena ligera kappa (Homo sapiens V-KAPPA-IGKC*01); dímero (227-227’’:230-230’’)-bisdisulfuro
C6452H9958N1722O2010S42
47 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
carfilzomibum carfilzomib {(2S)-2-[(morpholin-4-yl)acetamido]-4-phenylbutanoyl}-L-leucyl- N1-{(2S)-1-[(2R)-2-methyloxiran-2-yl]-4-methyl-1-oxopentan-2-yl}- L-phenylalaninamide
carfilzomib {(2S)-2-[(morpholin-4-yl)acétamido]-4-phénylbutanoyl}-L-leucyl- N1-{(2S)-1-[(2R)-2-méthyloxiran-2-yl]-4-méthyl-1-oxopentan-2-yl} -L-phénylalaninamide
carfilzomib {(2S)-2-[(morfolin-4-il)acetamido]-4-fenilbutanoil}-L-leucil- N1-{(2S)-1-[(2R)-2-metiloxiran-2-il]-4-metil-1-oxopentan-2-il}- L-fenilalaninamida
C40H57N5O7
O O H O H O H H N N N CH3 N N H H O H O H O CH3 CH3 H3C H3C
ceftarolinum fosamilum ceftaroline fosamil (6R,7R)-7-{(2Z)-2-(ethoxyimino)-2-[5-(phosphonoamino)- 1,2,4-thiadiazol-3-yl]acetamido}-3-{[4-(1-methylpyridin-1-ium-4-yl)- 1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate
céftaroline fosamil (6R,7R)-7-{(2Z)-2-(éthoxyimino)-2-[5-(phosphonoamino)- 1,2,4-thiadiazol-3-yl]acétamido}-3-{[4-(1-méthylpyridin-1-ium-4-yl)- 1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ène- 2-carboxylate
ceftarolina fosamilo (6R,7R)-7-{(2Z)-2-(etoxiimino)-2-[5-(fosfonoamino)-1,2,4-tiadiazol- 3-il]acetamido}-3-{[4-(1-metilpiridin-1-io-4-il)-1,3-tiazol-2-il]sulfanil}- 8-oxo-5-tia-1-azabiciclo[4.2.0]oct-2-eno-2-carboxilato
C22H21N8O8PS4
CH3 CO2 O O S N N N + H N CH3 N N S S S H H HO N O HO P NH O
48 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
cenersenum cenersen antisense oligonucleotide inhibitor of p53 expression 2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'- deoxy-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P- thioguanylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-P-thiothymidylyl- (3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl- (3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl- (3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl- (3'→5')-P-thiothymidylyl-(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'- deoxycytidine
cénersen oligonucléotide antisense inhibiteur de l'expression de p53 2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3' →5')-2'- déoxy-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P- thioguanylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-P-thiothymidylyl- (3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl- (3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl- (3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl- (3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'- déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'- déoxycytidine
cenersén oligonucleótido antisentido inhibidor de la expresión de p53 2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi- P-tiocitidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tioguanilil- (3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P- tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil- (3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'- desoxi-P-tiocitidilil-(3'→5')-P-tiotimidilil-(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'-desoxicitidina
C187H226N62O103P19S19
cholini fenofibratum choline fenofibrate 2-hydroxy-N,N,N-trimethylethanaminium 2-[4-(4-chlorobenzoyl)= phenoxy]-2-methylpropanoate
fénofibrate de choline 2-[4-(4-chlorobenzoyl)phénoxy]-2-méthylpropanoate de 2-hydroxy- N,N,N-triméthyléthanaminium
fenofibrato de colina 2-[4-(4-clorobenzoil)fenoxi]-2-metilpropanoato de 2-hidroxi- N,N,N-trimetiletanaminio
+ - C5H14NO .C17H14ClO4
- Cl O CO2 H3C CH3 + N H3CCH3 HO CH3 O
49 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
cinaciguatum cinaciguat 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)phenyl]methoxy}= phenyl)ethyl]amino}methyl)benzoic acid
cinaciguat acide 4-({(4-carboxybutyl)[2-(2-{[4-(2-phényléthyl)phényl]méthoxy}= phényl)éthyl]amino}méthyl)benzoïque
cinaciguat ácido 4-({(4-carboxibutil)[2-(2-{[4-(2-feniletil)fenil]metoxi}fenil)= etil]amino}metil)benzoico
C36H39NO5
CO2H
O N CO2H
contusugenum ladenovecum* contusugene ladenovec (Recombinant) replication restricted adenovirus (type 5) vector, E1 deleted, partial E3 deletion, containing/expressing a wild type p53 gene driven by a cytomegalovirus promoter
contusugène ladénovec Vecteur adénovirus (type 5) recombinant défectif, délété de E1 et partiellement de E3, contenant le gène p53 sauvage sous le contrôle du promoteur cytomégalovirus
contusugén ladenovec Vector adenovirus (tipo 5) recombinante defectivo, con deleción de E1 y parcialmente de E3, que contiene el gen p53 salvaje controlado por el promotor de cytomegalovirus
dapagliflozinum dapagliflozin (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}- D-glucitol
dapagliflozine (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-éhoxyphényl)méthyl]phényl}- D-glucitol
dapagliflozina (1S)-1,5-anhidro-1-C-{4-cloro-3-[(4-etoxifenil)metil]fenil}-D-glucitol
C21H25ClO6
O CH3
Cl
HO
O OH HO OH
50 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
delimotecanum delimotecan poly{[2-O-(carboxymethyl)-α-D-glucopyranosyl-(1→6)]-co-[2-O-(15- {[(4S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro- 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl]oxy}- 2,5,8,11-tetraoxo-3,6,9,12-tetraazapentadecyl)-α-D-glucopyranosyl- (1→6)]-co-[α-D-glucopyranosyl-(1→6)]}
délimotécan poly{[2-O-(carboxyméthyl)-α-D-glucopyranosyl-(1→6)]-co-[2-O-(15- {[(4S)-4,11-diéthyl-4-hydroxy-3,14-dioxo-3,4,12,14-tétrahydro- 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoléin-9-yl]oxy}- 2,5,8,11-tétraoxo-3,6,9,12-tétraazapentadécyl)-α-D-glucopyranosyl- (1→6)]-co-[α-D-glucopyranosyl-(1→6)]}
delimotecán poli{[2-O-(carboximetil)-α-D-glucopiranosil-(1→6)]-co-[2-O-(15-{[(4S)- 4,11-dietil-4-hidroxi-3,14-dioxo-3,4,12,14-tetrahidro- 1H-pirano[3',4':6,7]indolizino[1,2-b]quinolin-9-il]oxi}- 2,5,8,11-tetraoxo-3,6,9,12-tetraazapentadecil)-α-D-glucopiranosil- (1→6)]-co-[α-D-glucopiranosil-(1→6)]}
[C39H46N6O14[C6H10O5]x[C8H12O7]y]n
HO O OH HO O OH O x CH O 3 O OH OH O HO O N HO2C O y O N OH H3C HO O H O O H H O N N N N O H H O O n
dovitinibum dovitinib 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole- 2-yl]quinolin-2(1H)-one
dovitinib 4-amino-5-fluoro-3-[6-(4-méthylpipérazin-1-yl)-1H-benzimidazol- 2-yl]quinoléin-2(1H)-one
dovitinib 4-amino-5-fluoro-3-[6-(4-metilpiperazin-1-il)-1H-benzoimidazol- 2-il]quinolin-2(1H)-ona
51 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
C21H21FN6O
O N N N CH3
HN N H
NH2
F
eldecalcitolum eldecalcitol (5Z,7E)-2β-(3-hydroxypropoxy)-9,10-secocholesta-5,7,10(19)-triene- 1α,3β,25-triol
eldécalcitol (5Z,7E)-2β-(3-hydroxypropoxy)-9,10-sécocholesta-5,7,10(19)-triène- 1α,3β,25-triol
eldecalcitol (5Z,7E)-2β-(3-hidroxipropoxi)-9,10-secocolesta-5,7,10(19)-trieno- 1α,3β,25-triol
C30H50O5
H H3C CH 3 CH3 H CH3 HO
H
CH2
HO OH H H HO OH
elvitegravirum elvitegravir 6-[(3-chloro-2-fluorophenyl)methyl]-1-[(2S)-1-hydroxy-3-methylbutan- 2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
elvitégravir acide 6-[(3-chloro-2-fluorophényl)méthyl]-1-[(2S)-1-hydroxy- 3-méthylbutan-2-yl]-7-méthoxy-4-oxo-1,4-dihydroquinoline- 3-carboxylique
elvitegravir ácido 6-[(3-cloro-2-fluorofenil)metil]-1-[(2S)-1-hidroxi-3-metilbutan- 2-il]-7-metoxi-4-oxo-1,4-dihidroquinolina-3-carboxílico
C23H23ClFNO5
CH3 HO
CH3 H CH3 O N
Cl CO2H F O
52 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
epetirimodum epetirimod 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
épétirimod 1-(2-méthylpropyl)-1H-imidazo[4,5-c][1,5]naphtyridin-4-amine
epetirimod 1-(2-metilpropil)-1H-imidazo[4,5-c][1,5]naftiridin-4-amina
C13H15N5
H3C
H3C N N N
N NH2
epoetinum kappa epoetin kappa 1-165-erythropoietin (human JR-013), glycoform κ
époétine kappa érythropoïétine (humaine JR-013)-(1-165), glycoforme κ
epoetina kappa 1-165-eritropoyetina (humana JR-013), glicoforma κ
C809H1301N229O240S5
eribulinum eribulin (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24 S,26R,28R,29aS)-2-[(2S)-3-amino-2-hydroxypropyl]-3-methoxy- 26-methyl-20,27-dimethylidenehexacosahydro-11,15:18,21:24,28- triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2- i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one
éribuline (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24 S,26R,28R,29aS)-2-[(2S)-3-amino-2-hydroxypropyl]-3-méthoxy- 26-méthyl-20,27-diméthylidènehexacosahydro-11,15:18,21:24,28- triépoxy-7,9-éthano-12,15-méthano-9H,15H-furo[3,2- i]furo[2',3':5,6]pyrano[4,3- b][1,4]dioxacyclopentacosin-5(4H)-one
eribulina (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24 S,26R,28R,29aS)-2-[(2S)-3-amino-2-hidroxipropil]-26-metil- 20,27-dimetilideno-3-metoxihexacosahidro-11,15:18,21:24,28- triepoxi-7,9-etano-12,15-metano-9H,15H-furo[3,2-i]furo= [2',3':5,6]pirano[4,3-b][1,4]dioxaciclopentacosin-5(4H)-ona
C40H59NO11
H3C O H H H H N H 2 O H H H O HO H H O O CH2 O H H H H O O H H CH3 O O H H H
H2C
53 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
faxeladolum faxeladol 3-[(1R,2R)-2-(dimethylaminomethyl)cyclohexyl]phenol
faxéladol 3-{(1R,2R)-2-[(diméthylamino)méthyl]cyclohexyl}phenol
faxeladol 3-[(1R,2R)-2-(dimetilaminometil)ciclohexil]fenol
C15H23NO
CH3 N CH3 H H
OH
ferricum carboxymaltosum ferric carboxymaltose poly[D-glucopyranosyl(1→4)]-D-gluconic acid complex of hydrated iron(III) oxide
carboxymaltose ferrique complexe d'oxide de fer(III) et d'acide poly[D-glucopyranosyl(1→4)]- D-gluconique hydraté
carboximaltosa férrica ácido poli[D-glucopiranosil(1→4)]-D-glucónico complejo de óxido de hierro(III) hidratado
FeIIIw([C6H10O5]aC6H11O7)x(OH)yOz.nH2O
flovagatranum flovagatran (1R)-1-{N-[(benzyloxy)carbonyl]-D-phenylalanyl-L-prolinamido}= butylboronic acid
flovagatran acide (1R)-1-({N-[(benzyloxy)carbonyl]-D-phénylalanyl-L-prolyl}= amino)butylboronique
flovagatrán ácido (1R)-1-{N-[(benciloxi)carbonil]-D-fenilalanil-L-prolinamido}= butilborónico
C27H36BN3O7
CH3 O O O H H H O N OH N B N H O H OH
54 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
gantenerumabum* gantenerumab immunoglobulin G1, anti-(human beta-amyloid peptides Aβ42 and Aβ40) human monoclonal antibody; gamma1 heavy chain (Homo sapiens VH-IGHG1) (229-215’)-disulfide with kappa light chain (Homo sapiens V-KAPPA-IGKC); (235-235”:238-238”)-bisdisulfide dimer
ganténérumab immunoglobuline G1, anti-(peptides beta-amyloides Aβ42 et Aβ40 humains) anticorps monoclonal humain; chaîne lourde gamma1 (Homo sapiens VH-IGHG1) (229-215’)-disulfure avec la chaîne légère kappa (Homo sapiens V-KAPPA-IGKC); dimère (235- 235”:238-238”)-bisdisulfure
gantenerumab inmunoglobulina G1, anticuerpo monoclonal humano anti-(péptidos beta-amiloides Aβ42 et Aβ40 humanos); cadena pesada gamma1 (Homo sapiens VH-IGHG1) (229-215’)-disulfuro con la cadena ligera kappa (Homo sapiens V-KAPPA-IGKC); dimero (235-235”:238- 238”)-bisdisulfuro
γ1- heavy chain / Chaîne lourde γ1 / Cadena pesada γ1 QVELVESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSA 50 INASGTRTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARGK 100 GNTHKPYGYV RYFDVWGQGT LVTVSSASTK 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
κ-light chain / Chaîne légère κ / Cadena ligera κ
DIVLTQSPAT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY 50 GASSRATGVP ARFSGSGSGT DFTLTISSLE PEDFATYYCL QIYNMPITFG 100 QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150 VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200 GLSSPVTKSF NRGEC 215
The position of cysteine (C) residues that form disulphide bridges and asparagine residues that are N-glycosylated are in bold.
golotimodum golotimod D-γ-glutamyl-L-tryptophan
golotimod D-γ-glutamyl-L-tryptophane
golotimod D-γ-glutamil-L-triptófano
C16H19N3O5
H NH 2 H NCO2H HO2C O H
N H
55 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
ibalizumabum* ibalizumab immunoglobulin G4, anti-(human CD4) humanized monoclonal antibody Hu5A8 (TNX-355); gamma4 heavy chain [humanized VH (Homo sapiens FR/Mus musculus CDR [8.8.15] from clone Mu5A8)- Homo sapiens IGHG4*01] (136-219’)-disulfide with kappa light chain [humanized V-KAPPA (Homo sapiens FR/Mus musculus CDR [12.3.8] from clone Mu5A8)-Homo sapiens IGKC*01] ; (228- 228’:231-231”)-bisdisulfide dimer
ibalizumab immunoglobuline G4, anti-(CD4 humain) anticorps monoclonal humanisé Hu5A8 (TNX-355); chaîne lourde gamma4 [VH humanisé (Homo sapiens FR/Mus musculus CDR [8.8.15] du clone 5A8)-Homo sapiens IGHG4] (136-219’)-disulfure avec la chaîne légère kappa [V-KAPPA humanisé (Homo sapiens FR/Mus musculus CDR [12.3.8] du clone Mu5A8)-Homo sapiens IGKC*01]; dimère (228-228”:231-231”)-bisdisulfure
ibalizumab inmunoglobulina G4, anti-(CD4 humano) anticuerpo monoclonal humanizado Hu5A8 (TNX-355); cadena pesada gamma4 [VH humanizado (Homo sapiens FR/Mus musculus CDR [8.8.15] del clon 5A8)-Homo sapiens IGHG4] (136-219’)-disulfuro con la cadena ligera kappa [V-KAPPA humanizada (Homo sapiens FR/Mus musculus CDR [12.3.8] del clon Mu5A8)-Homo sapiens IGKC*01]; dímero (228-228”:231-231”)-bisdisulfuro
Ig γ4-heavy chain / Chaîne lourde Ig γ4 / Cadena pesada Ig γ4 QVQLQQSGPE VVKPGASVKM SCKASGYTFT SYVIHWVRQK PGQGLDWIGY 50 INPYNDGTDY DEKFKGKATL TSDTSTSTAY MELSSLRSED TAVYYCAREK 100 DNYATGAWFA YWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL 150 VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT 200 KTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV 350 YTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 449
Ig κ-light chain / Chaîne légère Ig κ / Cadena ligera Ig κ
DIVMTQSPDS LAVSLGERVT MNCKSSQSLL YSTNQKNYLA WYQQKPGQSP 50 KLLIYWASTR ESGVPDRFSG SGSGTDFTLT ISSVQAEDVA VYYCQQYYSY 100 RTFGGGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219
idrabiotaparinuxum natricum idrabiotaparinux sodium nonasodium methyl (2-deoxy-3,4-di-O-methyl-2-{6-[5-(2- oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido]= hexanamido}-6-O-sulfo-α-D-glucopyranosyl)-(1→4)-(2,3-di-O-methyl- β-D-glucopyranosyluronate)-(1→4)-(2,3,6-tri-O-sulfo- α-D-glucopyranoside)-(1→4)-(2,3-di-O-methyl- α-L-idopyranosyluronate)-(1→4)-2,3,6-tri-O-sulfo- α-D-glucopyranoside
idrabiotaparinux sodique 2-déoxy-3,4-di-O-méthyl-2-{[6-({5-[(3aS,4S,6aR)-2-oxohexahydro- 1H-thiéno[3,4-d]imidazol-4-yl]pentanoyl}amino)hexanoyl]amino}- 6-O-sulfo-α-D-glucopyranosyl-(1→4)-2,3-di-O-méthyl- β-D-glucopyranuronosyl-(1→4)-2,3,6-tri-O-sulfo-α-D-glucopyranosyl- (1→4)-2,3-di-O-méthyl-α-L-idopyranuronosyl-(1→4)-2,3,6-tri-O-sulfo- α-D-glucopyranoside de méthyle nonasodique
56 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
idrabiotaparinux sódico 2-desoxy-3,4-di-O-metil-2-{[6-({5-[(3aS,4S,6aR)-2-oxohexahidro- 1H-tieno[3,4-d]imidazol-4-il]pentanoil}amino)hexanoil]amino}- 6-O-sulfo-α-D-glucopiranosil-(1→4)-2,3-di-O-metil- β-D-glucopiranuronosil-(1→4)-2,3,6-tri-O-sulfo-α-D-glucopiranosil- (1→4)-2,3-di-O-metil-α-L-idopiranuronosil-(1→4)-2,3,6-tri-O-sulfo- α-D-glucopiranosido de metilo y nonasodico
C53H79N4Na9O51S8
O SO3Na O O NaO3S SO3Na O O O O O NaO3S O CO Na CH3 SO Na CO Na O 2 O 3 2 OCH 3 SO3Na O O O O OCH OCH O 3 3 OCH SO3Na 3 H3CO O S HN O OCH3 H H H N O NH H HN O
laropiprantum laropiprant [(3R)-4-[(4-chlorophenyl)methyl]-7-fluoro-5-(methanesulfonyl)- 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid
laropiprant acide [(3R)-4-[(4-chlorophényl)méthyl]-7-fluoro-5-(méthanesulfonyl)- 1,2,3,4-tétrahydrocyclopenta[b]indol-3-yl]acétique
laropiprant ácido [(3R)-4-[(4-clorofenil)metil]-7-fluoro-5-(metanosulfonil)- 1,2,3,4-tetrahidrociclopenta[b]indol-3-il]acético
C21H19ClFNO4S
F CO2H
N H
O S CH3 Cl O
levamlodipinum levamlodipine 3-ethyl 5-methyl (4S)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)- 6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
lévamlodipine (4S)-2-[(2-aminoéthoxy)méthyl]-4-(2-chlorophényl)-6-méthyl- 1,4-dihydropyridine-3,5-dicarboxylate de 3-éthyle et de 5-méthyle
levamlodipino (4S)-2-[(2-aminoetoxi)metil]-4-(2-clorofenil)-6-metil- 1,4-dihidropiridina-3,5-dicarboxilato de 3-etilo y 5-metilo
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C20H25ClN2O5
H H3C N NH2 O
O O CH3 H3C H O O Cl
lonaprisanum lonaprisan 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor- 17α-pregna-5,9-dien-3-one
lonaprisan 11β-(4-acétylphényl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor- 17α-prégna-5,9-dién-3-one
lonaprisán 11β-(4-acetilfenil)-20,20,21,21,21-pentafluoro-17-hidroxi-19-nor- 17α-pregna-5,9-dien-3-ona
C28H29F5O3
O
H C 3 OH CF H CH3 3 F H F
H O
metenkefalinum metenkefalin L-tyrosylglycylglycyl-L-phenylalanyl-L-methionine β-endorphin human-(1-5)-peptide
métenkefaline L-tyrosylglycylglycyl-L-phénylalanyl-L-méthionine β-endorphine humaine-(1-5)-peptide
metencefalina L-tirosilglicilglicil-L-fenilalanil-L-metionina β-endorfina humana-(1-5)-peptido
C27H35N5O7S
H L-Tyr Gly Gly L-Phe L-Met OH
milveterolum milveterol N-{2-hydroxy-5-[(1R)-1-hydroxy-2-{[2-(4-{[(2R)-2-hydroxy- 2-phenylethyl]amino}phenyl)ethyl]amino}ethyl]phenyl}formamide
milvétérol N-{2-hydroxy-5-[(1R)-1-hydroxy-2-{[2-(4-{[(2R)-2-hydroxy- 2-phényléthyl]amino}phényl)éthyl]amino}éthyl]phényl}formamide
milveterol N-{2-hidroxi-5-[(1R)-1-hidroxi-2-{[2-(4-{[(2R)-2-hidroxi- 2-feniletil]amino}fenil)etil]amino}etil]fenil}formamida
58 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
C25H29N3O4
H OH H N
HO N H HN H HOH
O
motesanibum motesanib N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[(pyridin- 4-yl)methyl]amino}pyridine-3-carboxamide
motésanib N-(3,3-diméthyl-2,3-dihydro-1H-indol-6-yl)-2-{[(pyridin- 4-yl)méthyl]amino}pyridine-3-carboxamide
motesanib N-(3,3-dimetil-2,3-dihidro-1H-indol-6-il)-2-{[(piridin- 4-il)metil]amino}piridina-3-carboxamida
C22H23N5O
HN CH3
NH O CH3 N N N H
nepiderminum nepidermin human epidermal growth factor, recombinant DNA origin
népidermine facteur humain de croissance épidermique, origine ADN recombinant
nepidermina factor de crecimiento epidérmico humano; origen: ADN recombinante
C270H401N73O83S7
HAsn Ser Asp Ser Glu Cys Pro Leu Ser His Asp Gly Tyr Cys 10 Leu His Asp Gly Val Cys Met Tyr Ile Glu Ala Leu Asp Lys 20 Tyr Ala Cys Asn Cys Val Val Gly Tyr Ile Gly Glu Arg Cys 30 40 Gln Tyr Arg Asp Leu Lys Trp Trp Glu Leu Arg OH 50
neratinibum neratinib (2E)-N-[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano- 7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
nératinib (2E)-N-[4-({3-chloro-4-[(pyridin-2-yl)méthoxy]phényl}amino)-3-cyano- 7-éthoxyquinoléin-6-yl]-4-(diméthylamino)but-2-énamide
neratinib (2E)-N-[4-({3-cloro-4-[(piridin-2-yi)metoxi]fenil}amino)-3-ciano- 7-etoxiquinolin-6-il]-4-(dimetilamino)but-2-enamida
59 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
C30H29ClN6O3
H3C O N
CH3 HN CN N HN Cl H3C O
O N
perampanelum perampanel 2-(6'-oxo-1'-phenyl-1',6'-dihydro[2,3'-bipyridin]-5'-yl)benzonitrile
pérampanel 2-(6'-oxo-1'-phenyl-1',6'-dihydro[2,3'-bipyridin]-5'-yl)benzonitrile
perampanel 2-(1'-fenil-6'-oxo-1',6'-dihidro[2,3'-bipiridin]-5'-il)benzonitrilo
C23H15N3O
O
N CN
N
peretinoinum peretinoin (2E,4E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,4,6,10,14- pentaenoic acid
pérétinoïne acide (2E,4E,6E,10E)-3,7,11,15-tétraméthylhexadéca-2,4,6,10,14- penténoïque
peretinoína ácido (2E,4E,6E,10E)-3,7,11,15-tetrametilhexadeca-2,4,6,10,14- pentaenoico
C20H30O2
CH3 CH3 CH3 CH3
CO2H H3C
pexacerfontum pexacerfont N-[(2R)-butan-2-yl]-8-(6-methoxy-2-methylpyridin-3-yl)- 2,7-dimethylpyrazolo[1,5-a][1,3,5]triazin-4-amine
pexacerfont N-[(2R)-butan-2-yl]-8-(6-méthoxy-2-méthylpyridin-3-yl)- 2,7-diméthylpyrazolo[1,5-a][1,3,5]triazin-4-amine
pexacerfont N-[(2R)-butan-2-il]-8-(6-metoxi-2-metilpiridin-3-il)- 2,7-dimetilpirazolo[1,5-a][1,3,5]triazin-4-amina
60 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
C18H24N6O
CH H C H N 3 3 N N H C 3 H N N H3C N OCH3 H3C
pimavanserinum pimavanserin 1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)- 3-{[4-(2-methylpropoxy)phenyl]methyl}urea
pimavansérine 1-[(4-fluorophényl)méthyl]-1-(1-méthylpipéridin-4-yl)- 3-{[4-(2-méthylpropoxy)phényl]méthyl}urée
pimavanserina 1-[(4-fluorofenil)metil]-1-(1-metilpiperidin-4-il)-3-{[4-(2-metilpropoxi)= fenil]metil}urea
C25H34FN3O2
CH3 N CH3 F O CH3 H N N
O
piragliatinum piragliatin (2R)-2-[3-chloro-4-(methanesulfonyl)phenyl]- 3-[(1R)-3-oxocyclopentyl]-N-(pyrazin-2-yl)propanamide
piragliatine (2R)-2-[3-chloro-4-(méthanesulfonyl)phényl]- 3-[(1R)-3-oxocyclopentyl]-N-(pyrazin-2-yl)propanamide
piragliatina (2R)-2-[3-cloro-4-(metanosulfonil)fenil]-3-[(1R)-3-oxociclopentil]- N-(pirazin-2-il)propanamida
C19H20ClN3O4S
OO S N H3C O
Cl N N H H H O
pomalidomidum pomalidomide 4-amino-2-[(3RS)-2,6-dioxopiperidin-3-yl]-2H-isoindole-1,3-dione
pomalidomide 4-amino-2-[(3RS)-2,6-dioxopipéridin-3-yl]-2H-isoindole-1,3-dione
pomalidomida 4-amino-2-[(3RS)-2,6-dioxopiperidin-3-il]-2H-isoindol-1,3-diona
61 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
C13H11N3O4
O O and enantiomer N NH et énantiomère H y enantiómero O O NH2
posaraprostum posaraprost propan-2-yl (5Z)-7-{(1R,2S)-2-[(1E,3S)-3-hydroxy-5-phenylpent- 1-en-1-yl]-5-oxocyclopent-3-en-1-yl}hept-5-enoate
posaraprost (5Z)-7-{(1R,2S)-2-[(1E,3S)-3-hydroxy-5-phénylpent-1-én-1-yl]- 5-oxocyclopent-3-én-1-yl}hept-5-énoate de propan-2-yle
posaraprost (5Z)-7-{(1R,2S)-2-[(1E,3S)-3-hidroxi-5-fenilpent-1-en-1-il]- 5-oxociclopent-3-en-1-ilo}-hept-5-enoato de propan-2-ilo
C26H34O4
O H O CH3
O CH3 H HOH
pyronaridinum pyronaridine 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]- 2,6-bis[(pyrrolidin-1-yl)methyl]phenol
pyronaridine 4-[(7-chloro-2-méthoxybenzo[b][1,5]naphthyridin-10-yl)amino]- 2,6-bis[(pyrrolidin-1-yl)méthyl]phénol
pironaridina 4-[(7-cloro-2-metoxibenzo[b][1,5]naftiridin-10-il)amino]- 2,6-bis[(pirrolidin-1-il)metil]fenol
C29H32ClN5O2
N Cl
H3CO N HN N
OH
N
62 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
rabeximod rabeximod 2-(9-chloro-2,3-dimethyl-6H-indolo[2,3-b]quinoxalin-6-yl)- N-[2-(dimethylamino)ethyl]acetamide
rabeximod 2-(9-chloro-2,3-diméthyl-6H-indolo[2,3-b]quinoxalin-6-yl)- N-[2-(diméthylamino)éthyl]acétamide
rabeximod 2-(9-cloro-2,3-dimetil-6H-indolo[2,3-b]quinoxalin-6-il)- N-[2-(dimetilamino)etil]acetamida
C22H24ClN5O
CH3 Cl N
CH3 N N H N CH3 N
O CH3
raltegravirum raltegravir N-[(4-fluorophenyl)methyl]-5-hydroxy-1-methyl-2-[2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl]-6-oxo- 1,6-dihydropyrimidine-4-carboxamide
raltégravir N-[(4-fluorophényl)méthyl]-5-hydroxy-1-méthyl-2-[2-(5-méthyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl]-6-oxo- 1,6-dihydropyrimidine-4-carboxamide
raltegravir N-[(4-fluorofenil)metil]-5-hidroxi-1-metil-2-[2-(5-metil-1,3,4-oxadiazol- 2-carboxamido)propan-2-il]-6-oxo-1,6-dihidropirimidina- 4-carboxamida
C20H21FN6O5
O O H3C CH3 O N N N H3C H H N N N H3C OH F O
regrelorum regrelor N6-(N-ethylcarbamoyl)-2',3'-O-[(1S,2E)-3-phenylprop-2-ene-1,1-diyl]- 5'-adenylic acid
régrélor acide N6-(N-éthylcarbamoyl)-2',3'-O-[(1S,2E)-3-phénylprop-2-ène- 1,1-diyl]-5'-adénylique
regrelor ácido N6-(N-etilcarbamoil)-2',3'-O-[(1S,2E)-3-fenilprop-2-eno- 1,1-diilo]-5'-adenílico
63 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
C22H25N6O8P
O
H3C N NH H N N
O O N N P O HO OH
O O
H
rolapitantum rolapitant (5S,8S)-8-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)- 8-phenyl-1,7-diazaspiro[4.5]decan-2-one
rolapitant (5S,8S)-8-({(1R)-1-[3,5-bis(trifluorométhyl)phényl]éthoxy}méthyl)- 8-phényl-1,7-diazaspiro[4.5]décan-2-one
rolapitant (5S,8S)-8-({(1R)-1-[3,5-bis(trifluorometil)fenil]etoxi}metil)-8-fenil- 1,7-diazaspiro[4.5]decan-2-ona
C25H26F6N2O2
O
HN CF3
NH O CF3 HCH3
romiplostimum* romiplostim L-methionyl[human immunogloblin heavy constant gamma 1- (227 C-terminal residues)-peptide (Fc fragment)] fusion protein with 41 amino acids peptide, (7-7':10,10')-bisdisulfide dimer
romiplostim (7-7':10,10')-bisdisulfure du dimère de la protéine de fusion entre le L-méthionyl[chaine constante gamma 1 de l’immunoglobuline humaine-(227 aminoacides C-terminaux)-peptide (fragment Fc)] et un peptide de 41 aminoacides
romiplostim (7-7':10,10')-bisdisulfuro del dímero de la proteína de fusión entre la L-metionil[cadena constante gamma 1 de la inmunoglobulina humana-(227 aminoácidos C-terminales)-péptido (fragmento Fc)] y un péptido de 41 aminoácidos
64 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
C2634H4086N722O790S18
Monomer / Monomère / Monómero MDKTHTCPPC PAPELLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE 50 DPEVKFNWYV DGVEVHNAKT KPREEQYNST YRVVSVLTVL HQDWLNGKEY 100 KCKVSNKALP APIEKTISKA KGQPREPQVY TLPPSRDELT KNQVSLTCLV 150 KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ 200 GNVFSCSVMH EALHNHYTQK SLSLSPGKGG GGGIEGPTLR QWLAARAGGG 250 GGGGGIEGPT LRQWLAARA 269
Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 7-7' 10-10' 42-102 42'-102' 148-206 148'-206'
ronacaleretum ronacaleret 3-{3-[(2R)-3-{[1-(2,3-dihydro-1H-inden-2-yl)-2-methylpropan- 2-yl]amino}-2-hydroxypropoxy]-4,5-difluorophenyl}propanoic acid
ronacaléret acide 3-{3-[(2R)-3-{[1-(2,3-dihydro-1H-indèn-2-yl)-2-méthylpropan- 2-yl]amino}-2-hydroxypropoxy]-4,5-difluorophényl}propanoïque
ronacaleret ácido3-{3-[(2R)-3-{[1-(2,3-dihidro-1H-inden-2-il)-2-metilpropan- 2-il]amino}-2-hidroxipropoxi]-4,5-difluorofenil}propanoico
C25H31F2NO4
F F H3C CH3
N O CO2H H HOH
ropidoxuridinum ropidoxuridine 1-(2-deoxy-β-D-erythro-pentofuranosyl)-5-iodopyrimidin-2(1H)-one
ropidoxuridine 1-(2-déoxy-β-D-érythro-pentofuranosyl)-5-iodopyrimidin-2(1H)-one
ropidoxuridina 1-(2-desoxi-β-D-eritro-pentofuranosil)-5-iodopirimidin-2(1H)-ona
C9H11IN2O4
I N
HO O N O
OH
rosonabantum rosonabant (5RS)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)- 4,5-dihydro-1H-pyrazole-3-carboxamide
rosonabant (5RS)-5-(4-chlorophényl)-1-(2,4-dichlorophényl)-N-(pipéridin-1-yl)- 4,5-dihydro-1H-pyrazole-3-carboxamide
rosonabant (5RS)-5-(4-clorofenil)-1-(2,4-diclorofenil)-N-(piperidin-1-il)- 4,5-dihidro-1H-pirazol-3-carboxamida
65 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
C21H21Cl3N4O
Cl O N N N N H and enantiomer Cl et énantiomère H y enantiómero
Cl
salirasibum salirasib 2-{[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]sulfanyl}benzoic acid
salirasib acide 2-{[(2E,6E)-3,7,11-triméthyldodéca-2,6,10-trién-1-yl]= sulfanyl}benzoïque
salirasib ácido 2-{[(2E,6E)-3,7,11-trimetildodeca-2,6,10-trien-1-il]= sulfanil}benzoico
C22H30O2S
CO2H CH3 CH3 CH3
S CH3
sergliflozinum etabonas sergliflozin etabonate 2-[(4-methoxyphenyl)methyl]phenyl 6-O-(ethoxycarbonyl)- β-D-glucopyranoside
étabonate de sergliflozine 6-O-(éthoxycarbonyl)-β-D-glucopyranoside de 2-[(4-méthoxyphényl)= méthyl]phényle
etabonato de sergliflozina 6-O-(etoxicarbonil)-β-D-glucopiranósido de 2-[(4-metoxifenil)= metil]fenilo
C23H28O9
OCH3
H3C O O
O O O OH HO OH
66 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
sitimagenum ceradenovecum* sitimagene ceradenovec (recombinant) replication restricted adenovirus (type 5) vector, E1 and E3 deleted, containing/expressing the Herpes simplex virus thymidine kinase (HSV-tk) gene
sitimagène céradénovec Vecteur adénovirus (type 5 recombinant défectif, délété de E1 et E3, contenant le gène thymidine kinase du virus de l’herpès simplex (Herpes simplex virus - HSV-tk)
sitimagén ceradenovec Vector adenovirus (tipo 5 recombinante defectivo,con deleción de E1 y E3, que contiene el gen timidina kinasa del virus del herpes simplex (Herpes simplex virus - HSV-tk)
sotrastaurinum sotrastaurin 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]- 1H-pyrrole-2,5-dione
sotrastaurine 3-(1H-indol-3-yl)-4-[2-(4-méthylpipérazin-1-yl)quinazolin-4-yl]- 1H-pyrrole-2,5-dione
sotrastaurina 3-(1H-indol-3-il)-4-[2-(4-metilpiperazin-1-il)quinazolin-4-il]-1H-pirrol- 2,5-diona
C25H22N6O2
H O N O
N N N H N
N CH3
taranabantum taranabant N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)butan-2-yl}- 2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide
taranabant N-[(2S,3S)-4-(4-chlorophényl)-3-(3-cyanophényl)butan-2-yl}- 2-méthyl-2-{[5-(trifluorométhyl)pyridin-2-yl]oxy}propanamide
taranabant N-[(2S,3S)-4-(4-clorofenil)-3-(3-cianofenil)butan-2-il}-2-metil- 2-{[5-(trifluorometil)piridin-2-il]oxi}propanamida
C27H25ClF3N3O2
O 3C HH O CF3 NC N H H H3CCH3 N
Cl
67 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
tarenflurbilum tarenflurbil (2R)-2-(2-fluoro-[1,1'-biphenyl-4-yl])propanoic acid
tarenflurbil acide (2R)-2-(2-fluoro-[1,1'-biphényl-4-yl])propanoïque
tarenflurbilo ácido (2R)-2-(2-fluoro-[1,1'-bifenil-4-il])propanoico
C15H13FO2
H CH3 F CO2H
teplizumabum* teplizumab immunoglobulin G1, anti-[human CD3 epsilon (CD3E)] humanized monoclonal antibody MGA031 [hOKT3gamma1(Ala-Ala)]; gamma1 heavy chain 236L>A, 337L>A [humanized VH (Homo sapiens FR/Mus musculus CDR from clone OKT3)-Homo sapiens IGHG1*01, 117L>A (CH2 1.3), 118L>A (CH2 1.2)] (222-213’)-disulfide with kappa light chain [humanized V-KAPPA (Homo sapiens FR/Mus musculus CDR from clone OKT3)-Homo sapiens IGKC*01] ; (228- 228”: 231-231”)-bisdisulfide dimer
téplizumab immunoglobuline G1, anti-[CD3 epsilon humain (CD3E)] anticorps monoclonal humanisé MGA031 [hOKT3gamma1(Ala-Ala)]; chaîne lourde gamma1 [VH humanisé (Homo sapiens FR/Mus musculus CDR du clone OKT3)-Homo sapiens IGHG1*01, 117L >A (CH2 1.3) , 118L>A (CH2 1.2)] (222-213’)-disulfure avec la chaîne légère kappa [V-KAPPA humanisé (Homo sapiens FR/Mus musculus CDR du clone OKT3)-Homo sapiens IGKC*01]; dimère (228-228”: 231- 231”)-bisdisulfure
teplizumab inmunoglobulina G1, anti-[CD3 epsilon humano (CD3E)] anticuerpo monoclonal humanizado MGA031 [hOKT3gamma1(Ala-Ala)]; cadena pesada gamma1 [VH humanizada (Homo sapiens FR/Mus musculus CDR del clon OKT3)-Homo sapiens IGHG1*01, 117L >A (CH2 1.3) , 118L>A (CH2 1.2)] (222-213’)-disulfuro con la cadena ligera kappa [V-KAPPA humanizada (Homo sapiens FR/Mus musculus CDR del clon OKT3)-Homo sapiens IGKC*01]; dímero (228-228”: 231-231”)-bisdisulfuro
C6462H9938N1738O2022S46
Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGGG VVQPGRSLRL SCKASGYTFT RYTMHWVRQA PGKGLEWIGY 50 INPSRGYTNY NQKVKDRFTI SRDNSKNTAF LQMDSLRPED TGVYFCARYY 100 DDHYCLDYWG QGTPVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPEAAGGP 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 ITCSASSSVS YMNWYQQTPG KAPKRWIYDT 50' SKLASGVPSR FSGSGSGTDY TFTISSLQPE DIATYYCQQW SSNPFTFGQG 100' TKLQITRTVA 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 22-96 22''-96'' 23'-87' 23'''-87''' 133'-193' 133'''-193''' 146-202 146''-202'' 213'-222 213'''-222'' 228-228'' 231-231'' 263-323 263''-323'' 369-427 369''-427''
68 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
terameprocolum terameprocol 1,1'-[(2R,3S)-2,3-dimethylbutane-1,4-diyl]bis(3,4-dimethoxybenzene)
térameprocol 1,1'-[(2R,3S)-2,3-diméthylbutane-1,4-diyl]bis(3,4-diméthoxybenzène)
terameprocol 1,1'-[(2R,3S)-2,3-dimetilbutano-1,4-diil]bis(3,4-dimetoxibenceno)
C22H30O4
OCH3 H CH3 H3CO OCH3 H3CH H3CO
thrombinum alfa* thrombin alfa human thrombin (recombinant, glycoform α)
thrombine alfa thrombine humaine (recombinante, glycoforme α)
trombina alfa trombina humana (recombinante, glicoforma α)
C1511H2342N418O436S15
Light chain / Chaîne légère / Cadena ligera TFGSGEADCG LRPLFEKKSL EDKTERELLE SYIDGR 36 Heavy chain / Chaîne lourde / Cadena pesada IVEG SDAEIGMSPW 50 QVMLFRKSPQ ELLCGASLIS DRWVLTAAHC LLYPPWDKNF TENDLLVRIG 100 KHSRTRYERN IEKISMLEKI YIHPRYNWRE NLDRDIALMK LKKPVAFSDY 150 IHPVCLPDRE TAASLLQAGY KGRVTGWGNL KETWTANVGK GQPSVLQVVN 200 LPIVERPVCK DSTRIRITDN MFCAGYKPDE GKRGDACEGD SGGPFVMKSP 250 FNNRWYQMGI VSWGEGCDRD GKYGFYTHVF RLKKWIQKVI DQFGE 295 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 9-155 64-80 209-223 237-267 Glycosylation site / Site de glycosylation / Posición de glicosilación Asn-89
totrombopagum totrombopag (4Z)-2-(3,4-dimethylphenyl)-4-(2-{2-hydroxy-3'-(1H-tetrazol-5-yl)= [1,1'-biphenyl-3-yl]}hydrazinylidene)-5-methyl-2,4-dihydro- 3H-pyrazol-3-one
totrombopag (4Z)-2-(3,4-diméthylphényl)-4-{2-[2-hydroxy-3'-(1H-tétrazol-5-yl)= [1,1'-biphényl-3-yl]]diazanylidène}-5-méthyl-2,4-dihydro-3H-pyrazol- 3-one
totrombopag (4Z)-2-(3,4-dimetilfenil)-4-{2-[2-hidroxi-3'-(1H-tetrazol-5-il)= [1,1'-bifenil-3-il]]hidrazinilideno}-5-metil-2,4-dihidro-3H-pirazol-3-ona
C25H22N8O2
N H3C HN N N N N N H N OH O
CH3 H3C
69 Recommended INN: List 59 WHO Drug Information, Vol. 22, No. 1, 2008
trabedersenum trabedersen 2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-2'- deoxy-P-thioguanylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'- deoxy-P-thioadenylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P- thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl- (3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P-thioadenylyl-(3'→5')-P- thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl- (3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-deoxyadenosine
trabédersen 2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'- déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'- déoxy-P-thioadénylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P- thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl- (3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thioadénylyl-(3'→5')-P- thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl- (3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-déoxyadénosine
trabedersén 2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi- P-tioguanilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P- tioadenilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')- P-tiotimidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-P-tiotimidilil- (3'→5')-2'-desoxi-P-tioadenilil-(3'→5')-P-tiotimidilil-(3'→5')-P- tiotimidilil-(3'→5')-P-tiotimidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi- P-tioguanilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxiadenosina
C177H225N60O94P17S17
trelanserinum trelanserin 2-(7-fluoro-2-oxo-4-{2-[4-(thieno[3,2-c]pyridin-4-yl)piperazin- 1-yl]ethyl}-1,2-dihydroquinolin-1-yl)acetamide
trélansérine 2-(7-fluoro-2-oxo-4-{2-[4-(thiéno[3,2-c]pyridin-4-yl)pipérazin- 1-yl]éthyl}-1,2-dihydroquinolein-1-yl)acétamide
trelanserina 2-(7-fluoro-2-oxo-4-{2-[4-(tieno[3,2-c]piridin-4-il)piperazin-1-il]etil}- 1,2-dihidroquinolin-1-il)acetamida
C24H24FN5O2S
O
H2N N O N N N F
S
70 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
tremelimumabum * tremelimumab immunoglobulin G2, anti-(human CTLA-4 (antigen)) (human monoclonal CP-675206 clone 11.2.1 heavy chain), disulfide with human monoclonal CP-675206 clone 11.2.1 light chain, dimer
trémélimumab immunoglobuline G2, anti-(protéine 4 cytotoxique du lymphocyte T humain (antigène CD 152)) dimère du disulfure entre la chaîne lourde et la chaîne légère de l’anticorps monoclonal humain clone 11.2.1 du CP-675206
tremelimumab inmunoglobulina G2, anti-(proteína 4 citotóxica de linfocitos T humanos (antígeno CD 152)) dímero del disulfuro entre la cadena pesada y la cadena ligera del anticuerpo monoclonal humano CP-675206 clon 11.2.1
C6500H9974N1726O2026S52
tridecactidum tridecactide alpha-1-13-corticotropin, human L-seryl-L-tyrosyl-L-seryl-L-methionyl-L-glutamyl-L-histidyl- L-phenylalanyl-L-arginyl-L-tryptophylglycyl-L-lysyl-L-prolyl-L-valine
tridécactide alpha-1-13-corticotropine, humaine L-séryl-L-tyrosyl-L-séryl-L-méthionyl-L-glutamyl-L-histidyl- L-phénylalanyl-L-arginyl-L-tryptophylglycyl-L-lysyl-L-prolyl-L-valine
tridecactida alfa-1-13-corticotropina, humana L-seril-L-tirosil-L-seril-L-metionil-L-glutamil-L-histidil-L-fenilalanil- L-arginil-L-triptofilglicil-L-lisil-L-prolil-L-valina
C75H106N20O19S
HSer Tyr Ser Met Glu His Phe Arg Trp Gly Lys Pro Val OH 10
tropantiolum tropantiol 2-({[(1R,2R,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]= octan-2-yl]methyl}{2-[(2-sulfanylethyl)amino]ethyl}amino)ethanethiol
tropantiol 2-({[(1R,2R,3S,5S)-3-(4-chlorophényl)-8-méthyl-8-azabicyclo[3.2.1]= octan-2-yl]méthyl}{2-[(2-sulfanyléthyl)amino]éthyl}amino)éthanethiol
tropantiol 2-({[(1R,2R,3S,5S)-3-(4-clorofenil)- 8-azabiciclo[ 3.2.1]octan- 2-il]metil}{2-[(2-sulfaniletil)amino]etil}amino)etanotiol
C21H34ClN3S2
Cl H
N CH3 H
H H N SH HS N H
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vatreptacogum alfa (activatum)* vatreptacog alfa (activated) [158-aspartic acid, 296-valine, 298-glutamine]human coagulation factor VII activated, recombinant DNA origin
vatreptacog alfa (activé) [158-acide aspartique, 296-valine, 298-glutamine]facteur de coagulation VII humain activé, origine ADN recombinant
vatreptacog alfa (activada) [158-ácido aspártico, 296-valina, 298-glutamina]factor de coagulación VII humano activado ; origen ADN recombinante
C1981H3051N561O620S27
Light chain / Chaîne légère / Cadena ligera ANAFLEELRP GSLERECKEE QCSFEEAREI FKDAERTKLF WISYSDGDQC 50 ASSPCQNGGS CKDQLQSYIC FCLPAFEGRN CETHKDDQLI CVNENGGCEQ 100 YCSDHTGTKR SCRCHEGYSL LADGVSCTPT VEYPCGKIPI LEKRNASKPQ 150 GR 152 Heavy chain / Chaîne lourde / Cadena pesada IVGGKDCP KGECPWQVLL LVNGAQLCGG TLINTIWVVS AAHCFDKIKN 200 WRNLIAVLGE HDLSEHDGDE QSRRVAQVII PSTYVPGTTN HDIALLRLHQ 250 PVVLTDHVVP LCLPERTFSE RTLAFVRFSL VSGWGQLLDR GATALVLQVL 300 NVPRLMTQDC LQQSRKVGDS PNITEYMFCA GYSDGSKDSC KGDSGGPHAT 350 HYRGTWYLTG IVSWGQGCAT VGHFGVYTRV SQYIEWLQKL MRSEPRPGVL 400 LRAPFP 406
Modified residues / Résidus modifiés / Residuos modificados H NH2 E HO2C H NH HO C 6-7-14-16-19-20-25-26-29-35 2 D 2 63 CO2H 4-carboxyGlu 3-hydroxyAsp HO2C CO2H OH
Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 17-22 50-61 55-70 72-81 91-102 98-112 114-127 135-262 159-164 178-194 310-329 340-368
Glycosylation sites / Sites de glycosylation / Posiciones de glicosilación Ser-52 Ser-60 Asn-145 Asn-322
velimogenum aliplasmidum* velimogene aliplasmid plasmid DNA vector, expressing HLA-B7 and beta-2 microglobulin, driven by a Rous sarcoma virus promoter
vélimogène aliplasmide vecteur ADN plasmidique, contenant les gènes HLA-B7 et beta2- microglobuline, sous le contrôle du promoteur virus de sarcome de Rous
velimogén aliplásmido vector ADN de plásmído, que contiene los genes HLA-B7 y beta2- microglobulina, controlado por el promotor de virus del sarcoma de Rous
voclosporinum voclosporin 1,11-anhydro[L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl- N-methyl-L-valyl-[(2S,3R,4R,6E)-3-hydroxy-4-methyl- 2-(methylamino)nona-6,8-dienoyl][(2S)-2-aminobutanoyl]- N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucine]
voclosporine 1,11anhydro{L-alanyl-D-alanyl-N-méthyl-L-leucyl-N-méthyl-L-leucyl- N-méthyl-L-valyl-[(2S,3R,4R,6E)-3-hydroxy-4-méthyl- 2-(méthylamino)nona-6,8-diénoyl]-(2S)-2-aminobutanoyl- N-méthylglycyl-N-méthyl-L-leucyl-L-valyl-N-méthyl-L-leucyl]
voclosporina 1,11-anhidro[L-alanil-D-alanil-N-metil-L-leucil-N-metil-L-leucil-N-metil- L-valil-[(2S,3R,4R,6E)-3-hidroxi-4-metil-2-(metilamino)nona- 6,8-dienoil][(2S)-2-aminobutanoil]-N-metilglicil-N-metil-L-leucil-L-valil- N-methyl-L-leucina]
72 WHO Drug Information, Vol. 22, No. 1, 2008 Recommended INN: List 59
C63H111N11O12
CH2
CH3 H3C CH H CH 3 OH 3 H C 3 H3C H H H H H CH3 H3C N N N N N H O CH3 O CH3 O O H3C O O H CH H3C N 3 CH3 H3C N O OH3C O H H H H N N N N CH O 3 O H3CH HCH3 H H CH3 H3C H3C CH3
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AMENDMENTS TO PREVIOUS LISTS MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES MODIFICACIONES A LAS LISTAS ANTERIORES
Recommended International Nonproprietary Names (Rec. INN): List 49 Dénominations communes internationales recommandées (DCI Rec.): Liste 49 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 49 (WHO Drug Information, Vol. 17, No. 2, 2003) p. 123 suprimáse insértese garenoxacina garenoxacino
Recommended International Nonproprietary Names (Rec. INN): List 52 Dénominations communes internationales recommandées (DCI Rec.): Liste 52 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 52 (WHO Drug Information, Vol. 18, No. 3, 2004) p. 248 certolizumabum pegolum certolizumab pegol insert the following CAS certolizumab pégol insérer le CAS suivant: certolizumab pegol insértese el nombre del CAS por el siguiente:
immunoglobulin, anti-(human tumor necrosis factor α) Fab' fragment (human mouse monoclonal CDP870 heavy chain, disulfide bonded with human mouse monoclonal CDP870 light chain), pegylated at Cys-227 on the heavy chain
immunoglobuline, anti-(facteur α de nécrose tumorale humain) ; (disulfure entre le fragment Fab' de la chaîne lourde et la chaîne légère de l'anticorps monoclonal de souris CDP870 humanisé), pégylée à Cyst-227 sur la chaîne lourde
inmunoglobulina, anti-(factor α de necrosis tumoral humano) fragmento Fab' (cadena pesada del anticuerpo monoclonal humanizado de ratón CDP870), disulfuro con la cadena ligera del anticuerpo monoclonal humanizado de ratón CDP870), pegilado Cis-227 de la cadena pesada
Recommended International Nonproprietary Names (Rec. INN): List 57 Dénominations communes internationales recommandées (DCI Rec.): Liste 57 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 57 (WHO Drug Information, Vol. 21, No. 1, 2007) p. 61 beroctocogum alfa* beroctocog alfa replace the chemical structure and molecular formula by the following ones béroctocog alfa remplacer la structure chimique et la formule brute par les suivantes beroctocog alfa sustitúyase la fórmula desarrollada y la fórmula molecular por las siguientes
C3821H5813N1003O1139S35 + C3547H5400N956O1033S35
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human blood-coagulation factor VIII-(1-740)-peptide ATRRYYLGAV ELSWDYMQSD LGELPVDARF PPRVPKSFPF NTSVVYKKTL 50 FVEFTDHLFN IAKPRPPWMG LLGPTIQAEV YDTVVITLKN MASHPVSLHA 100 VGVSYWKASE GAEYDDQTSQ REKEDDKVFP GGSHTYVWQV LKENGPMASD 150 PLCLTYSYLS HVDLVKDLNS GLIGALLVCR EGSLAKEKTQ TLHKFILLFA 200 VFDEGKSWHS ETKNSLMQDR DAASARAWPK MHTVNGYVNR SLPGLIGCHR 250 KSVYWHVIGM GTTPEVHSIF LEGHTFLVRN HRQASLEISP ITFLTAQTLL 300 MDLGQFLLFC HISSHQHDGM EAYVKVDSCP EEPQLRMKNN EEAEDYDDDL 350 TDSEMDVVRF DDDNSPSFIQ IRSVAKKHPK TWVHYIAAEE EDWDYAPLVL 400 APDDRSYKSQ YLNNGPQRIG RKYKKVRFMA YTDETFKTRE AIQHESGILG 450 PLLYGEVGDT LLIIFKNQAS RPYNIYPHGI TDVRPLYSRR LPKGVKHLKD 500 FPILPGEIFK YKWTVTVEDG PTKSDPRCLT RYYSSFVNME RDLASGLIGP 550 LLICYKESVD QRGNQIMSDK RNVILFSVFD ENRSWYLTEN IQRFLPNPAG 600 VQLEDPEFQA SNIMHSINGY VFDSLQLSVC LHEVAYWYIL SIGAQTDFLS 650 VFFSGYTFKH KMVYEDTLTL FPFSGETVFM SMENPGLWIL GCHNSDFRNR 700 GMTALLKVSS CDKNTGDYYE DSYEDISAYL LSKNNAIEPR S 741
human blood-coagulation factor VIII-(1649-2332)-peptide EI 1650 TRTTLQSDQE EIDYDDTISV EMKKEDFDIY DEDENQSPRS FQKKTRHYFI 1700 AAVERLWDYG MSSSPHVLRN RAQSGSVPQF KKVVFQEFTD GSFTQPLYRG 1750 ELNEHLGLLG PYIRAEVEDN IMVTFRNQAS RPYSFYSSLI SYEEDQRQGA 1800 EPRKNFVKPN ETKTYFWKVQ HHMAPTKDEF DCKAWAYSSD VDLEKDVHSG 1850 LIGPLLVCHT NTLNPAHGRQ VTVQEFALFF TIFDETKSWY FTENMERNCR 1900 APCNIQMEDP TFKENYRFHA INGYIMDTLP GLVMAQDQRI RWYLLSMGSN 1950 ENIHSIHFSG HVFTVRKKEE YKMALYNLYP GVFETVEMLP SKAGIWRVEC 2000 LIGEHLHAGM STLFLVYSNK CQTPLGMASG HIRDFQITAS GQYGQWAPKL 2050 ARLHYSGSIN AWSTKEPFSW IKVDLLAPMI IHGIKTQGAR QKFSSLYISQ 2100 FIIMYSLDGK KWQTYRGNST GTLMVFFGNV DSSGIKHNIF NPPIIARYIR 2150 LHPTHYSIRS TLRMELMGCD LNSCSMPLGM ESKAISDAQI TASSYFTNMF 2200 ATWSPSKARL HLQGRSNAWR PQVNNPKEWL QVDFQKTMKV TGVTTQGVKS 2250 LLTSMYVKEF LISSSQDGHQ WTLFFQNGKV KVFQGNQDSF TPVVNSLDPP 2300 LLTRYLRIHP QSWVHQIALR MEVLGCEAQD LY 2332
Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 153-179 528-554 1899-1903 2021-2169 2174-2326
Glycosylation sites / Sites de glycosylation / Posiciones de glicosilación Asn-41 Asn-239 Asn-582 Asn-1810 Asn-2118
Modifications / Modifications / Modificaciones Y = 4-O-sulfotyrosyl
* Electronic structure available on Mednet: http://mednet.who.int/ * Structure électronique disponible sur Mednet: http://mednet.who.int/ * Estructura electrónica disponible en Mednet: http://mednet.who.int/
Procedure and Guiding Principles / Procédure et Directives / Procedimientos y principios generales The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharmaceutical Substances will be reproduced in proposed INN lists only. Les textes de la Procédure à suivre en vue du choix de dénominations communes internationales recommandées pour les substances pharmaceutiques et des Directives générales pour la formation de dénominations communes internationales applicables aux substances pharmaceutiques seront publiés seulement dans les listes des DCI proposées. El texto de los Procedimientos de selección de denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas y de los Principios generales de orientación para formar denominaciones comunes internacionales para sustancias farmacéuticas aparece solamente en las listas de DCI propuestas.
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