WHO Drug Information Vol 23, No. 3, 2009 World Health Organization

WHO Drug Information

Contents International Nonproprietary Regulatory Action and News Names Withdrawal of 219 Besifloxacin: approved for bacterial Nomenclature for monoclonal antibodies 195 conjunctivitis 219 Prasugrel: approved for angioplasty Safety and Efficacy Issues patients 219 Mycophenolate mofetil: pure red cell Pemetrexed: approved for advanced aplasia 200 lung cancer 220 Swine flu ADR portal 200 Dronedarone: approved for heart rhythm Propylthiouracil: serious liver injury 201 disorder 220 Fosamprenavir: myocardial infarction 201 First advanced therapy medicinal TNF inhibitors and lupus erythematosus: product approved 221 an emerging association 202 Gemifloxacin: withdrawal of marketing Triamcinolone acetonide: serious ocular authorization application 221 reactions 202 Saxagliptin approved for diabetes 221 Safety updates on glargine 203 Contusugene ladenovec: withdrawal of Fentanyl transdermal patches and application for marketing 222 accidental child exposure 204 Rotigotine transdermal patch: restrictions Clopidogrel interactions with proton lifted 222 pump inhibitors 205 Impact of European Clinical Trials Long-acting beta- in chronic Directive 222 obstructive pulmonary disease 205 WHO list of recently prequalified and : serious medicinal products 223 mental health events 206 Pain containing propoxy- Current Topics phene: overdose 207 Forum on international pharmaceutical Latanoprost and rosiglitazone: macular crime 225 edema 207 Illegal online medicine suppliers Metformin, dehydration and lactic targeted 225 acidosis 208 Elimination of river blindness in Mali Montelukast: suicidality and other and Senegal 226 psychiatric reactions 208 Moxidectin for river blindness in Duloxetine: serotonin syndrome 209 phase III clinical trials 226 Is it leflunomide lung? 210 Malaria: evaluation of rapid diagnostic Isotretinoin and acquired hearing tests 227 impairment 210

Pharmacovigilance Focus ATC/DDD Classification ATC/DDD (Temporary) 229 Safety of medicinal products 212 ATC/DDD (Final) 231

Continued/

193 World Health Organization WHO Drug Information Vol 23, No. 3, 2009

Contents (continued)

Recent Publications, Dengue: evaluation of immuno- globulin M tests 235 Information and Events WHO/HAI student manual on Good clinical laboratory practices 234 pharmaceutical promotion 235 Laboratory diagnostic tools for tuberculosis control 234 Recommended International WorldPharma2010: clinical pharmacology 234 Nonproprietary Names Ethical guidelines for epidemiology 235 List 62 237

Announcement

The 14th International Conference of Drug Regulatory Authorities (ICDRA) will be hosted by the Health Sciences Authority, Singapore, in collaboration with the World Health Organization

The ICDRA will take place in Singapore from 30 November to 3 December 2010

Updated information is available at: http://www.icdra2010.sg http://www.who.int/medicines/icdra

194 WHO Drug Information Vol 23, No. 3, 2009 International Nonproprietary Names

Nomenclature for or four syllables. INNs are intended to provide information concerning mAbs to monoclonal antibodies scientists, physicians, pharmacists and other interested parties. In October 2008, the World Health Or- ganization’s (WHO) Programme on The linguistics concerning INNs for mAbs International Nonproprietary Names (INN) can be very problematic. Many groups of convened a Working Group meeting to INNs appear “overcrowded” and many discuss nomenclature for monoclonal have similarities in look or sound. This antibodies (mAbs). The objective of the situation is made more complex by the meeting was to review the current situa- need to include systems for pegylated tion in light of the challenges highlighted mAbs and for radiolabelled mAbs. Addi- during the 46th Consultation on Interna- tionally, mAb conjugates use a second tional Nonproprietary Names (INNs) for word for the non-mAb part. Pharmaceutical Substances in April 2008 (1, 2). The Working Group focused on The length and complexity of the words drafting recommendations for any neces- and stems has led to clumsy, long INNs sary modifications to the system to when compared to INNs for other classes facilitate development of INNs for mAbs. of biologicals and chemicals and the A report from that meeting has now been need to adopt INNs for an ever increasing published and is summarized below. number of mAb products is causing INNs to become ever longer. At present 52 The first INN for a names have 4 syllables, 99 have 5 (mAb), muromonab CD3, was adopted syllables and 5 have 6 syllables and this twenty years ago. Following this, the stem trend towards very long names is increas- Ðmab was proposed and adopted for all ing. The clinical success rate for mAbs is new INNs for mAbs. Between 1991 and relatively low compared with other prod- 1993, the basis of the INN system for ucts, which results in many adopted INNs mAbs was devised with the first infixes for finally remaining unused, at least as source and target of antibodies being names for approved products. formulated. Since 1998, 173 mAb INNs have been published and this class of Usage, stems and sub-stems products now represents a significant The stem -mab is well accepted and proportion of the total number of INNs for recognized as indicating a mAb. How- biologicals. This period also saw a move ever, several antibody products are away from rodent-sequence mAbs to fragments, such as Fab or F(ab’)2 while a humanized or human mAbs. range of other types of fragments (e.g., minibodies) are being developed. It would Requirements for INNs for mAbs be possible to adopt new stems for these, INNs for mAbs must be unique and e.g., -fab, but this would cause confusion unrelated to trade names/trademarks. since several Fab fragments have already They must be distinct and transposable been given an INN with the -mab stem. It into several languages. They need to be is also unclear if -fab would be used for convenient for users and it is preferable all fragments or whether further stems that they be limited to no more than three would also need to be adopted.

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Sub-stems (infixes) which indicate spe- also in the Fab part of the mAb. Differ- cies sequence/structure of mAbs are ences in glycosylation of mAbs can be widely understood and used. They may introduced deliberately (by glycoengineer- also include some information on how the ing) or occur unintentionally because of mAb may have been produced. Four differences in manufacturing processes. such sub-stems, -zu-,-o-,-u-,-xi- (human- Products are ‘mixtures’ containing differ- ized, mouse, human and chimeric) have ent glycoforms and are not all of one been used, but some e.g., -e- and -i- homogeneous glycoprotein structure. (hamster and primate mAbs), have never Different batches of a product can vary in been used. Nonetheless, it is possible microheterogeneity and, in addition, that this could change in the future: for modification to production processes can example, there is current interest in some result in changes in glycosylation pattern primate antibodies. It has been proposed (and other post-translational modifica- to discontinue the use of sub-stems and tions). Significant clinical effects of glyco- replace them with syllables indicating the sylation may need to be reflected in INNs. specific targets of the mAbs. However, Although most mAbs are glycosylated, this would cause discontinuity with their INNs have not been given terminal existing INNs and ignores any need to Greek letters as has been done for some consider the species origin of the se- other glycoproteins (e.g., hormones). The quence of mAbs. possibility exists that two or more mAbs could be produced which have the same Sub-stems for disease/target are less well amino acid sequence, but differ in glyco- known. The target sub-stems -li- (im- sylation. To introduce terminal Greek munomodulatory) and -tu- (tumour) have letters for all new INNs could cause been used mostly: 48 as -li(m)- and 50 as confusion and discontinuity with existing -tu(m)-, followed by -vi(r)-. Others have INNs. much lower usage. Specific tumour sub- stems (other than -tu(m)-) have been little At present all existing INNs for mAbs used and some have never been used. In relate to mAbs with different amino acid many cases it is possible to select more sequences. If future INN applications are than one sub-stem for a particular mAb. It received for mAbs with the same se- may be necessary to introduce new quence as an existing mAb, but different target-related sub-stems for some types glycosylation, the INN for the latter of antibodies such as bispecific mAbs. application could be the existing INN but with a terminal beta added. Subsequent Post-translational modifications Greek letters could be used for further and implications for INNs INNs for mAbs with this antibody se- MAbs undergo post-translational modifi- quence, as for other glycoproteins. cations which are dependent on the Concern was also raised that the use of expression system used for production. Greek letters to denote any difference in Most of these do not significantly affect glycosylation could lead to product clinical use but some can influence specific INNs which would undermine the and/or immunobio- nonproprietary nature of the INN. Never- logical functions. In particular, glycosyla- theless, this is consistent with the INN tion can, in some cases, be necessary for policy for recombinant DNA derived optimal clinical activity. Nearly all mAbs proteins. are glycosylated and show expression system and production process related Definitions glycan structures. Glycosylation sites are The INN cannot possibly fully describe all present in the Fc region and sometimes the characteristics of a mAb. The descrip-

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tion/definition should be the source of definition as well as details on glycosyla- detailed information concerning the mAb. tion, etc. The details of the type of infor- Definitions are very important but some mation needed are available on the INN are very complicated and detailed. They application form and the correct amino should consist of two parts, one general acid sequence must be stated. The clone and easy to follow and the other more name should also be included but not in detailed. The definition is linked to the the general definition. If mAbs contain a amino acid sequence. glycosylation site, then they will normally be glycosylated. If the mAb is glyco- Applicants will need to be asked to engineered this should be indicated in the provide the required information for the definition.

General policies for monoclonal antibodies

¥ INNs for monoclonal antibodies (mAbs) are composed of a prefix, a substem A, a substem B and a suffix. ¥ The common stem for mAbs is -mab, placed as a suffix. ¥ The stem -mab is to be used for all products containing an immunoglobulin variable domain which binds to a defined target. Sub-stem B indicates the species on which the immunoglobulin sequence of the mAb is based:

a rat axo (pre-sub-stem) rat/mouse e hamster i primate omouse u human xi chimeric -xizu- (under discussion) chimeric/humanized zu humanized

The distinction between chimeric and humanized antibodies is as follows:

A chimeric antibody is one that contains contiguous foreign-derived amino acids comprising the entire variable domain of both heavy and light chains linked to heavy and light constant regions of human origin. A has segments of foreign-derived amino acids interspersed among variable domain segments of human-derived amino acid residues and the humanized variable heavy and variable light domains are linked to heavy and light constant regions of human origin.

The -xizu- infix is used for an antibody having both chimeric and humanized chains.

The -axo- infix is used for an antibody having both rat and mouse chains. Continued overleaf ...

197 International Nonproprietary Names WHO Drug Information Vol 23, No. 3, 2009

General policies for monoclonal antibodies (continued)

Sub-stem A indicates the target (molecule, cell, organ) class:

-b(a)- bacterial -c(i)- cardiovascular -f(u)- fungal -k(i)- interleukin -l(i)- immunomodulating -n(e)- (under discussion) neural -s(o)- bone -tox(a) toxin t(u) tumour -v(i)- viral

In principle, a single letter, e.g., -b- for bacterial, is used as substem A. When- ever substem B starts with a consonant (e.g., x or z), an additional vowel indicated in the table, e.g., -ba-, is inserted to avoid problems in pronunciation.

Prefix The prefix should be random, e.g., the only requirement is to contribute to a euphonious and distinctive name.

Second word If the product is radiolabelled or conjugated to another chemical, identification of this conjugate is accomplished by use of a separate, second word or acceptable chemical designation. For instance, for mAbs conjugated to a toxin, the suffix -tox can be used in the second word.

If the monoclonal antibody is used as a carrier for a radio-isotope, the latter will be listed first in the INN, e.g., technetium (99mTc) nofetumomab merpentan (81).

The prefix peg- can be used for pegylated mAbs, but this should be avoided if it leads to over-long INNs. In most cases, it is best to adopt two-word INNs for pegylated mAbs, with the first word describing the mAb and the second being pegol or a related designation.

Other matters Companies should apply for an INN when Information relating to details of structure clinical evaluation begins. INNs are (which must be provided by the manufac- needed for a product at this stage be- turer/applicant) is crucial for deciding on cause an alternative means of identifica- an appropriate INN. It is up to manufac- tion, e.g., using manufacturer codes, is turers to approach WHO for an INN and very confusing. regulators should request companies to apply for an INN. They are also responsi- Many mAbs fail at phase III trials. This is ble for checking and validating if an INN late in the evaluation process when they is correctly used and corresponds to the will almost certainly have received an substance which is the subject of a INN. This accounts for the many INNs Marketing Authorization. which exist for clinically failed mAbs.

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Recommendations should be simplified to -tu(m)-, the other The present system needs modification, tumour sub-stems should be discontin- revision and improvement to deal with ued. But -tu(m)- should be truncated to - specific problems. However, it has been t- or -tu-. Similarly -li(m)- should be used successfully for twenty years and truncated to -m- or discontinued and changes should be carefully considered replaced with more precise sub-stems, and implemented only where necessary. which relate to the target. Also the other The following proposals have been sub-stems for ‘disease or target’ should highlighted in particular: be shortened, e.g., -fung- to -f-.

¥ The stem -mab should be retained. Also ¥ The use of Greek terminal letters to -mab is to continue to be used for mAb indicate differences in glycosylation fragments. The description should cannot be introduced retrospectively. clearly indicate if the product is a However, mAbs which have the same fragment. amino acid sequence but different glycosylation may need distinct INNs ¥ The system for conjugates and radio- unless significant differences on post- labelled mAbs need not be changed. translational modifications are excluded/ misproven. In particular, if the glycosyla- ¥ The stem -mab is to be used for all tion has been glycoengineered to products containing an immunoglobulin produce a different structure, then the variable domain which binds to a glycoengineered mAb should be given a defined target. different INN to the parent mAb.

¥ The prefix peg- can be used for ¥ When the antibody is directed against a pegylated mAbs, but this should be toxin, the infix -toxa- can be used in the avoided if it leads to an over-long INN. name. For monoclonals conjugated to a In most cases, it is best to adopt two- toxin, the suffix -tox can be used in the word INNs for pegylated mAbs, with the second word. This will be clarified in the first word describing the mAb and the mAb naming rules. second being pegol. This is consistent with INNs for other pegylated sub- References stances. 1. International Nonproprietary Names ¥ The use of sub-stems is valuable but for monoclonal antibodies: IFPMA proposal. possibly too complicated. The ‘source’ WHO Drug Information, vol 22, no 2, 2008. sub-stem should be kept but redefined 2. World Health Organization. 46th Consulta- as ‘the species on which the immu- tion on International Nonproprietary Names noglobulin sequence of the mAb is (INNs) for Pharmaceutical Substances. http:// based’. The ‘tumour group’ sub-stem www.who.int/medicines.

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Safety and Efficacy Issues

Mycophenolate mofetil: degree of anaemia can range from pure red cell aplasia subclinical to severe. Canada — The manufacturer of myco- As of 24 February 2008, 41 cases of phenolate mofetil (CellCept¨) has pro- PRCA have been reported in patients vided new safety information on reports of receiving mycophenolate mofetil in pure red cell aplasia (PRCA). Myco- combination with other immunosuppres- phenolate mofetil is an immunosuppres- sive agents (tacrolimus, cyclosporine, sive agent indicated for the prophylaxis of corticosteroids, azathioprine, acute transplant rejection in adults and alemtuzumab). receiving allogeneic renal, cardiac or hepatic transplants, and in children and Reference: Communication dated 3 June adolescents (2Ð18 years) receiving renal 2009 from Hoffmann-La Roche Limited posted transplants. Mycophenolate mofetil on the Health Canada site at http://www.hc- should be used concomitantly with sc.gc.ca cyclosporine and corticosteroids. Swine flu ADR portal The mechanism for mycophenolate mofetil induced PRCA is unknown. In United Kingdom — Oseltamivir some cases, PRCA was found to be (Tamiflu¨) and zanamivir (Relenza¨) reversible with dose reduction or cessa- have been stockpiled for management of tion of therapy. In transplant patients, the swine flu pandemic. In order to however, reduced immunosuppression efficiently monitor the safety of oseltamivir may place the graft at risk. PRCA is and zanamivir as their use increases, a usually treated by attending to the under- special web-based system for reporting lying condition (disease) or discontinuing suspected ADRs to these medicines Ð the the drug that causes PRCA. Swine Flu ADR Portal — has been set up.

PRCA is a type of anaemia that develops This is available at www.mhra.gov.uk/ secondary to failure of erythropoiesis. swineflu and will remain in operation for Erythropoiesis is a process by which red the duration of the pandemic. The portal blood cells (RBCs) are produced from has been designed to make completing a immature precursors in the bone marrow. report as quick and easy as possible. PRCA describes a condition in which When H1N1 swine flu vaccines become RBC precursors in bone marrow are available in the Autumn, the portal should nearly absent, while megakaryocytes and also be used to report suspected ADRs to white blood cell precursors are usually these vaccines. present at normal levels. PRCA may be idiopathic or occur as a manifestation of The Swine Flu ADR Portal will be open to an underlying condition. Approximately members of the public as well as health 5% of all cases of PRCA are drug in- care professionals. duced. Patients with PRCA may present Reference: MHRA. Swine flu - Reporting with fatigue, lethargy, and/or abnormal suspected adverse reactions to Tamiflu¨, paleness of the skin. Anaemia is the Relenza¨ and future Swine flu H1N1 vac- primary clinical concern in PRCA. The cines. http://www.mhra.gov.uk/

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Propylthiouracil: A nested case-control study conducted in serious liver injury the French Hospital Database on HIV has reported an association between expo- United States of America — The Food sure to fosamprenavir and an increased and Drug Administration (FDA) has risk of myocardial infarction. This may be warned health care professionals of the related to the propensity for this drug risk of serious liver injury associated with class to raise blood lipids. Triglyceride the use of propylthiouracil for the treat- and levels should therefore be ment of Graves disease. checked prior to initiating therapy with fosamprenavir and at periodic intervals Propylthiouracil was approved for market- during therapy. Other modifiable risk ing in 1947. A total of 32 cases of serious factors for cardiovascular disease (such liver injury associated with the use of as hypertension, diabetes and smoking) propylthiouracil were reported to the should also be monitored in HIV-infected FDA’s Adverse Event Reporting System subjects and managed as clinically since that system was established in appropriate. 1969 through October 2008. Of the 22 adult cases, the FDA identified 12 deaths Recent data presented at the 16th Con- and five liver transplants. Of the 10 ference on Retroviruses and Opportunis- paediatric cases, there was one death tic suggested a potential and six reports of liver transplant. association between fosamprenavir and myocardial infarction in HIV infected Propylthiouracil is considered second-line adults. The nested case-control study drug therapy except in certain patients reported an increased risk of myocardial who are allergic or intolerant of methim- infarction in association with cumulative azole. Because a rare birth defect has exposure to fosamprenavir. Myocardial been reported with methimazole and not infarction has already been identified as with propylthiouracil, propylthiouracil may being potentially associated with the PI be more appropriate for patients with class in the ongoing Data Collection on Graves disease who are in the first Adverse Events of Anti-HIV Drugs (DAD). trimester of pregnancy. Suppression of viral replication in HIV Reference: FDA News Release, 3 June 2009 disease with antiretroviral therapy is of at http://www.fda.gov the utmost importance. Physicians should monitor a patient’s cardiovascular risk as Fosamprenavir: myocardial part of the follow-up and seek to adjust infarction modifiable risk factors. Combination antiretroviral therapy is associated with Canada — The manufacturer of fosam- redistribution of body fat (lipodystrophy) in prenavir (Telzir¨) has informed health- HIV-infected patients. Clinical examina- care professionals of important safety tion should include evaluation for physical information regarding a potential associa- signs of fat distribution. HIV itself tion between myocardial infarction and has been associated with lipid disorders exposure to fosamprenavir in HIV- and ischaemic heart disease. infected patients. Fosamprenavir is a protease inhibitor (PI) used in combina- Reference: Communication from the manu- tion with low-dose ritonavir and other facturer dated 17 July 2009 at http://www.hc- antiretrovirals in the treatment of HIV-1 sc.gc.ca infection.

201 Safety and Efficacy Issues WHO Drug Information Vol 23, No. 3, 2009

TNF inhibitors and lupus References erythematosus: an 1. Khanna D, McMahon M, Furst D. Safety of emerging association tumour necrosis factor antagonists. Drug Safety 2004: 27; 307-324 Australia — Systemic lupus erythemato- sus (SLE) is considered drug-induced 2. Adalimumab (Humira) PI (version dated 28/ when, in relation to a suspect drug, both 10/08). of the following apply: 3. Costa M, Said N, Zimmermann B. Drug- induced lupus due to anti-tumor necrosis ¥ Idiopathic lupus features or antibodies factor agents. Seminars in Arthritis and are absent prior to treatment. Rheumatism 2008; 37: 381-387 4. Mañosa M, Domènech E, Marín L et al. ¥ Recovery occurs within one year of Adalimumab-induced lupus erythematosus in withdrawal of treatment. Crohn disease patients previously treated with infliximab. Gut 2008; 57: 559 Clinically, drug-induced lupus erythemato- sus (DILE) tends to be similar to and less severe than idiopathic SLE: arthralgia, Triamcinolone acetonide: myalgia and skin rash (not the classic serious ocular reactions malar rash) are prominent, renal or neurological involvement is rare. Manage- Canada —Triamcinolone acetonide is a ment requires withdrawal of the suspect synthetic corticosteroid primarily used for drug, after which improvement begins, its marked anti-inflammatory action (1). It generally within weeks. Arthralgia/arthritis was authorized for use in Canada as a may call for treatment with an NSAID, 10-mg/mL suspension (Kenalog-10¨) in and severe symptoms may require short 1966, and as a 40-mg/mL suspension courses of corticosteroids (1). (Kenalog-40¨) in 1973. Currently, generic products are also available. In Canada, Tumour necrosis factor (TNF) inhibitors the 40-mg/mL suspension has been (infliximab, adalimumab, etanercept) are authorized for intramuscular and intra- powerful immunosuppressants approved articular administration or for injection into for indications including rheumatoid and tendon sheaths or ganglia. It is indicated psoriatic arthritis, ankylosing spondylitis, for systemic corticosteroid therapy in and Crohn disease. However, the defi- conditions such as dermatoses or rheu- ciency of TNF caused by these drugs is matoid arthritis and other connective known to predispose some patients to tissue disorders (1). TNF inhibitor-induced SLE. Intravitreal or intra-ocular injection of this product is not an authorized route of In clinical studies of rheumatoid arthritis, administration in Canada. Diabetic two of 3000 adalimumab-treated patients macular edema, cystoid macular edema developed new-onset lupus-like syn- and choroidal neovascularization second- drome, remitting on withdrawal of adali- ary to age-related macular degeneration mumab (2). There are also case reports are among the conditions for which the of DILE in association with adalimumab, use of intravitreal injection of triamci- etanercept and infliximab (3, 4). nolone has been reported (2, 3). In 2007, a safety notice was published in France Extracted from Australian Adverse Drug regarding the occurrence of serious Reactions Bulletin, Volume 28, Number 3, ocular adverse reactions (ARs) following June 2009 at http://www.tga.gov.au/adr/ intravitreal injections of the 40-mg/mL aadrb/aadr0906.htm#a1 suspension (4).

202 WHO Drug Information Vol 23, No. 3, 2009 Safety and Efficacy Issues

Topical ophthalmic, oral and intravenous 3. Chaudhary V, Mao A, et al. Triamcinolone corticosteroids have long been associ- acetonide as adjunctive treatment to ated with ocular ARs. Local injections of verteporfin in neovascular age-related macular corticosteroids, even at sites far from the degeneration. A prospective randomized trial. eye, have been associated with eye Ophthalmology 2007;114(12):2183-9. complications such as the development of 4. Information importante de pharmacovigi- cataract, glaucoma, and even retinal and lance. Rueil-Malmaison (France): Bristol- choroidal emboli (5). Myers Squibb; 6 August 2007.

Intravitreal injection of triamcinolone has 5. Carnahan MC, Goldstein DA. Ocular several reported complications including complications of topical, peri-ocular, and retinal detachment and vitreous haemor- systemic corticosteroids. Curr Opin Opht- rhage. Complications developing later halmol 2000;11(6):478-83. include cataract progression, steroid- induced glaucoma and endophthalmitis 6. Jermak CM, Dellacroce JT, et al. Triamci- nolone acetonide in ocular therapeutics. Surv (2). Triamcinolone persists for long Ophthalmol 2007;52(5): 503Ð22. periods. Low concentrations were found in samples of aqueous humor up to 1.5 years after intravitreal injection (6). Cases Safety updates of increased intraocular pressure requir- on ing medical intervention following European Union — The European intravitreal injection have also been reported. Patients with a history of pri- Medicines Agency (EMEA) is looking into mary open-angle glaucoma are at a four recently published registry studies investigating a possible relationship higher risk of increased intra-ocular pressure (2). between insulin analogues, in particular insulin glargine, and the risk of cancer. A number of ocular ARs following intra- The studies were published on the vitreal injection of triamcinolone in Diabetologia website on 26 June 2009. Canada have been reported in the scientific literature (2). They included Insulin glargine is a long-acting insulin increased intraocular pressure requiring analogue, authorized in the European glaucoma (60 cases), cataract Union (EU) as Lantus¨ and Optisulin¨, progression requiring extraction (12), for the treatment of adults, adolescents endophthalmitis (1) and temporary and children aged six years or above with occlusion of the central retinal artery (1). diabetes when treatment with insulin is required. Extracted from Canadian Adverse Reac- tions Newsletter, volume 19, issue 3, july The results of the four studies were found to be inconsistent. In two studies (Scot- 2009 at http://www.hc-sc.gc.ca/dhp-mps/ medeff/bulletin/carn-bcei_v19n3-eng.php tish Diabetes Research Network Epidemi- ology Group and Jonasson et al) an References association between breast cancer was found in a group of patients taking insulin 1. Kenalog-40¨ Injection (sterile triamcinolone glargine as monotherapy, but not in acetonide suspension) [product monograph]. another group of patients using insulin Montreal (QC): Westwood Squibb; 1992. glargine together with other types of insulin. For other cancers, no association 2. Baath J, Ells AL, et al. Safety profile of was found. In these two studies, dose- intravitreal triamcinolone acetonide. J Ocul dependency was not evaluated. The third Pharmacol Ther 2007;23(3):304-10. study (Hemkens et al) reported a dose-

203 Safety and Efficacy Issues WHO Drug Information Vol 23, No. 3, 2009

dependent association between use of pain that cannot be managed by other insulin glargine and malignancies. How- means such as opioid combination ever, no information is available on the products or immediate-release opioids types of cancer found in this study. In the (1). The system has been marketed in fourth study (Currie et al), no association Canada under the brand name between cancer (either breast, colorectal, Duragesic¨ since 1992. In 2006, the pancreatic or prostate cancer) and the generic products Ratio-Fentanyl¨ and use of insulin glargine, or any other Ran-Fentanyl¨ transdermal systems insulin, was found. were introduced.

On the basis of currently available data, a Safety of the fentanyl transdermal system relationship between insulin glargine and is contingent on its use according to the cancer cannot be confirmed nor ex- conditions recommended in the Canadian cluded. However, concerns raised by the product monographs. The warnings and four studies require further in-depth precautions section of the monographs evaluation (1). have been updated to include accidental The Committee for Medicinal Products for exposure. Examples of accidental expo- Human Use (CHMP) has since carried sure include the transfer of a fentanyl out an in-depth review of four studies and transdermal patch while hugging, sharing their outcomes. Due to methodological a bed or moving a patient (1Ð3). limitations the studies were found to be inconclusive and did not allow a relation- In December 2008, Health Canada ship between insulin glargine and cancer received a report of suspected accidental to be confirmed or excluded. In addition, fentanyl exposure in a healthy 19-month- the Committee noted that the results of old child. He was sleeping in the same the studies were not consistent. bed as his mother, who was using a fentanyl patch for chronic pain. The patch Because of the limitations of the existing inadvertently became attached to the evidence, the Committee has requested child. He was taken to hospital and given the marketing authorization holder to 0.01mg/kg intramuscularly as develop a strategy for generation of required. The child was monitored over- further research in this area. In addition night, and his condition improved after the Committee is exploring possibilities treatment (1Ð4). for cooperation with academia to gener- ate further information. Extracted from Canadian Adverse Reac- tions Newsletter, volume 19, issue 3, july References 2009 at http://www.hc-sc.gc.ca/dhp-mps/ medeff/bulletin/carn-bcei_v19n3-eng.php 1. Press Release, Doc. Ref. EMEA/408474/ 2009. 29 June 2009 at http://www. emea.europa.eu/ References 2. Press Release, Doc. Ref. EMEA/470632/ 1. Duragesic (fentanyl transdermal system) 2009. 23 July 2009 at http://www. [product monograph]. Markham (ON): emea.europa.eu/ Janssen-Ortho Inc; 2008.

2. Ran-Fentanyl (fentanyl transdermal system) Fentanyl transdermal patches [product monograph]. Mississauga (ON): and accidental child exposure Ranbaxy Pharmaceuticals Canada Inc; 2006.

Canada — The fentanyl transdermal 3. Ratio-Fentanyl (fentanyl transdermal system is indicated in the management of system) [product monograph]. Mirabel (QC): persistent, moderate to severe chronic Ratiopharm Inc; 2008.

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4. Little patches ... Big problems: Protecting 3. Juurlink D, et al. A population-based study children from unintentional harm. ISMP of the drug interaction between proton pump Medication Safety Alert 2005;4(9). inhibitors and clopidogrel. CMAJ 2009; 180: 713Ð18 (external link). Clopidogrel interactions with Which PPI? proton pump inhibitors 4. http://www.mhra.gov.uk/Safety information/ Safetywarningsalertsandrecalls/Safety United Kingdom — The European warningsandmessagesformedicines/ Medicines Agency Committee for Medici- CON051743 nal Products for Human Use (CHMP) has recently considered the available evi- Long-acting beta-agonists dence for an interaction between clopi- in chronic obstructive dogrel and proton pump inhibitors (PPIs). pulmonary disease They concluded that PPIs reduce the effectiveness of clopidogrel in preventing United Kingdom — Chronic obstructive the recurrence of adverse cardiac events pulmonary disease (COPD) is a slowly such as heart attack and coronary artery progressive, mainly irreversible disease restenosis. characterized by airflow limitation. It is one of the few diseases associated with Clopidogrel (Plavix¨) is used to prevent an increasing mortality rate and, by 2020, atherothrombotic events in patients who is predicted to be the third most common have previously had one of these events, cause of death. or in at-risk patients who have peripheral arterial disease. In combination with The National Institute for Health and aspirin, it can also be used to prevent Clinical Excellence (NICE) and the Global atherothrombotic events in patients with initiative for chronic Obstructive Lung acute coronary syndrome. Disease (GOLD) guidelines recommend the addition of a long-acting beta- PPIs are used to treat gastrointestinal (LABA) to short-acting beta-2 agonists disorders, oesophageal reflux disease , when moderate COPD is diagnosed. dyspepsia or gastric ulcers. In the United The two LABAs currently licensed for Kingdom, five PPIs are available on treatment of COPD are salmeterol and prescription: , , formoterol (eformoterol). Both are , , and lanso- licensed in COPD either as monotherapy prazole. Omeprazole is also available or in conjunction with an ICS (fluticasone over the counter (Losec¨). propionate and budesonide, respectively). The Medicines and Healthcare Products Clopidogrel can cause side effects on the Regulatory Agency (MHRA) has recently gastrointestinal system and is therefore completed a comprehensive review of the frequently prescribed together with a PPI. use of LABAs, both as monotherapy and in combination with ICS. The review References assessed published literature and unpub- 1. Pezalla E, et al. Initial assessment of lished trials investigating the efficacy or clinical impact of a drug interaction between safety (or both) of LABA or LABA plus clopidogrel and proton pump inhibitors. J Am ICS against a range of clinical endpoints. Coll Cardiol 2008; 52: 1038 . The review concluded that: 2. Ho M, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel ¥ A LABA/ICS combination had greater and proton pump inhibitors following acute efficacy than either LABA or ICS mono- coronary syndrome. JAMA 2009; 301: 937. therapy in every study.

205 Safety and Efficacy Issues WHO Drug Information Vol 23, No. 3, 2009

¥ The extent of the additional benefit 2. Medicines and Healthcare Products provided by the LABA/ICS combination Regulatory Agency (MHRA). Drug Safety versus LABA alone was variable and Update Volume 2 Issue 12 July 2009. http:// was not always clinically significant. A www.mhra.gov.uk/ convincing additional benefit of combi- nation therapy was however seen in Varenicline and bupropion: reduction in the rate of exacerbations. serious mental health events

¥ A significant additional benefit of the United States of America — The Food LABA/ICS combination has not been and Drug Administration (FDA) has proven for milder disease and ICS announced that it is requiring manufactur- should not be introduced earlier than ers to put a boxed warning on the pre- guidelines suggest. scribing information for the smoking cessation drugs varenicline (Chantix¨) ¥ In terms of efficacy, no clear dose- and bupropion (Zyban¨). The warning will response relation was shown for either highlight the risk of serious mental health LABAs or ICS. To date, no treatment events including changes in behaviour, has been shown to influence the accel- depressed mood, hostility, and suicidal erated decline in lung function that is thoughts when taking these drugs. characteristic of COPD, highlighting the limited treatment options for this patient Similar information on mental health population. events will be required for bupropion marketed as the antidepressant A range of side effects have been re- Wellbutrin¨ and for generic versions of ported after LABA or LABA/ICS therapy. bupropion. These drugs already carry a However their incidence should be boxed warning for suicidal behaviour in considered in the context of systemic treating psychiatric disorders. inflammation and several co-existing conditions (including cardiovascular In addition, the FDA also is requesting disease). more information in the Warnings section of the prescribing information and up- The overall benefits of long-acting beta- dated information in the Medication Guide agonists (LABAs) both as monotherapy for patients that further discuss the risk of and in combination with inhaled corticos- mental health events when using these teroids (ICS) in the treatment of chronic products. obstructive pulmonary disease (COPD) continue to outweigh any risks. However, Manufacturers will also be required to healthcare professionals are reminded conduct a clinical trial to determine how that ICS should not be used alone in often serious neuropsychiatric symptoms COPD. A key issue remains the increased occur in patients using various smoking risk of pneumonia associated with the use cessation therapies, including patients of ICS in COPD. who currently have psychiatric disorders. The FDA’s review of adverse events for References patients using patches did not identify a clear link between those medi- 1. http://www.nice.org.uk/guidance/ cations and suicidal events. index.jsp?action=download&o=29303 and http://www.goldcopd.com Guide Reference: Public Health Advisory, 1 July lineitem.asp?l1=2&l2=1&intId=2003 2009 at http://www.fda.gov

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Pain medications containing multiple recurrences may result in macu- propoxyphene: overdose lar photoreceptor damage with permanent impairment of central vision (1). United States of America — The Food and Drug Administration (FDA) has taken To date, the Therapeutic Goods Adminis- action to reduce the risk of overdose in tration (TGA) has received 25 adverse patients using pain medications such as reaction reports of drug-associated Darvon¨ and Darvocet¨ that contain macular edema. Most have implicated propoxyphene. Action was taken because latanoprost (7 reports from a total of 216 of data linking propoxyphene and fatal for this drug) or rosiglitazone (9 reports overdoses. from a total of 344), and three each have reported use of an NSAID or a bisphos- The agency is requiring manufacturers of phonate. propoxyphene-containing products to Latanoprost is a F -alfa strengthen the label, including the boxed 2 warning, emphasizing the potential for analogue used as eye drops for the overdose when using these products. treatment of open angle glaucoma or Manufacturers will also be required to ocular hypertension either alone provide a medication guide to patients (Xalatan¨) or in combination with the stressing the importance of using the beta-blocker (Xalacom¨). It drugs as directed. reduces intraocular pressure by decreas- ing resistance and thereby increasing In addition, the FDA is requiring a new uveoscleral outflow of aqueous humor. It safety study assessing unanswered has not been found to have significant questions about the effects of propoxy- systemic pharmacological effects. phene on the heart at higher than recom- mended doses. Findings from this study, Macular edema is identified in the as well as other data, could lead to latanoprost product information as a additional regulatory action. potential adverse effect, more commonly occurring in patients with aphakia or Propoxyphene has been on the market pseudophakia with anterior chamber since 1957. It is widely prescribed and is lenses and/or torn posterior lens capsule, used as a treatment for mild to moderate or in patients with known risk factors for pain. The most frequent side effects of macular edema such as diabetic retinopa- propoxyphene include lightheadedness, thy and retinal vein occlusion. An associa- dizziness, sedation, nausea, and vomit- tion between the hypoglycaemic agent ing. rosiglitazone and macular edema is also Reference: FDA News Release, 7 July 2009 known. There is evidence that withdrawal at http://www.fda.gov of rosiglitazone is followed by resolution of macular edema (2, 3). Latanoprost and rosiglitazone: Macular edema should be suspected with macular edema any loss of visual acuity not correctible by pinhole refraction, and requires prompt Australia — Macular edema causes specialist evaluation for confirmation of blurred or distorted vision due to painless diagnosis and further measures as swelling of the macula. The condition is appropriate. relatively common and is frequently associated with various ocular conditions Extracted from Australian Adverse Drug including cataract surgery, age-related Reactions Bulletin, Volume 28, Number 3, macular degeneration and, rarely, drug June 2009 at http://www.tga.gov.au/adr/ toxicity. Chronic macular edema or aadrb/aadr0906.htm#a1

207 Safety and Efficacy Issues WHO Drug Information Vol 23, No. 3, 2009

References Patients should be educated about managing their diabetes and medications, 1. Telander DG & Cessna CT. Macular edema, particularly metformin, in the context of Irvine-Gass. http://emedicine.medscape.com/ acute illness. If a patient on metformin article/ develops vomiting and/or diarrhoea, 2. Ryan E, Han D, Ramsay R, Cantrill, H, especially when coupled with poor oral Bennett S, Dev, S, Williams D. Diabetic intake, they should see their doctor and macular edema associated with glitazone use. consideration should be given to tempo- Retina 2006; 26: 562-570 rarily ceasing metformin until a normal 3. Liazos E, Broadbent, D, Kumar N. Sponta- dietary intake can be tolerated. Consid- neous resolution of diabetic macular edema eration should also be given to temporar- after discontinuation of thiazolidinediones. ily withholding any concomitant diuretic Diabet Med 2008; 5: 860-862. therapy, as this will exacerbate acute renal impairment in a dehydrated patient. Metformin, dehydration Extracted from Australian Adverse Drug and lactic acidosis Reactions Bulletin, Volume 28, Number 3, June 2009 at http://www.tga.gov.au/adr/ Australia — Lactic acidosis is a rare but aadrb/aadr0906.htm#a1 extremely serious metabolic complication of metformin usage. The association has References featured in two issues of the Australian Adverse Drug Reaction Bulletin (1, 2) and 1. Fatal lactic acidosis with metformin. Aust the following boxed warning on this Adv Drug Reactions Bull 1995; 14 (2). http:// serious reaction appears in product www.tga.gov.au/adr/aadr9505. htm#lactic information for metformin-containing 2. Metformin and lactic acidosis — a reminder. products: Aust Adv Drug Reactions Bull 2001; 20 (1). http://www.tga.gov.au/adr/aadr0102.htm# “Life threatening lactic acidosis can occur metformin due to accumulation of metformin. The main risk factor is renal impairment; other Montelukast: suicidality and risk factors include old age associated other psychiatric reactions with reduced renal function and high doses of metformin (> 2g/day). Canada — Montelukast sodium (Singulair¨), a leukotriene-receptor ‘Metformin is contraindicated in acute antagonist, is indicated for the prophy- conditions with the potential to compro- laxis and chronic treatment of asthma in mise renal function, such as dehydration. patients two years of age and older (1). This highlights the importance of educat- It is also indicated for the relief of symp- ing patients about how to manage their toms of seasonal allergic rhinitis in diabetes, including their medications, patients 15 years of age and older when when they become acutely unwell.” other treatments are not effective or not tolerated. Montelukast has been mar- Since 1985, the Therapeutic Goods keted in Canada since 1997. Administration (TGA) has received 141 reports of lactic acidosis associated with Between September 2007 and July 2008, metformin, 25 of which described a fatal updates were made to the Canadian outcome. Many of the reports describe a product monograph to include depres- recent history of diarrhoea, vomiting or sion, suicidality and anxiety (1, 2). In gastrointestinal infection prior to the March 2008, the US Food and Drug development of acidosis. Administration (FDA) stated that it was

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investigating further the suspected included on the Australian reimbursement association between montelukast and system in June 2008 and, to up May suicidality (3). Following the FDA commu- 2009, over 200 000 prescriptions have nication, there was a sevenfold increase been dispensed. Over this same period, in the number of montelukast-related 108 reports of suspected adverse drug cases reported to the Adverse Event reactions with duloxetine have been Reporting System database in the United received. The commonly reported reac- States (4). tions include dizziness (10 cases), suicidal ideation (10), tremor (8), agitation From the date of marketing to 31 January (8) and serotonin syndrome (7). 2009, Health Canada has received 13 adverse reaction (AR) reports related to Serotonin syndrome is caused by the suicidality or self-injury suspected of accumulation of serotonin in the central being associated with the use of monte- nervous system. It is characterized by a lukast. triad of autonomic dysfunction, cognitive- behavioural changes and neuromuscular From the date of marketing to 31 January dysfunction. In five of the seven cases of 2009, Health Canada has received 29 reported serotonin syndrome, there was other AR reports relating to depression, no evidence of other risk factors normally hostility or psychosis suspected of being associated with this condition, such as associated with the use of montelukast. concomitant use of other Extracted from Canadian Adverse Reac- agents or excessive dosing. tions Newsletter, volume 19, issue 3, july A case report published recently de- 2009 at http://www.hc-sc.gc.ca/dhp-mps/ scribes a 70 year old female who devel- medeff/bulletin/carn-bcei_v19n3-eng.php oped serotonin syndrome within 48 hours References of commencing the drug (1). Symptoms rapidly resolved when duloxetine was 1. Singulair¨, montelukast (as montelukast ceased and re-emerged when duloxetine sodium) [product monograph]. Kirkland (QC): was re-introduced. Merck Frosst Canada Ltd; 2009. Based on this early post-market informa- 2. Singulair¨ (montelukast sodium) [prescrib- tion, it appears that serotonin syndrome ing information].Whitehouse Station (NJ): can occur with duloxetine treatment Merck & Co., Inc.: 2008. alone, even at therapeutic doses, as well 3. US Food and Drug Administration. Early as in combination with other drugs known communication about an ongoing safety to cause this syndrome. The Cymbalta¨ review of montelukast (Singulair¨). Rockville product information has recently been (MD): 28 March 2008. updated to reflect this new information (2). 4. Institute for Safe Medication Practices. QuarterWatch: 2008 quarter 2. Alexandria Extracted from Australian Adverse Drug (VA) 2009. Reactions Bulletin, Volume 28, Number 4, August 2009 at http://www.tga.gov.au/adr/ Duloxetine: serotonin adrac-bulletin syndrome References Australia — Duloxetine (Cymbalta®) is a serotonin and noradrenaline reuptake 1. Hadikusumo B, Ng B. Serotonin syndrome inhibitor recently approved for the treat- induced by duloxetine. Aust NZ J Psychiatry ment of major depressive disorder. It was 2009; 43: 581-582.

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2. Cymbalta (duloxetine) Product Information. In addition to ILD, leflunomide and Eli Lilly Australia Pty Ltd. methotrexate are both associated with a number of other severe, potentially fatal Is it leflunomide lung? adverse effects, including liver failure, Stevens-Johnson syndrome and agranu- Australia — The Australian Adverse locytosis. It is expected that the risks for Reactions Committee (ADRAC) continues ILD and other severe toxicities would be to receive reports of severe pulmonary at the least additive when these drugs are disease, including interstitial lung disease used concomitantly. (ILD) in association with leflunomide (Arava¨, Arabloc¨). In some cases, the Extracted from Australian Adverse Drug association with leflunomide was not Reactions Bulletin, Volume 28, Number 4, recognized early enough and resulted in August 2009 at http://www.tga.gov.au/adr/ a fatal outcome. adrac-bulletin

Reports of ILD with leflunomide alone or References in combination with methotrexate (also unilaterally associated with ILD) were 1. Leflunomide: serious hepatic, blood, skin described in two previous Adverse Drug and respiratory reactions Aust Adv Drug Reactions Bulletins (1, 2). In December Reactions Bull 2001; 20(2). 2006, 142 of the 699 reports with 2. Leflunomide and interstitial lung disease. leflunomide described respiratory symp- Aust Adv Drug Reactions Bull 2006; 25(6). toms including 22 of ILD. In June 2009, the number of leflunomide reports had 3. Arava, Arabloc (leflunomide) Product increased to 845, 196 of which describe Information. Sanofi-Aventis Australia Pty Ltd. respiratory symptoms including 39 of ILD. Of the 196 reports describing respiratory Isotretinoin and acquired symptoms, 78% described concomitant use of methotrexate; 23 of the 39 ILD hearing impairment reports involved this combination. Australia — Isotretinoin is a retinoid therapy indicated for the treatment of Although clinically variable, manifesta- severe cystic acne unresponsive to tions of drug-induced pulmonary toxicity conventional treatments. commonly include fever, cough (espe- cially dry and non-productive), dyspnoea, Isotretinoin therapy has been associated pleurisy, chest pain, hypoxaemia and/or with acquired hearing impairment in radiological evidence of pulmonary previously well individuals, although the infiltrates (usually diffuse and/or alveolar). mechanism/s have not been established. This should not be confused with con- New onset or worsening pulmonary genital hearing impairment, which is a symptoms with or without associated known potential complication following fever in those taking leflunomide with or fetal exposure to isotretinoin in-utero. without methotrexate may indicate development of leflunomide lung and The Therapeutic Goods Administration should prompt further investigation. (TGA) has received 609 adverse event reports for isotretinoin dating back to If ILD develops, discontinuation of these 1982. These include two cases of unilat- therapies and implementation of a wash- eral hearing loss, one case of hearing out with cholestyramine (as recom- loss at low frequencies and two cases of mended in the leflunomide Product tinnitus. Isotretinoin was the sole suspect Information) may be appropriate (3). in all five cases. The ages ranged from 14

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to 46 years of age and, where reported, whether hearing impairment is perma- duration of therapy ranged from 2Ð8 nent. If isotretinoin-associated auditory months. In all cases the outcomes were toxicity is suspected, the drug should be unknown. ceased and the patient referred for audiology assessment. Prescribers are reminded that isotretinoin has been associated with acquired Extracted from Australian Adverse Drug hearing impairment which can be unilat- Reactions Bulletin, Volume 28, Number 4, eral or bilateral. Symptoms may include August 2009 at http://www.tga.gov.au/adr/ tinnitus, impaired hearing at certain adrac-bulletin frequencies and deafness. It is unknown

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Pharmacovigilance Focus

Safety of medicinal products agreed that both core and supplementary indicators should be developed. The World Health Organization’s (WHO) Advisory Committee on Safety of Medici- A sub-group was assigned to continue nal Products (ACSoMP) meets regularly developing a set of practical indicators for to provide advice on current pharmaco- developing countries. These will be vigilance policy and issues related to the prepared in draft for presentation at the safety and effectiveness of medicinal annual meeting of National Pharmacovigi- products. The following summary cap- lance Centres to be held in Morocco in tures much of the discussion and recom- November 2009 and a final draft will be mendations from the Committee’s Sixth resubmitted to the next meeting of Meeting in 2009. ACSoMP in 2010.

Global awareness of medicines safety Guidelines for acute safety A CD-ROM is being prepared for those issues management interested in pharmacovigilance. A key This item dealt with the management of objective is to highlight the importance of acute safety issues by regulatory authori- risk-benefit assessment based on infor- ties. Major considerations focused on: mation available. It is hoped that the CD- ROM will further convince governments of ¥ evidence for decision-making after the cost-effectiveness of implementing a signal detection. pharmacovigilance system. ¥ analytical and methodological chal- Three phases are proposed as a frame- lenges. work for action. ¥ optimal design and organization of a ¥ social marketing. signal detection system. ¥ identifying a medium for disseminating ¥ signal detection and public health. messages. ¥ risk communication. ¥ creating social networking through patient participation. Several matters were discussed including how people in developing countries react Developing impact indicators when regulatory decisions are made in specific to pharmacovigilance developed countries which impact on Discussion on benchmarking and out- their work. Also what should constitute come assessment in pharmacovigilance the basis for decisions and how to pre- covered rationale for pharmacovigilance pare for any potentially embarrassing indicators, broad and specific objectives, public health crisis. characteristics, types of indicators, data sources and the process of developing Two associated issues were also consid- indicators. Structural indicators, process ered. The first was how and when to take indicators and outcome (impact) indica- action on an acute drug safety issue and tors were also reviewed and ACSoMP the second was how to communicate and

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share information once action has been organized in parallel with the next annual taken so that others can appreciate the meeting of National Pharmacovigilance underlying reasons. The need for devel- Centres to share common concerns and opment of a protocol was identified to objectives, and to facilitate collaboration help in dealing with acute safety issues in between IMSN and pharmacovigilance light of limitations in the WHO ICSR networks. (Individual Case Safety Reports) data- base in providing complete information. Collaboration with the Expert While WHO should provide leadership Committee on the Selection and guidance, national governments and and Use of Essential Medicines regional agencies need to take on local A comprehensive draft guideline on the roles and responsibilities. Confidentiality safety evaluation of medicines was agreements regarding information ex- presented, outlining the information change should be made by and among needed to accompany an application for all members of the WHO International inclusion or deletion of a medicine in the Drug Monitoring Programme rather than WHO Model List of Essential Medicines bilaterally or within specific regions. (EML). Members agreed that ACSoMP should General issues concerning safety evalua- design a protocol on how and when to tion requirements were discussed includ- take action on drug safety issues. How- ing sources of information, advice on the ever, when it comes to information handling of safety information, drug sharing between regulators, the appropri- administration, adverse drug reactions ate platform would be the International and references. Consideration was given Conference for Drug Regulatory Authori- to whether every new EML application ties (ICDRA). Consequently, a recom- should be accompanied by a risk man- mendation will be made to the planning agement plan for the medicine involved. committee for the 14th ICDRA to include In which case, risk management plans a session on information sharing between should cover any adverse drug reaction regulators. A guideline for the manage- already known to be associated with use ment of acute safety issues will be of a medicine. It was also suggested that prepared accordingly. cohort event monitoring studies should accompany the deployment of any new International network of safe medicine being proposed for mass medication practice centres administration in order to ensure that The International Medication Safety potential problems are quickly identified Network (IMSN) is a growing network of before patients are affected. countries that are working together to promote safe medication practices. The Current EML applications do not contain IMSN Group made a presentation on why sufficient information to provide an pharmacovigilance centres should be adequate safety evaluation. The concerned with medication error reports. safety component of most applications Medication errors are a system issue and passed to ACSoMP for assessment until involve different regulatory bodies. Since now meet neither the proposed guide- there may be reluctance to report medica- lines nor the current requirements. tion errors for fear of litigation and puni- Consequently, there is a need for applica- tive measures, there is a need to develop ble guidelines. strategies to encourage reporting. It was recommended that a training ACSoMP is willing to provide guidance workshop and/or group activity should be and leadership in the development and

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adoption of these guidelines. The princi- systems with a broad scope to respond to ples of the new guideline on safety questions covering several health areas. evaluation of products proposed for ACSoMP was requested to discuss inclusion in the EML should be complete, specific strategic components and help up-to-date, rigorous, and scientifically identify a core group to lead the develop- valid. These principles should be applica- ment. Consequently, a document will be ble to all safety assessments for the EML. drafted for circulation and comment by This proposal will be presented to the other ACSoMP members and presented next meeting of the WHO Expert Commit- at the annual meeting of National Phar- tee on the Selection and Use of Essential macovigilance Centres. Medicines. Leishmaniasis Public access to signals Safety monitoring of medicines used in A proposal was made to open the WHO the leishmaniasis elimination programme ICSR database to the public and provide in Bangladesh, India and Nepal was wider distribution of the signal document. described. The presentation included an In principle, opening the WHO database assessment of the risk of preventable to the public and consumers was sup- ADRs using surrogate markers, risk ported. However, it was agreed that the minimization through use of checklists of narrative section should remain hidden in precautions and contra-indications, use of order to protect patient confidentiality. It patient cards, training and supervision of was also noted that publication in the healthcare workers, analysis of ADRs, scientific media was a way of promoting and evaluation of pharmacovigilance pharmacovigilance activities spearheaded activity. There are serious safety con- by WHO and the Uppsala Monitoring cerns concerning miltefosine, a recently Centre (UMC). developed medicine which is effective in The Committee therefore agreed that it controlling the disease. In this respect, would be acceptable to provide informa- control programmes should work closely tion without narrative to academia to help with pharmacovigilance personnel to with research provided there is a declara- develop risk management and risk tion of interest and the usual caveats minimization plans. inserted. The proposal will be revised accordingly and presented at the next Chagas disease annual meeting of National Pharmacovigi- WHO activities in the area of Chagas lance Centres and the subject of making disease were presented. In 2007, WHO the signal document more available will and Bayer Healthcare agreed on distribut- be discussed further. ing 500 000 tablets of nifurtimox free of charge each year. Chagas disease, which Global strategy for best practice used to be encountered only in Latin in pharmacovigilance America, is now present in other regions The broad outline of a global strategy for of the world including Europe and the best practice in pharmacovigilance was Western Pacific. In 2008, for example, presented. It is part of the overall WHO around 150 patients were diagnosed in strategy for the next five years, with which Geneva, Switzerland, with Chagas the UMC four-year plan will be aligned. disease within a period of six months. The principal objectives will be to provide an advocacy tool for stakeholders, to Currently, there are two medicines avail- develop a plan for a health systems able for Chagas disease: nifurtimox and approach to pharmacovigilance and to benznidazole, both developed in the build cost-effective pharmacovigilance 1960s. In Bolivia, deaths have been

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reported in children following incorrect and oversight on all activities related to use of nifurtimox. WHO is assisting with vaccine safety and acts as an independ- the distribution of benznidazole and ent advisory committee to WHO. A nifurtimox, both of which are on the WHO member of ACSoMP serves on GACVS Essential Medicines List. to ensure collaboration and sharing of information. Even though nifurtimox and benznidazole were developed in the 1960s, available Malaria information on safety is limited. It is A presentation was made on the rationale important not only to implement pharma- and need for collaboration between covigilance but also to consider what kind malaria and medicines safety pro- of operational research needs to be grammes in WHO, challenges at country, implemented to ensure the collection, regional and global levels, and the way analysis and dissemination of safety forward to improving access to artemisi- information on these products to patients nin combination therapy (ACT). The move and healthcare providers. Further discus- to deregulate ACT to over the counter sion is necessary to determine optimal medicines as a way to improve treatment pharmacovigilance systems in these will involve home-based care. The way settings. forward will be to promote risk manage- ment plans, empower consumers, and Vaccines strengthen integration between pharma- A dedicated vaccine safety specialist has covigilance and public health pro- been appointed at the WHO Collaborating grammes. Centre for International Drug Monitoring (Uppsala Monitoring Centre) to strength- The Affordable Medicines Facility for en the signal detection process and Malaria (AMFm) aims to lower the net improve tools used for reporting vaccines. cost of ACTs and expand availability for Activities are being undertaken to ad- this treatment. The initiative should be dress key safety challenges with new accompanied by increased safety moni- vaccines, such as quality of safety data in toring for these medicines in all settings individual countries, capacity to respond and under all conditions of use. The first to crises, quality of data for signal detec- phase of the AMFm will be rolled out in tion and risk assessment at global level. eleven countries and will provide a Activities also include routine capacity challenge and an opportunity to develop strengthening, developing a global crisis pharmacovigilance systems and management plan and strengthening the strengthen those already existing. Global Network for Postmarketing Sur- veillance of Newly Prequalified Vaccines. Various initiatives run by different organi- The Network will provide data and sup- zations exist in the area of pharmacovigi- port to the WHO vaccine prequalification lance of antimalarials and tropical dis- system by generating data in the post- eases in general. These activities should marketing phase. be coordinated and members suggested that WHO should take a leading role in Other collaboration between the WHO coordinating these initiatives which vaccines and medicines safety depart- involve several different players. ments and the UMC includes develop- ACSoMP should be informed of all the ment of a vaccine dictionary (part of the safety studies being undertaken so that it WHO Drug Dictionary) and an ATC can provide independent scientific and classification for vaccines. The Global technical advice to WHO and Member Advisory Committee on Vaccine Safety States. Future WHO plans in this disease (GACVS) continues to provide support area include a meeting with the Medi-

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cines for Malaria Venture (MMV) and tries. Given the issues of co-morbidity other partners to develop a joint protocol and drug interactions, collaboration with and guidelines for the pharmacovigilance other programmes is important to ensure of antimalarials. Such joint meetings the safe use of ARVs. will ensure harmonization in safety monitoring. An ACSOMP member will Review of artesunate+amodiaquine assist WHO by coordinating various Based on a draft proposal for action, the ongoing initiatives in Africa. safety issues of artesunate+amodiaquine (ASAQ) were discussed. A meeting with HIV/AIDS DNDi and Sanofi-Aventis had resulted in A presentation was made on methods to a risk management plan for ASAQ. improve the safety of antiretroviral medi- Sanofi-Aventis is currently carrying out cines (ARVs) in public health use, phar- studies in Cote d’Ivoire on the real-life macovigilance for ARVs — including safety of this fixed dose combination. identifying gaps and needs — and a pilot Weaknesses in the study design were project for improving the safety of ARVs. identified and discussed by ACSoMP. Several groups are planning to undertake Different toxicities are expected of medi- active ASAQ pharmacovigilance but cines when used for post-exposure there are currently delays in engaging key prophylaxis of HIV and management of personnel and local associations. Safety patients with HIV/AIDS. As more and and use of concomitant medicines admin- more people stay on treatment, toxicities istered with ASAQ should also be studied. are becoming an important issue. Gap analysis has identified specific needs in ACSoMP members will review the risk ART programmes such as development management plans and offer suggestions of additional definitions and newer meth- to WHO. In addition, a consultant, cur- odologies for capturing data relating to rently reviewing some adverse events toxicity. Towards this, a pilot project that is reported with ASAQ will be requested to being funded by the Bill and Melinda outline the safety profile of ASAQ. Gates Foundation will establish interna- Pharmacovigilance and tionally agreed reporting tools, strengthen dependence inducing drugs pharmacovigilance capacity in selected Feedback on use of pharmacovigilance countries, support key studies, and data for the assessment of dependence coordinate the analysis of safety data on and abuse potential of drugs of depend- ARVs. ence has been generated through e-mail Switching of patients from a first to consultation. Conclusions point out that second-line regimen has huge cost pharmacovigilance is useful for evaluating implications. Safety data on ARVs is very drug dependence liability but that a limited regarding a second-line regimen. distinction should be made between For example, the pharmacokinetic effects ADRs from clinical trials and those made of protease inhibitors in children are little from spontaneous reporting. It was documented. It is particularly important to agreed that using defined daily doses learn the reasons why patients are (DDDs) provided the best assessment switched. Subjective reasons may domi- tool. Various drug classes should con- nate the switching of patients and this tinue to be dealt with separately. must be determined. A presentation on “opioids, safety surveil- ACSoMP agreed that guidelines on lance and risk management: elaborating management of adverse events and key challenges in the review of postmar- treatment limiting toxicities should be keting safety information on opioids in the developed and disseminated to all coun- USA” was made. Quantifying known

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adverse events including those which connectivity in Africa. Expected deliver- indicate abuse is very difficult. While ables include better access to informa- geographic clustering of abuse and tion, telemedicine, e-Learning, and abuse potential may occur, reporting disease surveillance. Since WHO’s practices are variable and many reports mandate does not include establishing focus on the active ingredient rather than internet infrastructure, a collaborative the finished product. agreement has been entered into with the International Telecommunications Union. Understanding prescribing decisions is Partnerships have also been set up with very hard in post-approval setting. The regional organizations, including the number of persons at risk is often un- African Union Commission through which known and information is not always funding is being sought. available in a timely manner. There are also several important factors that are Several initiatives are aimed at improving difficult to ascertain in spontaneous Internet infrastructure in Africa. One reports, including medication theft, over- initiative, the Telemedicine Task Force, use of prescribed medication, abuse/ involves the European Space Agency, the dependence/addiction, overdose, nonpre- European Union, African Union, WHO scription use, etc. It is also important to and others. This initiative proposes the understand the abuse potential of new use of satellite technology for e-health. formulations. Thus, definitions related to ACSoMP has requested updates on abuse potential should be broadened to progress and has proposed collaborating include non-opioids. The legal classifica- by communicating the usefulness of this tion for products is also an important project to management, policy makers, issue which needs attention. and donors.

Ethics in observational studies The WHO Medicines Safety team has A wider understanding of the importance proposed cooperation with Africa Health of ethical aspects of epidemiological and Infoway in the following ways. observational studies must be recognized globally. There are currently few docu- ¥ The pharmacovigilance programme ments discussing ethical review and tools VigiFlow and CEMFlow will be ethical applications in pharmacovigilance. incorporated into the AHI plan. The Council for International Organiza- tions of Medical Sciences (CIOMS) has ¥ A priority list of countries will be identi- recently published International Guide- fied for support by this initiative. lines for Ethical Review of Epidemiologi- cal Studies. ¥ Promotion of Africa Health Infoway will Ethical committee approval must be be made in all workshops. sought in all settings and in particular where there are vulnerable groups and Review of existing definitions populations. In preparing a study proto- Support is strong for a review of existing col, it is important to comply with national definitions in pharmacovigilance. This legislation and internationally approved topic was also discussed at the annual guidelines in order to ensure that studies meeting of National Pharmacovigilance are scientifically and ethically acceptable. Centres in 2008. Signals and adverse reactions/adverse events are top priori- Internet connectivity in Africa ties. During the past year, the CIOMS A WHO initiative Africa Health Infoway Working Group on Signal Detections has has been launched to improve internet been moving ahead with new definitions.

217 Pharmacovigilance Focus WHO Drug Information Vol 23, No. 3, 2009

ACSoMP was requested to provide Programme for International Drug Moni- guidance on WHO’s role in this activity. toring should prepare a set of definitions. A concept paper will be drafted for the ACSoMP agreed that WHO should take next annual meeting of National Pharma- this activity forward because it has the coviiglance Centres. mandate and capacity to coordinate activities for developing global norms and Reference: WHO Pharmaceuticals Newsletter standards. Led by ACSoMP, the WHO No. 3, 2009 at http://www.who.int/medicines

218 WHO Drug Information Vol 23, No. 3, 2009

Regulatory Action and News

Withdrawal of Bacterial forms of conjunctivitis are dextropropoxyphene common in childhood but can occur in people of any age. Symptoms of bacterial European Union — Finalizing a review conjunctivitis include red eyes, swelling, of the safety and efficacy of dextropro- eyelids sticking together, itching, watering poxyphene-containing medicines, the and a white or yellow sticky discharge European Medicines Agency (EMEA) from the eyes. Bacterial conjunctivitis is Committee for Medicinal Products for generally a condition that runs its course Human Use (CHMP) concluded that the in 7Ð14 days. risks, particularly the risk of potentially fatal overdose, are greater than the Patients using the drug in clinical trials benefits. The Committee therefore recom- had a faster rate of resolution of infection mended that the marketing authorizations than those treated with a solution contain- for these medicines be withdrawn across ing only a preservative. The drug was the European Union. The withdrawal will shown to be effective in treating patients be gradual to allow time for the safe age one year and older. transfer of patients to appropriate alterna- tive therapies, in line with national recom- Adverse events were reported in less mendations. than three percent of patients in clinical trials. Adverse reactions included redness Dextropropoxyphene is a painkiller used of the eyes, blurred vision, eye pain, to treat acute and chronic pain. It has irritation and itching, and headache. been available as a prescription-only medicine for about 40 years, either on its Reference: FDA News Release, 6 July 2009 own or in combination primarily with at http://www.fda.gov , as tablets, capsules, sup- positories and solutions for injection. Prasugrel: approved for The Agency’s recommendation has been angioplasty patients forwarded to the European Commission United States of America — The Food for the adoption of a legally binding and Drug Administration (FDA) has decision. approved the blood-thinning drug Reference: Press Release, Doc. Ref. EMEA/ prasugrel (Effient¨ tablets) to reduce risk 401062/2009. 25 June 2009 at http:// of blood clots forming in patients who www.emea.europa.eu/pdfs/human/opinion undergo angioplasty.

Besifloxacin: approved for During an angioplasty, a balloon is used to open the artery that has been nar- bacterial conjunctivitis rowed by atherosclerotic plaque.Often, a United States of America — The Food stent is inserted into the blood vessel to and Drug Administration (FDA) has help keep the artery open after the approved besifloxacin ophthalmic sus- procedure. Platelets in the blood can pension 0.6 percent (Besivance¨) for the clump around the procedure site, causing treatment of bacterial conjunctivitis (non- clots that may lead to heart attack, stroke, viral). and death.

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The fraction of patients who had subse- Alimta¨ was initially approved in 2004 for quent non-fatal heart attacks was re- the treatment of patients with mesothe- duced from 9.1% in patients who received lioma, a cancer frequently related to Plavix¨ to 7.0% in patients who received asbestos exposure. The drug was later Effient¨. While the numbers of deaths approved for the treatment of patients and strokes were similar with both drugs, with non-small cell lung cancer whose patients with a history of stroke were disease worsened on prior chemotherapy more likely to have another stroke while drugs and also as an initial therapy for taking Effient¨. In addition, there was a advanced non-small cell lung cancer. greater risk of significant, sometimes fatal bleeding seen in patients who took Reference: FDA News Release, 2 July 2009 Effient¨. at http://www.fda.gov The drug’s labeling will include a boxed Dronedarone: approved for warning alerting physicians that the drug can cause significant, sometimes fatal, heart rhythm disorder bleeding. United States of America — The Food Reference: FDA News Release, 10 July 2009 and Drug Administration (FDA) has at http://www.fda.gov approved dronedarone (Multaq¨) to help maintain normal heart rhythm in patients Pemetrexed: approved for with a history of atrial fibrillation or atrial flutter. The drug is approved for use in advanced lung cancer patients whose hearts have returned to United States of America — The Food normal rhythm or will undergo drug or and Drug Administration (FDA) has electric-shock treatment to restore a approved pemetrexed (Alimta¨), the first normal heart beat. drug available for maintenance therapy of advanced or metastatic lung cancer. Multaq¨ may cause critical adverse reactions, including death, in patients with Pemetrexed disrupts metabolic processes recent severe heart failure. The drug’s that are dependent on the B-vitamin label will contain a boxed warning cau- folate, a necessary ingredient for cell tioning that the drug should not be used replication. Non-small cell lung cancer in severe heart failure patients. has several subtypes, including squa- mous cell, large cell, adenocarcinoma In a multinational clinical trial with more and mixed histology cancers. In a 600- than 4600 patients, Multaq¨ reduced patient clinical trial, people with predomi- cardiovascular hospitalization or death nantly squamous cell cancer did not from any cause by 24%, when compared benefit from Alimta¨ but those with other with placebo. Most of that effect repre- subtypes of non-small lung cancer sents reduced hospitalizations, especially survived an average 15.5 months follow- those related to atrial fibrillation. ing treatment compared with 10.3 months for patients who received an inactive The most common adverse reactions substance (placebo). All patients in the reported by patients in clinical trials were study received standard medical care. diarrhoea, nausea, vomiting, fatigue and weakness. Reported adverse events included damage to blood cells, fatigue, nausea, Reference: FDA News Release, 2 July 2009 loss of appetite, tingling or numbness in at http://www.fda.gov the hands and feet, and skin rash.

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First advanced therapy draw an application for a centralized medicinal product approved marketing authorization for the medicine Factive¨ (gemifloxacin), 320 mg film- European Union — The European coated tablets. Factive¨ was expected to Medicines Agency (EMEA) has recom- be used for the treatment of bacterial mended the first marketing authorization infections causing mild to moderate for an advanced therapy medicinal community-acquired pneumonia and product following a positive opinion from acute exacerbation of chronic bronchitis. the Agency’s Committee for Advanced Therapies (CAT) and the Committee for At the time of the withdrawal, it was under Medicinal Products for Human Use review by the Agency’s Committee for (CHMP). The CAT, is a multidisciplinary Medicinal Products for Human Use committee that brings together experts in (CHMP). In its official letter, the company gene therapy, somatic cell therapy and stated that the withdrawal of the tissue engineering. application was based on the CHMP’s view that the data provided did not ChondroCelect¨ is a cell-based medicine allow the Committee to conclude on a that is used to repair defects in the positive benefit-risk balance. cartilage of the femoral condyle (the end of the thighbone) in the knee. It consists Reference: Press Release, Doc. Ref. EMEA/ 382408/2009. 23 June 2009 at http:// of chondrocytes (cartilage-forming cells) www.emea.europa.eu/ that are taken from a healthy region of the patient’s cartilage, grown outside the body, and then re-implanted during Saxagliptin approved surgery. for diabetes

This is the first product to benefit from the United States of America — The Food new legal and regulatory framework for and Drug Administration (FDA) has approved saxagliptin (Onglyza¨), a once- advanced therapy medicinal products (Regulation (EC) No. 1394/2007). This daily tablet to treat Type 2 diabetes in framework is designed to ensure the free adults. The medication is intended to be used with diet and exercise to control movement of advanced medicines within the European Union (EU), to facilitate high blood sugar levels. Saxagliptin is in a their access to the EU market, and to class of drugs known as dipeptidyl peptidase-4 (DPP-4) inhibitors which foster the competitiveness of European pharmaceutical companies in the field stimulate the pancreas to make more while guaranteeing the highest level of insulin after eating a meal. health protection for patients. The most common side effects observed Reference: Press Release, Doc. Ref. EMEA/ with saxagliptin are upper respiratory tract CHMP/394741/2009. 26 June 2009 at http:// infection, urinary tract infection, and www.emea.europa.eu/pdfs/human/opinion headache. Other side effects include allergic-like reactions such as rash and Gemifloxacin: withdrawal of hives. marketing authorization Approval of Onglyza¨ was primarily application based on the results of eight clinical trials. The application seeking FDA approval European Union — The European was submitted before December 2008 Medicines Agency (EMEA) has been when the agency recommended that formally notified of the decision to with- manufacturers of new diabetes drugs

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carefully design and evaluate their clinical Union will then be able to prescribe trials for cardiovascular safety. Although Neupro¨ to all patients in accordance saxagliptin was not associated with an with the approved product information. increased risk for cardiovascular events Prescriptions will no longer be limited to in patients who were mainly at low risk for one month. these events, the FDA is requiring a postmarket study that will specifically Rotigotine transdermal patch is currently evaluate cardiovascular safety in a higher indicated for the treatment of Parkinson risk population. disease and restless legs syndrome. It is applied as transdermal patches that Reference: FDA News Release, 31 July 2009 deliver the active substance, rotigotine, at http://fda.hhs.gov across the skin.

Contusugene ladenovec: At its May 2008 meeting, the Agency’s Committee for Medicinal Products for withdrawal of application for Human Use (CHMP) recommended marketing immediate changes to the storage condi- tions for Neupro following reports of European Union — The European crystallisation of the active substance in Medicines Agency (EMEA) has been some patches. The recommendations formally notified by the manufacturer of included the requirement that the medi- the decision to withdraw its application for cine be stored in a refrigerator at a a centralized marketing authorization for temperature of between 2 and 8 C. the medicine contusugene ladenovec ° (Contususgene ladenovec Gendux¨) Following assessment of the cold-chain suspension for injection expected to be system that has been put in place by the used for the treatment of squamous cell company, the CHMP is now re-assured carcinoma in head and neck cancer. that no significant crystallisation should occur under these storage conditions and In its official letter, the company stated that Neupro¨ supplied to patients now that the withdrawal of the application was meets the required quality standards. based on the difficult financial situation of its parent company which prohibits them Reference: Press Release, Doc. Ref. EMEA/ to fund further activities related to this CHMP/322964/2009. 29 May 2009 application. Reference: Press Release, Doc. Ref. EMEA/ Impact of European Clinical 412751/2009. 23 July 2009 at http:// Trials Directive www.emea.europa.eu The Impact on Clinical Research of Rotigotine transdermal patch: European Legislation Project (ICREL) restrictions lifted was a one-year project financed by the European 7th Framework Programme European Union — The European and coordinated by the European Forum Medicines Agency has recommended that for Good Clinical Practice (EFGCP). The the supply and treatment restrictions for European Clinical research Infrastruc- rotigotine transdermal patch (Neupro¨), tures Network (ECRIN), the European be lifted. Once this recommendation is Organization for research and Treatment endorsed by the European Commission, of Cancer (EORTC), as well as the the ban on prescribing Neupro¨ to Hospital Clínic of Barcelona and the patients not yet taking the medicine will Ethics Committee of the Medical Univer- be reversed. Doctors in the European sity of Vienna collaborated in this project.

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Its aim was to measure and analyse the using marketed drugs or applying mini- direct and indirect impact of the Clinical mally invasive procedures. Academic Trials Directive 2001/20/EC and related institutions and industry, including SMEs, legislations in the EU on all categories of face major difficulties in fulfilling sponsor clinical research and on the different responsibilities. stakeholders: commercial and non- commercial sponsors, ethics committees The Clinical Trials Directive objectives and competent authorities. This initiative were transposed into divergent national responds to the need to adapt the current legislations, partly missing the harmoniza- legislation and will help determine the tion goal and making multinational trials, most relevant pathways for improvement. in particular, difficult to perform. This could raise doubts about the competitive- Directive 2001/20/EC was adopted with ness and attractiveness of the EU for the objective of harmonizing the EU clinical research. The ICREL project was regulatory environment for clinical re- designed to measure the impact of the search, improving the protection of current EU legislation, analysing its direct participants, optimizing the use of safety and indirect consequences. information, and ensuring the credibility of data through strengthened responsibility In order to reach a maximum of informa- of the sponsors and harmonized trial tion, a survey was conducted. The first authorization procedures for Member results of this survey were presented and States. discussed during a conference in Brus- sels in December 2008. Conclusions of However, this legislation only protects the meeting are presented in a final report participants in clinical trials on medicinal which has been published by the Euro- products. It requires almost similar pean Commission. procedures for all types of clinical trials with medicinal products from registration Reference: European Forum for Good Clinical studies on innovative treatments to Practice (EFGCP) at http://www.efgcp.be/ ICREL/ studies comparing treatment strategies WHO list of recently prequalified medicinal products The following products have recently been added to the list of prequalified products by the WHO Prequalification of Medicines Programme. (http://www.who.int/prequal). This additional list covers the period 1 January 2009 to 2 July 2009.

Product Presentation Manufacturer

Abacavir(as sulfate) Tablets 60mg Matrix Laboratories +Lamivudine+Zidovudine +30mg+60mg Sinnar, Maharashtra,India

Ciprofloxacin Infusion 2mg/ml Claris Life Sciences Ahmedabad, Gujarat, India

Efavirenz Tablets 200mg Strides Arcolab, Bangalore, India

Efavirenz Tablets 600mg Strides Arcolab, Bangalore, India

Efavirenz Tablets 600mg Hetero Drugs, Hyderabad, India

Continued ...

223 Regulatory Action and News WHO Drug Information Vol 23, No. 3, 2009

WHO list of recently prequalified medicinal products (Continued)

Product Presentation Manufacturer

Lamivudine Film-coated tablets Cipla +Nevirapine+Zidovudine 150mg+200mg+300mg Goa, India Lamivudine Tablets 150mg Matrix Laboratories +Nevirapine+Zidovudine +200mg+300mg Sinnar, Maharashtra, India Lamivudine Tablets Aurobindo Pharma +Stavudine 150mg+30mg Hyderabad, India Lamivudine Tablets Aurobindo Pharma +Stavudine 150mg+40mg Hyderabad, India Lopinavir Tablets Matrix Laboratories +Ritonavir 200mg+50mg Sinnar, Maharashtra, India

Lopinavir Tablets Matrix Laboratories +Ritonavir 100mg+25mg Sinnar, Maharashtra, India

Lamivudine Tablets Matrix Laboratories +Zidovudine 30mg+60mg Andhra Pradesh, India

Nevirapine Oral susp. 50mg/5ml Cipla, Unit-1, Goa India

Tenofovir Tablets 300mg Cipla, Goa, India disoproxil fumarate

Oseltamivir Capsules 75mg Cipla, Goa, India (as phosphate)

Artemether Tablets Cipla, Patalganga, +Lumefantrine 20mg+120mg India

Artemether Dispersible Tablets Novartis Pharma +Lumefantrine 20mg+120mg Suffern, USA

Ethinylestradiol Tablets Bayer Schering Pharma +Levonorgestrel 30µg+150µgWeimar, Germany

Levonorgestrel Tablets 30µg Bayer Schering, Weimar, Germany

Cycloserine Capsules 250mg Aspen Pharmacare Port Elizabeth, South Africa

Isoniazid Tablets Macleods Pharmaceuticals +Pyrazinamide+Rifampicin 30mg+150mg+60mg Kachigam, Daman, India

Rifampicin Tablets Macleods Pharmaceuticals +Isoniazid 60mg+30mg Kachigam, Daman, India

Pyrazinamide Tablets 400mg Micro Labs, Hosur, Tamilnadu, India

Pyrazinamide Tablets 500mg Micro Labs, Hosur, Tamilnadu, India

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Current Topics

Forum on international (www.who.int/impact/en/). IMPACT is pharmaceutical crime aimed at combating counterfeit medicines in countries with a high proportion of The Permanent Forum on International counterfeit products but with insufficient Pharmaceutical Crime (PFIPC) com- enforcement facilities of their own. Many prises members from 15 countries experts from the PFIPC work in interna- throughout the world: Australia, Belgium, tional organizations and promote global Canada, Germany, Ireland, Israel, Italy, collaboration. Netherlands, New Zealand, Singapore, South Africa, Spain, Switzerland, United Experts from ILFCM international control Kingdom and United States of America. laboratories in 10 countries met in parallel Members come from both pharmaceutical to this conference to exchange experi- regulatory and law enforcement compo- ences. The meeting featured presenta- nents of member countries with the tions on new technological developments objective of combating worldwide phar- in the analysis of counterfeit pharmaceuti- maceutical crime. cals and focused on tracking new illegal products. These medicines, which are International Conference on mainly sold over the Internet without any Pharmaceutical Crime correct indication of ingredients often The Swiss Agency for Therapeutic contain new active substances of largely Products, Swissmedic, as a member of unknown effect and which may be haz- PFIPC and the International Laboratory ardous when ingested by humans. Forum on Counterfeit Medicines (ILFCM) has organized the annual conference Discussions in both conferences showed for these two organizations in Bern from once again that repeated published 8Ð12 June 2009. warnings about purchasing pharmaceuti- cals from illegal sources, especially over A total of 33 delegates from 18 countries the Internet, are justified. International attended the conference. Participants pharmaceutical crime is on the increase included enforcement experts and repre- and illegally sold medicines are a major sentatives from international organiza- risk to the health of the general public. tions that work to fight against pharma- ceutical crime. The conference enabled Reference: http://www.swissmedic.ch/aktuell/ delegates to exchange experience and information about trends and activities and develop joint projects to improve Illegal online medicine international collaboration. Particular suppliers targeted emphasis was placed on preparing The first international Internet day of coordinated action against illegal Internet action co-coordinated by the Permanent trade in therapeutic products. Forum on International Pharmaceutical The PFIPC also supports the work of the Crime (PFIPC), INTERPOL and the International Medical Products Anti- International Medical Products Anti- Counterfeiting Taskforce (IMPACT), an Counterfeiting Taskforce (IMPACT), has initiative of the World Health Organization targeted illegal online sale of medicines to

225 Current Topics WHO Drug Information Vol 23, No. 3, 2009

the public. This action has resulted in a Tropical Diseases. Onchocerciasis often series of arrests and the seizure of blinds people, as well as causing potentially harmful medicines in opera- debilitating skin disease. Over 37 million tions carried out around the world. people are infected, often living in poor, Codenamed Pangea, the operation rural African communities. The multi- focused on those individuals behind country study showed that treatment with Internet sites which illegally sell and stopped further infections and supply unlicensed or prescription-only transmission in three specific endemic medicines claiming to treat a range of areas in Africa. ailments. Ivermectin kills the larvae but not the While many countries have previously adult worms of Onchocerca volvulus, the carried out individual law enforcement parasite that causes the disease, so activities targeting ‘Internet pharmacies’, annual or biannual treatments are re- Operation Pangea was the first time that quired to prevent resurgence. Donations action was taken on an international of the drug by the manufacturer to coun- scale, with participating countries. (Aus- tries where onchocerciasis is endemic tralia, Canada, Germany, Ireland, Israel, have resulted in annual treatments to all New Zealand, Singapore, Switzerland, eligible community members — over 60 United Kingdom and United States of million people in 26 African countries in America.) 2008.

Locations in each country were identified, This new study in three areas in Mali and with investigators visiting residential and Senegal where onchocerciasis was commercial addresses relating to Internet endemic has provided the first evidence sites believed to be selling unlicensed or of the feasibility of onchocerciasis elimi- prescription-only medicines claiming to nation with ivermectin in endemic areas treat many conditions such as diabetes, in Africa. The studies showed that after obesity or hair loss. 15 to 17 years of six-monthly or annual treatments, only a few infections re- Investigations in a number of countries mained in the human population and are still ongoing, with the final results transmission levels were below predicted from Operation Pangea to be released thresholds for elimination. upon their conclusion. For more informa- tion on individual activities and opera- References: tions, please contact the national enforce- 1. News on UNICEF/UNDP/WorldBank/WHO- ment agencies in the countries con- TDR http://www.who.int/tdr/svc/news-events cerned. 2. Full article available at http://www. Reference: Illegal online medicine suppliers plosntds.org/article/info%3Adoi%2F10. targeted in first international Internet day of 1371%2Fjournal.pntd.0000 497 action. Interpol media release. http:// www.interpol.int 3. TDR press release, 21 July 2009 http://www.who.int/tdr/svc/news-events/news/ Elimination of river blindness onchocerciasis-elimination in Mali and Senegal Moxidectin for river blindness The first evidence that onchocerciasis in phase III clinical trials elimination is feasible with ivermectin treatment has been published in the A clinical trial is being launched in three open-access journal PLoS Neglected African countries of a medicine that could

226 WHO Drug Information Vol 23, No. 3, 2009 Current Topics

speed up elimination of onchocerciasis, have been provided with necessary one of the leading infectious causes of equipment and the research teams blindness across Africa. The medicine, trained on how to conduct the trial ac- moxidectin, is being investigated for its cording to international standards. potential to kill or sterilize the adult worms of Onchocer-ca volvulus which cause The trial will take place over the next two onchocerciasis. and a half years. Currently, the disease is controlled by ivermectin which has been Onchocerciasis, also called river blind- donated for more than twenty years by ness, is transmitted by the blackfly which the pharmaceutical company Merck & Co. breeds in fast flowing rivers. Blindness is Inc. for use in onchocerciasis endemic the most incapacitating symptom of the countries. Treatment with ivermectin has disease which also causes debilitating enabled significant progress in the control skin disease. of onchocerciasis, and currently reaches more than 60 million people in Africa The development of moxidectin for annually. However, ivermectin kills the onchocerciasis is being conducted O. volvulus larvae but not the adult through a collaboration of the Special worms, so annual treatments for an Programme for Research and Training in extended period of time (at least 11Ð14 Tropical Diseases, which is executed by years) are required to ensure disease the World Health Organization (WHO/ control. TDR), and Wyeth Pharmaceuticals. The work ranges from the development of a If moxidectin kills not only the larvae but formulation for human use and initial also sterilizes or kills the adult worms, it studies in healthy volunteers, to clinical has the potential to interrupt the disease studies and community studies in Africa. transmission cycle within around six annual rounds of treatment. The medicine WHO/TDR, working in partnership with could be distributed through community- African investigators and institutions, is directed mechanisms set up in collabora- building capacity and managing the tion among APOC, African control pro- conduct of clinical trials conducted in grammes, and NGOs for the distribution Africa. If the development is successful of ivermectin. and results in a positive scientific opinion from the European Medicines Evaluation Reference: World Health Organization. Agency (EMEA), the manufacturer will Moxidectin could dramatically speed up request approval by national regulatory elimination of disease across Africa. Press authorities in the countries where on- release, 1 July 2009 at http://apps.who.int/tdr/ chocerciasis is endemic. svc/news-events/news/phase3-trial-moxidectin In conducting this trial, TDR will be Malaria: evaluation of rapid working with African investigators and diagnostic tests institutions. Fifteen hundred people at four sites in Ghana, Liberia and the The largest-ever independent, laboratory- Democratic Republic of Congo will be based evaluation of rapid diagnostic tests enrolled in the study. Preparation has (RDTs) for malaria has shown that some been ongoing since 2007 and included tests on the market perform exceptionally building a clinical research centre in Lofa well in tropical temperatures and can County, Liberia, and in Nord-Kivu in the detect even low parasite densities in Democratic Republic of Congo (DRC). blood samples, while other tests were Buildings not used since the war in Ituri, only able to detect the parasite at high DRC, have been renovated. All centres parasite densities.

227 Current Topics WHO Drug Information Vol 23, No. 3, 2009

The evaluation was co-sponsored by the densities, have low false-positive rates, WHO Regional Office for the Western are stable at tropical temperatures, are Pacific (WPRO), WHO-based Special relatively easy to use, and can detect Programme for Research and Training in P. falciparum, P. vivax infections, or Tropical Diseases (TDR) and the Founda- both. tion for Innovative New Diagnostics (FIND). Testing was performed at the US ¥ Performance between products varied Centers for Disease Control and Preven- widely at low parasite density (200 tion (CDC). Forty-one commercially parasites/microlitre); however, most available RDTs went through a blinded products showed a high level of detec- laboratory evaluation. tion at 2000 to 5000 parasites/microlitre.

The findings will serve as a tool for ¥ P. falciparum tests targeting the histidine countries to make informed choices from rich protein 2 (HRP2) demon- among the dozens of tests commercially strated the highest detection rates, but available and on the purchase and use of some tests targeting Plasmodium rapid diagnostics that are best suited to lactate dehydrogenase (pLDH) also local conditions. This performance evalu- exhibited high detection rates. ation will also inform procurement and ¥ Test performance varied between lots, prioritization for diagnostic test entry into and widely between similar products, the WHO Prequalification Diagnostics confirming the advisability of lot testing Programme and WHO Procurement post-purchase and prior to use in the Schemes. Donor agencies also regularly field. refer to WHO recommendations on diagnostics when making their own ¥ The results highlight the need for purchases. manufacturers to have adequate refer- ence materials for product development In addition to product testing FIND , TDR and lot-release. The WHO-FIND Malaria and WHO have also collaborated to esta- RDT Evaluation Programme, in collabo- blish procedures and quality assured ration with the CDC, will soon offer facilities for routine lot testing of rapid quality standard panels to manufactur- diagnostics in Asia and Africa. Evaluation ers to assist in this process. of malaria diagnostic tests by WHO and partners has found variation in test A second round of performance evalua- performance. tions for 29 products is currently being During the evaluation, samples of blood carried out by TDR, FIND and CDC, with from patients infected with P. falciparum results due to be published in 2010. An and P. vivax in diverse geographic executive summary of findings along locations were diluted to achieve both a with the detailed evaluation of test per- low parasite density and high parasite formance results are provided in the densities . At low parasite density, sam- report available online at http:// ples were tested against two rapid tests www.who.int/tdr. per lot (2 lots) and at high parasite density samples were tested against one References rapid test per lot (2 lots). 1. Special Programme for Research & Train- ing in Tropical Diseases (TDR). News Re- Conclusions from the findings: lease, 24 April 2009 at http://www.who.int/tdr

¥ Several RDTs demonstrated consistent 2. Foundation for Innovative New Diagnostics detection of malaria at low parasite (FIND) at http://www.finddiagnostics.org

228 WHO Drug Information Vol 23, No. 3, 2009

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 Statis- tics Methodology, 24 March 2009. Comments or objections to the decisions 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 2010 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 level): Agents for atopic dermatitis, excluding corticosteroids D11AH Angiotensin II antagonists, other combinations C09DX Other blood products B05AX Other throat preparations R02AX

New ATC 5th level codes: alfuzosin and finasteride G04CA51 alogliptin A10BH04 bendamustine L01AA09 biapenem J01DH05 bisoprolol, combinations C07AB57 blood plasma B05AX03 canakinumab L04AC08 carisbamate N03AX19 cefozopran J01DE03 cholic acid A05AA03 dapoxetine G04BX14 denosumab M05BX04 erythrocytes B05AX01 fluoromethylcholine (18F) V09IX07 flurbiprofen R02AX01 indacaterol R03AC18 iodine (124I) 2beta-carbo- methoxy-3beta-(4iodo- phenyl)- V09AX02 maribavir J05AX10 nomegestrol and G03AA14 ofatumumab L01XC10

229 ATC/DDD Classification WHO Drug Information Vol 23, No. 3, 2009

ATC level INN/Common name ATC code

S02AA16 pioglitazone and alogliptin A10BD09 prasugrel B01AC22 pravastatin and fenofibrate C10BA03 sodium iodide (124I) V09FX04 stem cells from umbilical cord blood B05AX04 tapentadol N02AX06 telmisartan and amlodipine C09DB04 thrombocytes B05AX02 valsartan, amlodipine and hydrochlorothiazide C09DX01 valsartan and aliskiren C09DX02

INN/Common name Previous ATC code New ATC code

ATC code changes: cromoglicic acid D11AX17 D11AH03 pimecrolimus D11AX15 D11AH02 tacrolimus D11AX14 D11AH01

Previous name New name New ATC code

ATC name changes: hydroxybutyric acid N01AX11 hydroxybutyric acid sodium oxybate N07XX04

New DDDs:

INN/common name DDD Unit Adm.R ATC code

alitretinoin 20 mg O D11AX19 biapenem 1.2 g P J01DH05 cefozopran 4 g P J01DE03 dapoxetine 30 mg O G04BX14 degarelix 2.7 mg P L02BX02 etravirine 0.4 g O J05AG04 flurbiprofen 44 mg O R02AX01 lacosamide 0.3 g O,P N03AX18 prasugrel 10 mg O B01AC22 rivaroxaban 10 mg O B01AX06 ustekinumab 0.54 mg P L04AC05

230 WHO Drug Information Vol 23, No. 3, 2009

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 Sta- tistics Methodology in October 2008. They will be included in the January 2010 issue of the ATC index. The inclusion of a substance in the lists does not imply any recom- mendation 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 level): Peripheral antagonists A06AH

New ATC 5th level codes: aciclovir, combinations D06BB53 alvimopan A06AH02 asenapine N05AH05 bacitracin J01XX10 bazedoxifene G03XC02 becaplermin A01AD08 benzethonium chloride D08AJ08 bromfenac S01BC11 casopitant A04AD13 cefcapene J01DD17 cevimeline N07AX03 cilostazol C04AX33 corifollitropin alfa G03GA09 dalbavancin J01XA04 dapsone D10AX05 N06BA11 doxercalciferol H05BX03 eltrombopag B02BX05 eperisone M03BX09 L01XE10 fluocinolone acetonide S02BA08 golimumab L04AB06 iclaprim J01EA03 , amoxicillin and clarithromycin A02BD0 lisinopril and amlodipine C09BB03

231 ATC/DDD Classification WHO Drug Information Vol 23, No. 3, 2009

ATC level INN/Common name ATC code

meningococcus, tetravalent purified polysaccharide antigen conjugated J07AH08 meptazinol N02AX05 methylnaltrexone A06AH01 mitiglinide A10BX08 nabiximols N02BG10 nalfurafine V03AX01 oritavancin J01XA05 pazopanib L01XE11 pegloticase M04AX02 phenazone S02DA03 potassium acetate B05XA17 pralatrexate L01BA05 regadenoson C01EB21 saxagliptin A10BH03 silodosin G04CA04 sodium fluoride (18F) V09IX06 sodium levofolinate V03AF10 stavudine, lamivudine and nevirapine J05AR07

tamsulosin and dutasteride G04CA52 vinflunine L01CA05

INN/Common name Previous ATC code New ATC code

ATC code changes: N05AX09 N05AH06 paricalcitol A11CC07 H05BX02

* Please note that the changes will not be implemented before January 2010

Previous name New name New ATC code

ATC name changes:

Diazepines, oxazepines and Diazepines, oxazepines, thiazepines thiazepines and oxepines N05AH

232 WHO Drug Information Vol 23, No. 3, 2009 ATC/DDD Classification

New DDDs:

INN/common name DDD Unit Adm.R ATC code

cefcapene 0.45 g O J01DD17 cefotiam 1.2 g O J01DC07 cevimeline 90 mg O N07AX03 cilostazol 0.2 g O C04AX33 dabigatran etexilate 0.22 g O B01AE07 doripenem 1.5 g P J01DH04 eperisone 0.15 g O M03BX09 febuxostat 80 mg O M04AA03 30 mg P C01EB19 meptazinol 1.2 g O,P N02AX05 methylnaltrexone 6 mg P A06AH01 bromide micafungin 0.1 g P J02AX05 mitiglinide 30 mg O A10BX08 polymyxin B 3 MU O A07AA05 rilonacept 23 mg P L04AC04 romiplostim 30 mcg P B02BX04 sodium levofolinate 30 mg1) P V03AF10 tafluprost 0.3 ml2) S01EE05

(1) Expressed as levofolinic acid (2) Single dose package

Change of DDDs

INN/common name Previous DDD New temporary DDD ATC Code

Risperidone* 1.8 mg P depot 2.7 mg P depot N05AX08

* Please note that the changes will not be implemented before January 2010

233 WHO Drug Information Vol 23, No. 3, 2009 Recent Publications, Information and Events

Good clinical laboratory diagnostic tools for tuberculosis control practices describes 19 new or improved diagnostic tools from many initiatives under way In 2006, WHO/TDR convened a meeting worldwide. Three of the tools described in of organizations engaged in clinical trials this document have already been en- in disease endemic countries to discuss dorsed by WHO and are being imple- the applicability of Good clinical labora- mented by countries, while others are still tory practices (GCLP) guidelines to their under development or in the pilot phase work. It was agreed that GCLP would be and expected to be ready for use in the a valuable tool for improving quality coming years. laboratory practice. In line with that agreement, WHO/TDR recently acquired The brochure stands in as an interim copyright to GCLP guidelines that were document until a more complete blueprint originally published in 2003 by a working of current R&D efforts can be developed. party of the Clinical Committee of the The purpose is not to recommend specific British Association of Research Quality tools, but rather to provide summary Assurance (BARQA), with the aim of information about tools being developed disseminating them widely in developing and becoming available so that all who countries and developing related training play a part in TB control, especially in materials. Compliance with GCLP guide- national TB programmes, can make well- lines will allow clinical laboratories to informed decisions when retooling. ensure that safety and efficacy data is repeatable, reliable, auditable and easily Reference: Stop TB Partnership: Retooling reconstructed in a research setting. Task Force and New Diagnostic Working Additionally, GCLP guidelines set a Group at http://apps.who.int/tdr/svc/publica- standard for compliance by laboratories tions/non-tdr-publications/diagnostic-tool-tb involved in the analysis of samples from TDR-supported clinical trials. WorldPharma2010: clinical pharmacology Reference: Special Programme for Research & Training in Tropical Diseases (TDR). Good The 16th World Congress on Basic and Clinical Laboratory Practice (GCLP). DOI: Clinical Pharmacology will be held from 10.2471/TDR.09.978-924-1597852. 13 March 17Ð23 July 2010 in Copenhagen, Den- 2009 at http://www.who.int/tdr mark

Laboratory diagnostic tools The WorldPharma2010 event will include for tuberculosis control a two-day focused conference on Clinical pharmacology in emerging countries. There is currently a lack of information Other sessions will include: available to national tuberculosis pro- grammes and funding and technical ¥ Addiction and doping: neurobiological agencies on new TB diagnostic tools and clinical basis of emerging treat- under development and in implementa- ments. tion. With this in mind, New laboratory

234 WHO Drug Information Vol 23, No. 3, 2009 Recent Publications, Information and Events

¥ Developments in treatment of sexual Ethical guidelines for dysfunction and diseases of the lower epidemiology urinary tract. The newly published and revised CIOMS ¥ Drugs for half the world: paediatric International Ethical Guidelines for clinical pharmacology. Epidemiological Studies are intended to draw the attention of investigators, ¥ Endothelium in health and disease. sponsors and ethical review committees to the need to consider carefully the ¥G protein-coupled 7TM receptors: from ethical implications of research protocols molecular to physiological function. and the manner in which research is conducted in order to attain high scientific ¥ Inflammation and immunopharmac- and ethical standards in epidemiological ology: new tools for old diseases. studies and research.

¥ Ion channelopathies: new windows on Reference: Council for International organiza- complex disease and therapy. tions of Medical Sciences (CIOMS) at http:// www.cioms.ch ¥ Ion channels in analgesia and anaes- thesia. Dengue: evaluation of immunoglobulin M tests ¥ Maximizing benefits and minimizing harm from drugs. Dengue infection can produce a broad spectrum of symptoms and range from ¥ Natural products: past and future? mild febrile illness to severe disease. Clinical features are often nonspecific and ¥ New approaches and targets in psychia- therefore require laboratory confirmation. try. Accurate but sophisticated methods, including isolation or polymerase ¥ Nuclear receptor targets for treatment of chain reaction (PCR), require advanced diseases. equipment and infrastructure.

¥ Pharmacoepidemiology, current contro- Serological assays that can detect versies and opportunities. specific immunoglobulin M (IgM) or immunoglobulin G (IgG) antibodies to ¥ Simulation and data modelling in drug dengue virus are widely available. These development. Better drugs faster? assays can provide an alternative to virus isolation or PCR to support the diagnosis ¥ The heart gone wrong; stabilization of of dengue fever. First-time (primary) cardiac function. dengue virus infections typically have a stronger and more specific IgM response ¥ Translational science in the metabolic and subsequent (secondary) infections syndrome. show a weaker IgM response but a strong IgG response. These differing IgM res- ¥ Transmembrane transport: perspec- ponse patterns to infection underscore tives for disease and drug discovery. the need to evaluate the sensitivity and specificity of commercially available tests, Reference: http://www.WorldPharma2010.org especially for diagnosis of secondary dengue virus infections.

235 Recent Publications, Information and Events WHO Drug Information Vol 23, No. 3, 2009

WHO/TDR and the Paediatric Dengue However, numerous concerns have been Vaccine Initiative have collaborated to raised about the relationship between evaluate commercially available anti- healthcare professionals and the pharma- dengue virus IgM diagnostic tests. A ceutical industry — particularly the network of seven laboratories in Asia and industry’s influence on prescribing and Latin America has been established to dispensing decisions. This influence can carry out the work. Evaluation of commer- lead to less than optimal treatment cially available anti-dengue virus immu- choices and can even be detrimental to noglobulin M tests describes the results patient health. of an evaluation of nine commercially available anti-dengue virus IgM tests, Research shows that while in training, using a panel of well-characterized, many healthcare professionals receive archived serum specimens from patients little or no instruction on how to assess with confirmed dengue virus infections pharmaceutical promotion and how to and from patients with other potentially understand its often subtle influence on confounding infections and conditions. their behaviour. In response, WHO and Health Action International (HAI) have Reference: World Health Organization developed a new publication: Under- Special Programme for Research & Training in standing and Responding to Pharmaceu- Tropical Diseases (TDR). Evaluation of tical Promotion Ð A Practical Guide. This commercially available anti-dengue virus draft manual can assist educators and immunoglobulin M tests. Diagnostics Evalua- tion Series No. 3. at http://www.who.int/tdr healthcare professionals in teaching medical and pharmacy students about pharmaceutical promotion. WHO/HAI student manual on pharmaceutical promotion Reference: World Health Organization at http://www.who.int/medicines and Health Medicines are a vital part of improving Action International at http://www.haiweb.org and maintaining health. Healthcare professionals, such as doctors and pharmacists, play a key role in ensuring that medicines are prescribed and used rationally.

WHO Drug Information is also available online at http://www.who.int/druginformation

WHO Drug Information DIGITAL LIBRARY with search facility at http://www.who.int/druginformation

Subscribe to our e-mail service and receive the table of contents of the latest WHO Drug Information (To subscribe: send a message to [email protected] containing the text: subscribe druginformation)

236 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

International Nonproprietary Names for Pharmaceutical Substances (INN)

RECOMMENDED International Nonproprietary Names: List 62

Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances [Off. Rec. Wld Health Org., 1955, 60, 3 (Resolution EB15.R7); 1969, 173, 10 (Resolution EB43.R9); Resolution EB115.R4 (EB115/2005/REC/1)], the following names are selected as Recommended International Nonproprietary Names. The inclusion of a name in the lists of Recommended International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy. Lists of Proposed (1–96) 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 62

Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org. mond. Santé, 1955, 60, 3 (résolution EB15.R7); 1969, 173, 10 (résolution EB43.R9); Résolution EB115.R4 (EB115/2005/REC/1)] les dénominations ci-dessous sont choisies par l’Organisation mondiale de la Santé en tant que dénominations communes internationales recommandées. L’inclusion d’une dénomination dans les listes de DCI recommandées n’implique aucune recommandation en vue de l’utilisation de la substance correspondante en médecine ou en pharmacie. On trouvera d’autres listes de Dénominations communes internationales proposées (1–96) 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 62

De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (Resolución EB15.R7); 1969, 173, 10 (Resolución EB43.R9); Resolución EB115.R4 (EB115/2005/REC/1)], se comunica por el presente anuncio que las denominaciones que a continuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas. La inclusión de una denominación en las listas de las Denominaciones Comunes Recomendadas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia. Las listas de Denominaciones Comunes Internacionales Propuestas (1–96) y Recomendadas (1–57) se encuentran reunidas en Cumulative List No. 12, 2007 (disponible sólo en CD-ROM).

237 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

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

adarotenum adarotene (2E)-3-[3'-(adamantan-1-yl)-4'-hydroxy-1,1'-biphenyl-4-yl]prop- 2-enoic acid

adarotène acide (2E)-3-[4'-hydroxy-3'-(adamantan-1-yl)biphényl-4-yl]prop- 2-énoïque

adaroteno ácido 3-[3'-(adamantan-1-il)-4'-hidroxi-1,1'-bifenil-4-il]prop-2-enoico

C25H26O3

HO

CO2H

afamelanotidum afamelanotide N-acetyl-L-serinyl-L-tyrosyl-L-seryl-(2S)-2-aminohexanoyl-L-glutamyl- L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanylglycyl-L-lysyl- L-prolyl-L-valinamide

afamélanotide N-acétyl-L-sérinyl-L-tyrosyl-L-séryl-(2S)-2-aminohexanoyl-L-glutamyl- L-histidyl-D-phénylalanyl-L-arginyl-L-tryptophanylglycyl-L-lysyl- L-prolyl-L-valinamide

afamelanotida N-acetil-L-serinil-L-tirosil-L-seril-(2S)-2-aminohexanoil-L-glutamil- L-histidil-D-fenilalanil-L-arginil-L-triptofanilglicil-L-lisil-L-prolil- L-valinamida

C78H111N21O19

H3C H

H3C Ser Tyr Ser N Glu His D-Phe Arg Trp Gly Lys Pro Val NH2 H O O

alisporivirum alisporivir [8-(N-methyl-D-alanine),9-(N-ethyl-L-valine)]cyclosporine

alisporivir [8-(N-méthyl-D-alanine),9-(N-éthyl-L-valine)]cyclosporine

alisporivir [8-(N-metil-D-alanina),9-(N-etil-L-valina)]ciclosporina

238 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

C63H113N11O12

CH3

CH3 H3C CH H CH 3 OH 3 H C 3 H3C H H H H H CH3 H3C H N N N N N H CH3 O CH3 O CH3 O O H3C O H3C O N H CH3 H H3C N O OH3C O CH H H H 3 N N N N O O CH3 H3CH HCH3 H H CH3 H3C H3C CH3

amenamevirum amenamevir N-(2,6-dimethylphenyl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}- 2-oxoethyl)-1,1-dioxothiane-4-carboxamide

aménamévir N-(2,6-diméthylphényl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phényl]amino}- 2-oxoéthyl)-1,1-dioxothiane-4-carboxamide

amenamevir N-(2,6-dimetilfenil)-N-(2-{[4-(1,2,4-oxadiazol-3-il)fenil]amino}- 2-oxoetil)-1,1-dioxotiano-4-carboxamida

C24H26N4O5S

N O O H3C CH3 O S O N N N H O

atigliflozinum atigliflozin 2-[(4-methoxyphenyl)methyl]thiophen-3-yl β-D-glucopyranoside

atigliflozine β-D-glucopyranoside de 2-[(4-méthoxyphényl)méthyl]thiophén-3-yle

atigliflozina β-D-glucopiranósido de 2-[(4-metoxifenil)metil]-3-tienilo

C18H22O7S

OCH3

HO S

O O OH HO OH

239 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

balapiravirum balapiravir 4'-C-azido-2',3',5'-tris[O-(2-methylpropanoyl)]cytidine

balapiravir 4'-C-azido-2',3',5'-tris[O-(2-méthylpropanoyl)]cytidine

balapiravir 4'-C-azido-2',3',5'-tris[O-(2-metilpropanoil)]citidina

C21H30N6O8

NH2 CH3 O N H3C O O N O

N 3 CH3 O O O CH3 O H3C CH3

beloranibum beloranib (3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut- 2-en-1-yl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl (2E)-3-{4-[2- (dimethylamino)ethoxy]phenyl}prop-2-enoate

béloranib (2E)-3-{4-[2-(diméthylamino)éthoxy]phényl}prop-2-énoate de (3R,4S,5S,6R)-5-méthoxy-4-[(2R,3R)-2-méthyl-3-(3-méthylbut-2-én- 1-yl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yle

beloranib (2E)-3-{4-[2-(dimetilamino)etoxi]fenil}prop-2-enoato de (3R,4S,5S,6R)- 4-[(2R,3R)-2-metil-3-(3-metilbut-2-en-1-il)oxiran-2-il]- 5-metoxi-1-oxaspiro[2.5]octan-6-ilo

C29H41NO6

O CH3 CH3 H OCH N O 3 O CH3 H3C H H H O CH3 O

blinatumomabum # blinatumomab immunoglobulin scFv-scFv, anti-[Homo sapiens CD19 (B lymphocyte surface antigen B4, Leu-12)]/anti-[Homo sapiens CD3 epsilon (CD3E, Leu-4)] Mus musculus monoclonal antibody bispecific single chain; Mus musculus scFv anti-CD19 [V-KAPPA (IGKV3-4-IGKJ1*01) [10.3.9] (1-111) -tris(tetraglycyl-seryl) -VH (IGHV1-54-(IGHD)- IGHJ4*01, S123>T) [8.8.17] (127-250)] -tetraglycyl-seryl -Mus musculus scFv anti-CD3E [VH (IGHV1-4-(IGHD)-IGHJ2*01) [8.8.12] (256-374) -valyl-glutamyl-tetrakis(diglycyl-seryl)-diglycyl-valyl- aspartyl -V-KAPPA (IGKV4-59-IGKJ5*01) [5.3.9] (393-498)] - hexahistidine

240 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

blinatumomab immunoglobuline scFv-scFv, anti-[Homo sapiens CD19 (antigène de surface B4 des lymphocytes B, Leu-12)]/anti-[Homo sapiens CD3 epsilon (CD3E, Leu-4)] Mus musculus anticorps monoclonal bispécifique à chaîne unique; Mus musculus scFv anti-CD19 [V-KAPPA (IGKV3-4-IGKJ1*01) [10.3.9] (1-111) -tris(tétraglycyl-séryl) -VH (IGHV1-54-(IGHD)- IGHJ4*01, S123>T [8.8.17] (127-250) -tétraglycyl-séryl -Mus musculus scFv anti-CD3E [VH (IGHV1-4-(IGHD)-IGHJ2*01 [8.8.12] (256-374) -valyl-glutamyl-tétrakis(diglycyl-seryl)-diglycyl-valyl- aspartyl -V-KAPPA (IGKV4-59-IGKJ5*01 [5.3.9] (393-498)] – hexahistidine

blinatumomab inmunoglobulina scFv-scFv, anti-[Homo sapiens CD19 (antígeno de superficie B4 de los linfocitos B, Leu-12)]/anti-[Homo sapiens CD3 epsilon (CD3E, Leu-4)] anticuerpo monoclonal biespecífico de Mus musculus de cadena única; Mus musculus scFv anti-CD19 [V-KAPPA (IGKV3-4-IGKJ1*01) [10.3.9] (1-111) -tris(tetraglicil-seril) -VH (IGHV1-54-(IGHD)- IGHJ4*01, S123>T [8.8.17] (127-250) -tetraglicil-seril -Mus musculus scFv anti-CD3E [VH (IGHV1-4-(IGHD)-IGHJ2*01 [8.8.12] (256-374) - valil-glutamil-tetrakis(diglicil-seril)-diglicil-valil-aspartil -V-KAPPA (IGKV4-59-IGKJ5*01 [5.3.9] (393-498)] –hexahistidina

C2367H3577N649O772S19

DIQLTQSPAS LAVSLGQRAT ISCKASQSVD YDGDSYLNWY QQIPGQPPKL 50 LIYDASNLVS GIPPRFSGSG SGTDFTLNIH PVEKVDAATY HCQQSTEDPW 100 TFGGGTKLEI KGGGGSGGGG SGGGGSQVQL QQSGAELVRP GSSVKISCKA 150 SGYAFSSYWM NWVKQRPGQG LEWIGQIWPG DGDTNYNGKF KGKATLTADE 200 SSSTAYMQLS SLASEDSAVY FCARRETTTV GRYYYAMDYW GQGTTVTVSS 250 GGGGSDIKLQ QSGAELARPG ASVKMSCKTS GYTFTRYTMH WVKQRPGQGL 300 EWIGYINPSR GYTNYNQKFK DKATLTTDKS SSTAYMQLSS LTSEDSAVYY 350 CARYYDDHYC LDYWGQGTTL TVSSVEGGSG GSGGSGGSGG VDDIQLTQSP 400 AIMSASPGEK VTMTCRASSS VSYMNWYQQK SGTSPKRWIY DTSKVASGVP 450 YRFSGSGSGT SYSLTISSME AEDAATYYCQ QWSSNPLTFG AGTKLELKHH 500 HHHH 504 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 23-92 148-222 277-351 415-479

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 307 (but Pro in 308)

canosimibum canosimibe N-(1-deoxy-D-glucitol-1-C-yl)-N'-[(4-{(2S,3R))-3-[(3S)-3-(4- fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin- 1-yl}phenyl)methyl]dodecanediamide

canosimibe N-(1-déoxy-D-glucitol-1-C-yl)-N'-[(4-{(2S,3R))-3-[(3S)-3-(4- fluorophényl)-3-hydroxypropyl]-2-(4-méthoxyphényl)-4-oxoazétidin- 1-yl}phényl)méthyl]dodécanediamide

canosimiba N-(1-desoxi-D-glucitol-1-C-il)-N'-[(4-{(2S,3R))-3-[(3S)-3-(4- fluorofenil)-3-hidroxipropil]-2-(4-metoxifenil)-4-oxoazetidin- 1-il}fenil)metil]dodecanediamida

C44H60FN3O10

OH OH H OH O H H H HO NH H H N OH OH O F H H N H3CO O

241 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

cixutumumabum # cixutumumab immunoglobulin G1-lambda, anti-[Homo sapiens insulin-like growth factor I receptor (IGF-1R, CD221)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-460) [Homo sapiens VH (IGHV1-69*06 (99.00%) -(IGHD)-IGHJ6*01) [8.8.23] (1-130) -IGHG1*03, R120>K (131-460)], (233-213')-disulfide with lambda light chain (1'-214') [Homo sapiens V-LAMBDA (IGLV3-19*01 (92.70%) -IGLJ2*01) [6.3.11] (1'-108') -IGLC2*01, T124>A (109'-214')]; (239-239'':242- 242'')-bisdisulfide dimer

cixutumumab immunoglobuline G1-lambda, anti-[Homo sapiens récepteur du facteur de croissance analogue à l'insuline-1 (IGF-1R, CD221)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-460) [Homo sapiens VH (IGHV1-69*06 (99.00%) -(IGHD)-IGHJ6*01) [8.8.23] (1-130) -IGHG1*03, R120>K (131-460)], (233-213')-disulfure avec la chaîne légère lambda (1'-214') [Homo sapiens V-LAMBDA (IGLV3-19 (92.70%) -IGLJ2*01) [6.3.11] (1'-108') -IGLC2*01, T124>A (109'-214')]; dimère (239- 239'':242-242'')-bisdisulfure

cixutumumab inmunoglobulina G1-lambda, anti-[receptor del factor de crecimiento insulínico-tipo 1 de Homo sapiens (conocido como: IGF-1R, CD221)], Homo sapiens anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-460) [VH (IGHV1-69*06 (99.00%) - (IGHD)-IGHJ6*01) [8.8.23] (1-130) -IGHG1*03, R120>K (131-460)], (233-213')-disulfuro con la cadena ligera lambda (1'-214') [Homo sapiens V-LAMBDA (IGLV3-19 (92.70%) -IGLJ2*01) [6.3.11] (1'-108') -IGLC2*01, T124>A (109'-214')]; dímero (239-239'':242- 242'')-bisdisulfuro

C6500H10052N1724O2036S44

Heavy chain / Chaîne lourde / Cadena pesada EVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYAISWVRQA PGQGLEWMGG 50 IIPIFGTANY AQKFQGRVTI TADKSTSTAY MELSSLRSED TAVYYCARAP 100 LRFLEWSTQD HYYYYYMDVW GKGTTVTVSS ASTKGPSVFP LAPSSKSTSG 150 GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT 200 VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 250 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA 300 KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS 350 KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP 400 ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT 450 QKSLSLSPGK 460 Light chain / Chaîne légère / Cadena ligera SSELTQDPAV SVALGQTVRI TCQGDSLRSY YATWYQQKPG QAPILVIYGE 50 NKRPSGIPDR FSGSSSGNTA SLTITGAQAE DEADYYCKSR DGSGQHLVFG 100 GGTKLTVLGQ PKAAPSVTLF PPSSEELQAN KATLVCLISD FYPGAVTVAW 150 KADSSPVKAG VETTTPSKQS NNKYAASSYL SLTPEQWKSH RSYSCQVTHE 200 GSTVEKTVAP AECS 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 157-213 274-334 380-438 22''-96'' 157''-213'' 274''-334'' 380''-438'' Intra-L 22'-87' 136'-195' 22'''-87''' 136'''-195''' Inter-H-L 233-213' 233''-213''' Inter-H-H 239-239'' 242-242''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 310, 310''

242 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

coleneuramidum coleneuramide 5-acetamido-N-(5α-cholestan-3α-yl)-3,5-dideoxy-2-O-methyl- D-glycero-α-D-galacto-non-2-ulopyranosonamide

coléneuramide 5-acétamido-N-(5α-cholestan-3α-yl)-3,5-didéoxy-2-O-méthyl- D-glycéro-α-D-galacto-non-2-ulopyranosonamide

coleneuramida 5-acetamido-N-(5α-colestan-3α-il)-3,5-didesoxi-2-O-metil-D-glicero- α-D-galacto-non-2-ulopiranosonamida

C39H68N2O8

H H3C

CH3 H CH3

CH3 H H3C H O N H H O O H H H3C NH O CH HO 3 OH OH HO

cositecanum cositecan (4S)-4-ethyl-4-hydroxy-11-[2-(trimethylsilyl)ethyl]-1,12-dihydro- 14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione

cositécan (4S)-4-éthyl-4-hydroxy-11-[2-(triméthylsilyl)éthyl]-1,12-dihydro- 14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoléine-3,14(4H)-dione

cositecán (4S)-4-etil-4-hidroxi-11-[2-(trimetilsilil)etil]-1,12-dihidro- 14H-pirano[3',4':6,7]indolizino[1,2-b]quinolina-3,14(4H)-diona

C25H28N2O4Si

H3C CH3 O Si H3C N O

O

N HO CH3

cutamesinum cutamesine 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)

cutamésine 1-[2-(3,4-diméthoxyphényl)éthyl]-4-(3-phénylpropyl)pipérazine

cutamesina 1-[2-(3,4-dimetoxifenil)etil]-4-(3-fenilpropil)piperazina

243 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

C23H32N2O2

N

N OCH3

OCH3

davunetidum davunetide human activity-dependent neuroprotector (ADNP)-(354-361)-

davunétide neuroprotecteur activité-dépendant humain (ADNP)-(354-361)- peptide

davunetida neuroprotector humano dependiente de actividad (ADNP)-péptido- (354-361)

C36H60N10O12

HAsn Ala Pro Val Ser Ile Pro Gln OH

delafloxacinum delafloxacin 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro- 7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

délafloxacine acide 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro- 7-(3-hydroxyazétidin-1-yl)-4-oxo-1,4-dihydroquinoléine- 3-carboxylique

delafloxacino ácido 1-(6-amino-3,5-difluoropiridin-2-il)-8-cloro-6-fluoro- 7-(3-hidroxiazetidin-1-il)-4-oxo-1,4-dihidroquinolina-3-carboxílico

C18H12ClF3N4O4

F

H2N

N HO Cl F N N

F CO2H O

dirucotidum dirucotide human myelin basic protein (myelin membrane encephalitogenic protein)-(216-232)-peptide L-α-aspartyl-L-α-glutamyl-L-asparaginyl-L-prolyl-L-valyl-L-valyl- L-histidyl-L-phenylalanyl-L-phenylalanyl-L-lysyl-L-asparaginyl- L-isoleucyl-L-valyl-L-threonyl-L-prolyl-L-arginyl-L-threonine

244 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

dirucotide protéine basique de la myéline humaine (protéine encéphalitogénique de la membrane de la myéline)-(216-232)- peptide L-α-aspartyl-L-α-glutamyl-L-asparaginyl-L-prolyl-L-valyl-L-valyl- L-histidyl-L-phénylalanyl-L-phénylalanyl-L-lysyl-L-asparaginyl- L-isoleucyl-L-valyl-L-thréonyl-L-prolyl-L-arginyl-L-thréonine

dirucotida proteina básica de la mielina humana (proteina encefalitogénica de la membrana de mielina)-péptido (216-232) L-α-aspartil-L-α-glutamil-L-asparaginil-L-prolil-L-valil-L-valil-L-histidil- L-fenilalanil-L-fenilalanil-L-lisil-L-asparaginil-L-isoleucil-L-valil-L-treonil- L-prolil-L-arginil-L-treonina

C92H141N25O26

HAsp Glu Asn Pro Val Val His Phe Phe

Lys Asn Ile Val Thr Pro Arg Thr OH 10 17

dutogliptinum dutogliptin [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid

dutogliptine acide [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acétyl}pyrrolidin- 2-yl]boronique

dutogliptina àcido [(2R)-1-{[(3R)-pirrolidin-3-ilamino]acetil}pirrolidin-2-il]borónico

C10H20BN3O3

OH O H H B HN N OH N H

elacytarabinum elacytarabine 4-amino-1-{5-O-[(9E)-octadec-9-enoyl]-β-D-arabinofuranosyl}= pyrimidin-2(1H)-one

élacytarabine 4-amino-1-[5-O-[(9E)-octadéc-9-énoyl]-β-D-arabinofuranosyl]= pyrimidin-2(1H)-one

elacitarabina 4-amino-1-{5-O-[(9E)-octadec-9-enoil]-β-D-arabinofuranosil}pirimidin- 2(1H)-ona

C27H45N3O6

NH2

N

O N H3C O O O HO

OH

245 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

elotuzumabum # elotuzumab immunoglobulin G1-kappa, anti-[Homo sapiens SLAM family member 7 (SLAM7, CD2 subset 1, CS1, CD2-like receptor-activating cytotoxic cells, CRACC, 19A24, CD319), humanized monoclonal antibody; gamma1 heavy chain (1-449) [humanized VH (Homo sapiens IGHV3-74*01 (81.60%) -IGHJ2*01, R120>Q) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-27*01 (84.20%) -IGKJ2*01, L124>V) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (228-228'':231-231'')-bisdisulfide dimer

elotuzumab immunoglobuline G1-kappa, anti-[Homo sapiens membre 7 de la famille SLAM (SLAM7, CD2 subset 1, CS1, CD2-like receptor- activating cytotoxic cells, CRACC, 19A24, CD319), anticorps monoclonal humanisé; chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiens IGHV3-74*01 (81.60%) -IGHJ2*01, R120>Q) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1- 27*01 (84.20%) IGKJ2*01, L124>V) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (228-228'':231-231'')-bisdisulfure

elotuzumab inmunoglobulina G1-kappa, anti-[Homo sapiens miembro 7 de la familia SLAM (conocido como: SLAM7, CD2 subset 1, CS1, CD2- like receptor-activating cytotoxic cells, CRACC, 19A24, CD319), anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-449) [VH humanizada (Homo sapiens IGHV3-74*01 (81.60%) -IGHJ2*01, R120>Q) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizada (Homo sapiens IGKV1- 27*01 (84.20%) IGKJ2*01, L124>V) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero(228-228'':231-231'')-bisdisulfuro

C6476H9982N1714O2016S42

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFDFS RYWMSWVRQA PGKGLEWIGE 50 INPDSSTINY APSLKDKFII SRDNAKNSLY LQMNSLRAED TAVYYCARPD 100 GNYWYFDVWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCKASQDVG IAVAWYQQKP GKVPKLLIYW 50 ASTRHTGVPD RFSGSGSGTD FTLTISSLQP EDVATYYCQQ YSSYPYTFGQ 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 222-214' 222''-214''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

246 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

farletuzumabum # farletuzumab immunoglobulin G1-kappa, anti-[Homo sapiens folate receptor 1 (FOLR1, folate receptor alpha, FR-alpha, adult folate-binding protein, FBP, ovarian tumor-associated antigen MOv18)], humanized monoclonal antibody; gamma1 heavy chain (1-449) [humanized VH (Homo sapiens IGHV3-30*03 (82.70%) -(IGHD)-IGHJ5*01, L123>P) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-217')-disulfide with kappa light chain (1'-217') [humanized V-KAPPA (Homo sapiens IGKV1-33*01 (80.20%) -IGKJ2*01, L124>V) [7.3.11] (1'-110') -Homo sapiens IGKC*01 (111'-217')]; (228-228'':231-231'')-bisdisulfide dimer

farletuzumab immunoglobuline G1-kappa, anti-[Homo sapiens réceptor 1 du folate (FOLR1, folate receptor alpha, FR-alpha, adult folate-binding protein, FBP, ovarian tumor-associated antigen MOv18)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiens IGHV3-30*03 (82.70%) -(IGHD)-IGHJ5*01, L123>P) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-217')-disulfure avec la chaîne légère kappa (1'-217') [V-KAPPA humanisé (Homo sapiens IGKV1-33*01 (80.20%) -IGKJ2*01, L124>V) [7.3.11] (1'-110') -Homo sapiens IGKC*01 (111'-217')]; dimère (228-228'':231-231'')- bisdisulfure

farletuzumab inmunoglobulina G1-kappa, anti-[receptor 1 de folato de Homo sapiens (conocido como: FOLR1, folate receptor alpha, FR-alpha, adult folate-binding protein, FBP, ovarian tumor-associated antigen MOv18)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-449) [VH humanizada (Homo sapiens IGHV3-30*03 (82.70%) -(IGHD)-IGHJ5*01, L123>P) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-217')-disulfuro con la cadena ligera kappa (1'-217') [V-KAPPA humanizada (Homo sapiens IGKV1-33*01 (80.20%) -IGKJ2*01, L124>V) [7.3.11] (1'-110') -Homo sapiens IGKC*01 (111'-217')]; dimero (228-228'':231-231'')- bisdisulfuro

C6466H9928N1716O2020S42

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG VVQPGRSLRL SCSASGFTFS GYGLSWVRQA PGKGLEWVAM 50 ISSGGSYTYY ADSVKGRFAI SRDNAKNTLF LQMDSLRPED TGVYFCARHG 100 DDPAWFAYWG QGTPVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera DIQLTQSPSS LSASVGDRVT ITCSVSSSIS SNNLHWYQQK PGKAPKPWIY 50 GTSNLASGVP SRFSGSGSGT DYTFTISSLQ PEDIATYYCQ QWSSYPYMYT 100 FGQGTKVEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ 150 WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT 200 HQGLSSPVTK SFNRGEC 217 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-89' 137'-197' 23'''-89''' 137'''-197''' Inter-H-L 222-217' 222''-217''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

247 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

fidaxomicinum fidaxomicin (3E,5E,8S,9E,11S,12R,13E,15E,18S)-3-{[(6-deoxy- 4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl- β-D-mannopyranosyl)oxy]methyl}-12-{[6-deoxy-5-C-methyl- 4-O-(2-methylpropanoyl)-β-D-lyxo-hexopyranosyl]oxy}-11-ethyl- 8-hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyloxacycloocta- 3,5,9,13,15-pentaen-2-one

fidaxomicine (3E,5E,8S,9E,11S,12R,13E,15E,18S)-3-({[6-déoxy- 4-O-(3,5-dichloro-2-éthyl-4,6-dihydroxybenzoyl)-2-O-méthyl- β-D-mannopyranosyl]oxy}méthyl)-12-{[6-déoxy-5-C-méthyl- 4-O-(2-méthylpropanoyl)-β-D-lyxo-hexopyranosyl]oxy}-11-éthyl- 8-hydroxy-18-[(1R)-1-hydroxyéthyl]-9,13,15- triméthyloxacyclooctadéca-3,5,9,13,15-pentaén-2-one

fidaxomicina 3-{[(6-desoxi-4-O-(3,5-dicloro-2-etil-4,6-dihidroxibenzoil)-2-O-metil- β-D-manopiranosil)oxi]metil}-12-{[6-desoxi-5-C-metil- 4-O-(2-metilpropanoil)-β-D-lixo-hexopiranosil]oxi}-11-etil-8-hidroxi- 18-[(1R)-1-hidroxietil]-9,13,15-trimetiloxacicloocta-3,5,9,13,15- pentaen-2-ona

C52H74Cl2O18

H OH

CH3 H

CH3 CH3 H3C O O H OH H CO CH 3 H3C 3 O O O O O O H H C 3 CH3 HO CH OH HO 3 HOH O O Cl Cl OH H3C CH3

figitumumabum # figitumumab immunoglobulin G2-kappa, anti-[Homo sapiens insulin-like growth factor 1 receptor (IGF-1R, CD221)], Homo sapiens monoclonal antibody; gamma2 heavy chain (1-450) [Homo sapiens VH (IGHV3-23*01 (93.90%) -(IGHD)-IGHJ6*01) [8.8.18] (1-125) -IGHG2*01, CH3 K130>del (126-450)], (139-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV1-17*01 (95.80%) - IGKJ2*04) [6.3.9] (1'-107') -IGKC*01] (108'-214'); (227-227'':228- 228'':231-231'':234-234'')-tetradisulfide dimer

figitumumab immunoglobuline G2-kappa, anti-[Homo sapiens récepteur du facteur de croissance analogue à l'insuline 1 (IGF-1R, CD221)], Homo sapiens anticorps monoclonal; chaîne lourde gamma2 (1-450) [Homo sapiens VH (IGHV3-23*01 (93.90%) -(IGHD)-IGHJ6*01) [8.8.18] (1-125) -IGHG2*01, CH3 K130>del (126-450)], (139-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-17*01 (95.80%) - IGKJ2*04) [6.3.9] (1'-107') -IGKC*01] (108'-214'); dimère (227- 227'':228-228'':231-231'':234-234'')-tétradisulfure

248 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

figitumumab inmunoglobulina G2-kappa, anti-[Homo sapiens receptor del factor de crecimiento insulínico tipo 1 de Homo sapiens (conocido como: IGF-1R, CD221)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma2 (1-450) [Homo sapiens VH (IGHV3-23*01 (93.90%) -(IGHD)-IGHJ6*01) [8.8.18] (1-125) -IGHG2*01, CH3 K130>del (126-450)], (139-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-17*01 (95.80%) - IGKJ2*04) [6.3.9] (1'-107') -IGKC*01] (108'-214'); dímero (227- 227'':228-228'':231-231'':234-234'')-tetradisulfuro

C6450H9924N1732O2018S54

Heavy chain / Chaîne lourde / Cadena pesada EVQLLESGGG LVQPGGSLRL SCTASGFTFS SYAMNWVRQA PGKGLEWVSA 50 ISGSGGTTFY ADSVKGRFTI SRDNSRTTLY LQMNSLRAED TAVYYCAKDL 100 GWSDSYYYYY GMDVWGQGTT VTVSSASTKG PSVFPLAPCS RSTSESTAAL 150 GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSN 200 FGTQTYTCNV DHKPSNTKVD KTVERKCCVE CPPCPAPPVA GPSVFLFPPK 250 PKDTLMISRT PEVTCVVVDV SHEDPEVQFN WYVDGVEVHN AKTKPREEQF 300 NSTFRVVSVL TVVHQDWLNG KEYKCKVSNK GLPAPIEKTI SKTKGQPREP 350 QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP 400 MLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG 450 Light chain / Chaîne légère / Cadena ligera DIQMTQFPSS LSASVGDRVT ITCRASQGIR NDLGWYQQKP GKAPKRLIYA 50 ASRLHRGVPS RFSGSGSGTE FTLTISSLQP EDFATYYCLQ HNSYPCSFGQ 100 GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 152-208 265-325 371-429 22''-96'' 152''-208'' 265''-325'' 371''-429'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 139-214' 139''-214''' Inter-H-H 227-227'' 228-228'' 231-231'' 234-234''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 301, 301''

fosbretabulinum fosbretabulin 2-methoxy-5-[(1Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl dihydrogen phosphate

fosbrétabuline dihydrogénophosphate de 2-méthoxy-5-[(1Z)-2-(3,4,5- triméthoxyphényl)éthényl]phényle

fosbretabulina dihidrògenofosfato de 2-metoxi-5-[(1Z)-2-(3,4,5- trimetoxifenil)etenil]fenilo

C18H21O8P

H3CO

H3CO O

OCH3 P OH O OH OCH3

fostamatinibum fostamatinib [6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)- 2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin- 4-yl]methyl dihydrogen phosphate

249 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

fostamatinib dihydrogénophosphate de [6-({5-fluoro-2-[(3,4,5- triméthoxyphényl)amino]pyrimidin-4-yl}amino)-2,2-diméthyl-3-oxo- 2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]méthyle

fostamatinib dihidrògenofosfato de [6-({5-fluoro-2-[(3,4,5- trimetoxifenil)amino]pirimidin-4-il}amino)-2,2-dimetil-3-oxo- 2,3-dihidro-4H-pirido[3,2-b][1,4]oxazin-4-il]metilo

C23H26FN6O9P

OH O P OH O F H O N N N

H3C NN O H3C HN OCH3

OCH3 OCH3

indeglitazarum indeglitazar 3-[5-methoxy-1-(4-methoxybenzenesulfonyl)-1H-indol-3-yl]propanoic acid

indéglitazar acide 3-{5-méthoxy-1-(4-méthoxybenzènesulfonyl)-1H-indol- 3-yl}propanoïque

indeglitazar ácido 3-[5-metoxi-1-(4-metoxibencenosulfonil)-1H-indol- 3-il]propanoico

C19H19NO6S

O O H3CO S N

CO2H

H3CO

ingenoli mebutatum ingenol mebutate (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihydroxy- 4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a- octahydro-1H-2,8a-methanocyclopenta[a]cyclpropa[e][10]annulen- 6-yl (2Z)-2-methylbut-2-enoate

mébutate d'ingénol (2Z)-2-méthylbut-2-énoate de (1aR,2S,5R,5aS,6S,8aS,9R,10aR)- 5,5a-dihydroxy-4-(hydroxyméthyl)-1,1,7,9-tétraméthyl-11-oxo- 1a,2,5,5a,6,9,10,10a-octahydro-1H-2,8a- méthanocyclopenta[a]cyclpropa[e][10]annulén-6-yle

250 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

mebutato de ingenol (2Z)-2-metilbut-2-enoato de (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a- dihidroxi-4-(hidroximetil)-1,1,7,9-tetrametil-11-oxo- 1a,2,5,5a,6,9,10,10a-octahidro-1H-2,8a- metanociclopenta[a]ciclopropa[e][10]anulen-6-ilo

C25H34O6

H3C CH3 O H CH H 3 O O HO H CH3 H H

HO CH3 H HO CH3

laninamivirum laninamivir (2R,3R,4S)-3-acetamido-2-[(1R,2R)-2,3-dihydroxy- 1-methoxypropyl]-4-guanidino-3,4-dihydro-2H-pyran- 6-carboxylic acid

laninamivir acide (2R,3R,4S)-3-acétamido-2-[(1R,2R)-2,3-dihydroxy- 1-méthoxypropyl]-4-guanidino-3,4-dihydro-2H-pyran- 6-carboxylique

laninamivir ácido (2R,3R,4S)-3-acetamido-2-[(1R,2R)-2,3-dihidroxi- 1-metoxipropil]-4-guanidino-3,4-dihidro-2H-piran- 6-carboxílico

C13H22N4O7

HO OH

H3CO H H O CO2H H HN NH2 H3C H HN O H NH

lesogaberanum lesogaberan (2R)-3-amino-2-fluoropropylphosphinic acid

lésogabéran acide [(2R)-3-amino-2-fluoropropyl]phosphinique

lesogaberán ácido (2R)-3-amino-2-fluoropropilfosfínico

C3H9FNO2P

H F O H

H2N P OH

limiglidolum limiglidole 2-(2,3-dihydro-9H-imidazo[1,2-a]benzimidazol-9-yl)- N,N-dimethylethanamine

251 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

limiglidole 2-(2,3-dihydro-9H-imidazo[1,2-a]benzimidazol-9-yl)- N,N-diéthyléthanamine

limiglidol 2-(2,3-dihidro-9H-imidazo[1,2-a]benzoimidazol-9-il)- N,N-dimetiletanamina

C15H22N4

H3C N H3CN N N

lotilibcinum lotilibcin 3-{(3S,6R,9R,12R,15S,18R,21S,24R,30S,33R,36S,40R)-33-[(1R)-2- amino-1-hydroxy-2-oxoethyl]-12-(2-amino-2-oxoethyl)-6,18-bis(3- aminopropyl)-24-benzyl-30,36-bis(hydroxymethyl)-9-(1H-indol- 3-ylmethyl)-4,25-dimethyl-40-(4-methylpentyl)-21-(2-methylpropyl)- 3-(propan-2-yl)-2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxo- 1-oxa-4,7,10,13,16,19,22,25,28,31,34,37-dodecaazatetracontan- 15-yl}propanoic acid

lotilibcine acide 3-{(3S,6R,9R,12R,15S,18R,21S,24R,30S,33R,36S,40R)-33- [(1R)-2-amino-1-hydroxy-2-oxoéthyl]-12-(2-amino-2-oxoéthyl)- 6,18-bis(3-aminopropyl)-24-benzyl-30,36-bis(hydroxyméthyl)- 9-(1H-indol-3-ylméthyl)-4,25-diméthyl-40-(4-méthylpentyl)- 21-(2-méthylpropyl)-3-(propan-2-yl)- 2,5,8,11,14,17,20,23,26,29,32,35,38-tridécaoxo-1-oxa- 4,7,10,13,16,19,22,25,28,31,34,37-dodécaazatétracontan- 15-yl}propanoïque

lotilibcina ácido 3-{(3S,6R,9R,12R,15S,18R,21S,24R,30S,33R,36S,40R)-33- [(1R)-2-amino-1-hidroxi-2-oxoetil]-12-(2-amino-2- oxoetil)-6,18-bis(3- aminopropil)-24-bencil-30,36-bis(hidroximetil)-9-(1H-indol-3-ilmetil)- 4,25-dimetil-40-(4-metilpentil)-21-(2-metilpropil)-3-(propan-2-il)- 2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxo-1-oxa- 4,7,10,13,16,19,22,25,28,31,34,37-dodecaazatetracontan- 15-il}propanoico

C73H111N17O21

O

H2N NH2 H O H H H N N NH CH3 HN N H H C H H 3 O H O O O NH O NH CO H O 2 CH H 3 CH3 N N H2N H C CH H 3 3 HO HO H O H O H O O O CH3 H H HN N N N CH3 H H H O O H O OH NH2

252 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

macimorelinum macimorelin N2-(2-amino-2-methylpropanoyl-N1-[(1R)-1-formamido-2-(1H-indol- 3-yl)ethyl]-D-tryptophanamide

macimoréline N2-(2-amino-2-méthylpropanoyl-N1-[(1R)-1-formamido-2-(1H-indol- 3-yl)éthyl]-D-tryptophanamide

macimorelina N2-(2-amino-2-metilpropanoil-N1-[(1R)-1-formamido-2-(1H-indol- 3-il)etil]-D-triptofanamide

C26H30N6O3

NH

H C CH O H O 3 3 H N H2N N N H H H O H

N H

namitecanum namitecan (4S)-11-{(E)-[(2-aminoethoxy)imino]methyl}-4-ethyl-4-hydroxy- 1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline- 3,14(4H)-dione

namitécan (4S)-11-{(E)-[(2-aminoéthoxy)imino]méthyl}-4-éthyl-4-hydroxy- 1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoléine- 3,14(4H)-dione

namitecán (4S)-11-{(E)-[(2-aminoetoxi)imino]metil}-4-etil-4-hidroxi-1,12-dihidro- 14H-pirano[3',4':6,7]indolizino[1,2-b]quinolina-3,14(4H)-diona

C23H22N4O5

H2N O O N N O

O

N HO CH3

necitumumabum # necitumumab immunoglobulin G1-kappa, anti-[Homo sapiens epidermal (EGFR, ERBB1, HER1)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-451) [Homo sapiens VH (IGHV4-30-4*01 (96.00%) -(IGHD)-IGHJ4*01) [10.7.13] (1-121) -IGHG1*03, CH1 F5>L (122-451)], (224-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (93.70%) -IGKJ4*01, V124>A) [6.3.9] (1’-107’) -IGKC*01 (108’-214’)]; (230-230'':233- 233'')-bisdisulfide dimer

253 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

necitumumab immunoglobuline G1-kappa, anti-[Homo sapiens récepteur du facteur de croissance épidermique (EGFR, ERBB1, HER1)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-451) [Homo sapiens VH (IGHV4-30-4*01 (96.00%) -(IGHD)-IGHJ4*01) [10.7.13] (1-121) -IGHG1*03, CH1 F5>L (122-451)], (224-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (93.70%) - IGKJ4*01, V124>A) [6.3.9] (1’-107’) -IGKC*01 (108’-214’)]; dimère (230-230'':233-233'')-bisdisulfure

necitumumab inmunoglobulina G1-kappa, anti-[receptor del factor de crecimiento epidérmico de Homo sapiens (conocido como: EGFR, ERBB1, HER1)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-451) [Homo sapiens VH (IGHV4-30- 4*01 (96.00%) -(IGHD)-IGHJ4*01) [10.7.13] (1-121) -IGHG1*03, CH1 F5>L (122-451)], (224-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (93.70%) - IGKJ4*01, V124>A) [6.3.9] (1’-107’) -IGKC*01 (108’-214’)]; dímero (230-230'':233-233'')-bisdisulfuro

C6436H9958N1702O2020S42

Heavy chain / Chaîne lourde / Cadena pesada QVQLQESGPG LVKPSQTLSL TCTVSGGSIS SGDYYWSWIR QPPGKGLEWI 50 GYIYYSGSTD YNPSLKSRVT MSVDTSKNQF SLKVNSVTAA DTAVYYCARV 100 SIFGVGTFDY WGQGTLVTVS SASTKGPSVL PLAPSSKSTS GGTAALGCLV 150 KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ 200 TYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK 250 PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300 NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP 350 QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP 400 VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG 450 K 451 Light chain / Chaîne légère / Cadena ligera EIVMTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD 50 ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCHQ YGSTPLTFGG 100 GTKAEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-97 148-204 265-325 371-429 22''-97'' 148''-204'' 265''-325'' 371''-429'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 224-214' 224''-214''' Inter-H-H 230-230'' 233-233''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 301, 301''

oportuzumabum monatoxum # oportuzumab monatox immunoglobulin scFv fusion protein, anti-[Homo sapiens tumor- associated calcium signal transducer 1 (TACSTD1, gastrointestinal tumor-associated protein 2, GA733-2, epithelial glycoprotein 2, EGP- 2, epithelial cell adhesion molecule Ep-CAM, KSA, KS1/4 antigen, M4S1, tumor antigen 17-1A, CD326)] humanized monoclonal antibody scFv fused with Pseudomonas aeruginosa exotoxin A; hexahistidyl -humanized scFv [V-KAPPA (Homo sapiens IGKV1- 39*01 (78%)- IGKJ1*01, I126>L) [11.3.9] (7-118) -26-mer linker -VH (Homo sapiens IGHV7-4-1*02 -(IGHD)-IGHJ4*01, V124>L) [8.8.9] (145-260)] -20-mer linker -Pseudomonas aeruginosa exotoxin A (ETA) [277-633 precursor fragment, containing domain II (281-393) with furin proteolytic cleavage site (302-313), domain Ib (394-433), domain III (434-637)] (281-637) -hexahistidyl-lysyl-aspartyl-glutamyl- leucyl

254 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

oportuzumab monatox immunoglobuline scFv protéine de fusion, anti-[Homo sapiens transducteur 1 du signal calcium associé aux tumeurs (TACSTD1, protéine 2 associée aux tumeurs gastrointestinales, GA733-2, glycoprotéine épithéliale 2, EGP-2, molécule d’adhésion des cellules épithéliales Ep-CAM, KSA, antigène KS1/4, M4S1, antigène tumoral 17-1A, CD326)] anticorps monoclonal humanisé scFv fusionné avec l’exotoxine A de Pseudomonas aeruginosa; hexahistidyl -scFv humanisé [V-KAPPA (Homo sapiens IGKV1- 39*01 (78%)- IGKJ1*01, I126>L) [11.3.9] (7-118) -linker 26-mer -VH (Homo sapiens IGHV7-4-1*02 -(IGHD)- IGHJ4*01, V124>L) [8.8.9] (145-260)] -linker 20-mer -Pseudomonas aeruginosa exotoxine A (ETA) [fragment précurseur 277-633, comprenant domaine II (281- 393) dont site de clivage protéolytique par la furine (302-313), domaine Ib (394-433), domaine III (434-637)] (281-637) - hexahistidyl-lysyl-aspartyl-glutamyl-leucyl

oportuzumab monatox inmunoglobulina scFv proteína de fusión, anti-[Homo sapiens transductor 1 de la señal de calcio asociado a los tumores (TACSTD1, proteína 2 asociada a los tumores gastrointestinales, GA733-2, glicoproteína epitelial 2, EGP-2, molécula de adhesión de las células epiteliales Ep-CAM, KSA, antígeno KS1/4, M4S1, antígeno tumoral 17-1A, CD326)] anticuerpo monoclonal humanizado scFv fusionado con la exotoxina A de Pseudomonas aeruginosa; hexahistidil -scFv humanizado [V-KAPPA (Homo sapiens IGKV 1-39*01 (78%)- IGKJ1*01, I126>L) [11.3.9] (7-118) -linker 26-mer - VH (Homo sapiens IGHV7-4-1*02 -(IGHD)- IGHJ4*01, V124>L) [8.8.9] (145-260)] -linker 20-mer -Pseudomonas aeruginosa exotoxina A (ETA) [fragmento precursor 277-633, que comprende el dominio II (281-393) con el sitio de ruptura proteolítica por furina (302-313), dominio Ib (394-433), dominio III (434-637)] (281-637) - hexahistidil-lisil-aspartil-glutamil-leucil

C3072H4723N877O952S12

scFv fusion protein / scFv protéine de fusion / scFv proteína de fusión HHHHHHDIQM TQSPSSLSAS VGDRVTITCR STKSLLHSNG ITYLYWYQQK 50 PGKAPKLLIY QMSNLASGVP SRFSSSGSGT DFTLTISSLQ PEDFATYYCA 100 QNLEIPRTFG QGTKVELKRA TPSHNSHQVP SAGGPTANSG TSGSEVQLVQ 150 SGPGLVQPGG SVRISCAASG YTFTNYGMNW VKQAPGKGLE WMGWINTYTG 200 ESTYADSFKG RFTFSLDTSA SAAYLQINSL RAEDTAVYYC ARFAIKGDYW 250 GQGTLLTVSS EFGGAPEFPK PSTPPGSSGL EGGSLAALTA HQACHLPLET 300 FTRHRQPRGW EQLEQCGYPV QRLVALYLAA RLSWNQVDQV IRNALASPGS 350 GGDLGEAIRE QPEQARLALT LAAAESERFV RQGTGNDEAG AASADVVSLT 400 CPVAAGECAG PADSGDALLE RNYPTGAEFL GDGGDVSFST RGTQNWTVER 450 LLQAHRQLEE RGYVFVGYHG TFLEAAQSIV FGGVRARSQD LDAIWRGFYI 500 AGDPALAYGY AQDQEPDARG RIRNGALLRV YVPRSSLPGF YRTGLTLAAP 550 EAAGEVERLI GHPLPLRLDA ITGPEEEGGR LETILGWPLA ERTVVIPSAI 600 PTDPRNVGGD LDPSSIPDKE QAISALPDYA SQPGKPPHHH HHHKDEL 647 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 29-99 166-240 294-316 401-408

N-glycosylation site / Site de N-glycosylation / Posición de N-glicosilación 445

255 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

panobacumabum # panobacumab immunoglobulin M-kappa [Pseudomonas aeruginosa serotype IATS O11], Homo sapiens monoclonal antibody with a Mus musculus ; mu heavy chain (1-569) [Homo sapiens VH (IGHV3-74*01 (92.90%) -(IGHD)-IGHJ3*01) [8.7.10] (1-116) -IGHM*03 (117-569)], (130- 219’)-disulfide with kappa light chain (1'-219') [Homo sapiens V-KAPPA (IGKV2-30*01 (100%) -IGKJ4*01) [11.3.9] (1'-112') - IGKC*01 (113'-219'); (330-330”)-monodisulfide dimer; (407- 407”:568-568”)-octadisulfide between 5 dimers (a-e) to form a pentamer; pentamer (407''a-15'''':568e-69'''')-bisdisulfide with Mus musculus J chain (1''''-138'''')

panobacumab immunoglobuline M-kappa [Pseudomonas aeruginosa sérotype IATS O11], Homo sapiens anticorps monoclonal avec la chaîne J de Mus musculus; chaîne lourde mu (1-569) [Homo sapiens VH (IGHV3-74*01(92.90%) -(IGHD)-IGHJ3*01) [8.7.10] (1-116) -IGHM*03 (117-569)], (130- 219’)-disulfure avec la chaîne légère kappa (1'-219') [Homo sapiens V-KAPPA (IGKV2-30*01 (100%) -IGKJ4*01) [11.3.9] (1'-112') - IGKC*01 (113'-219'); dimère (330-330”)-monodisulfure; pentamère fait de 5 dimères (407-407”:568-568”)-octadisulfure; pentamère (407''a-15'''':568e-69'''')-bisdisulfure avec la chaîne J de Mus musculus (1''''-138'''')

panobacumab inmunoglobulina M-kappa [Pseudomonas aeruginosa serotipo IATS O11], anticuerpo monoclonal de Homo sapiens con una cadena J de Mus musculus ; cadena pesada mu (1-569) [Homo sapiens VH (IGHV3- 74*01(92.90%) -(IGHD)-IGHJ3*01) [8.7.10] (1-116) -IGHM*03 (117- 569)], (130-219’)-disulfuro con la cadena ligera kappa (1'-219') [Homo sapiens V-KAPPA (IGKV2-30*01 (100%) -IGKJ4*01) [11.3.9] (1'-112') -IGKC*01 (113'-219']; dímero (330-330”)-monodisulfuro; pentámero compuesto de 5 dímeros (407-407”:568-568”)- octadisulfuro; pentámero (407''a-15'''':568e-69'''')-bisdisulfuro con la cadena J de Mus musculus (1''''-138'''')

C38714H60189N10637O12187S322 Heavy chain / Chaîne lourde / Cadena pesada EEQVVESGGG FVQPGGSLRL SCAASGFTFS PYWMHWVRQA PGKGLVWVSR 50 INSDGSTYYA DSVKGRFTIS RDNARNTLYL QMNSLRAEDT AVYYCARDRY 100 YGPEMWGQGT MVTVSSGSAS APTLFPLVSC ENSPSDTSSV AVGCLAQDFL 150 PDSITFSWKY KNNSDISSTR GFPSVLRGGK YAATSQVLLP SKDVMQGTDE 200 HVVCKVQHPN GNKEKNVPLP VIAELPPKVS VFVPPRDGFF GNPRKSKLIC 250 QATGFSPRQI QVSWLREGKQ VGSGVTTDQV QAEAKESGPT TYKVTSTLTI 300 KESDWLSQSM FTCRVDHRGL TFQQNASSMC VPDQDTAIRV FAIPPSFASI 350 FLTKSTKLTC LVTDLTTYDS VTISWTRQNG EAVKTHTNIS ESHPNATFSA 400 VGEASICEDD WNSGERFTCT VTHTDLPSPL KQTISRPKGV ALHRPDVYLL 450 PPAREQLNLR ESATITCLVT GFSPADVFVQ WMQRGQPLSP EKYVTSAPMP 500 EPQAPGRYFA HSILTVSEEE WNTGETYTCV VAHEALPNRV TERTVDKSTG 550 KPTLYNVSLV MSDTAGTCY 569 Light chain / Chaîne légère / Cadena ligera DVVMTQSPLS LPVTLGQPAS ISCRSSQSLV YSDGNTYLNW FQQRPGQSPR 50 RLIYKVSNRD SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCMQGTHWP 100 LTFGGGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219 J chain / Chaîne J / Cadena J GDDEATILAD NKCMCTRVTS RIIPSTEDPN EDIVERNIRI VVPLNNRENI 50 SDPTSPLRRN FVYHLSDVCK KCDPVEVELE DQVVTATQSN ICNEDDGVPE 100 TCYMYDRNKC YTTMVPLRYH GETKMVQAAL TPDSCYPD 138 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra chain -IG monomer Intra-H 22-95 144-204 250-313 360-419 467-529 22''-95'' 144''-204'' 250''-313'' 360''-419'' 467''-529'' Intra-L 23'-93' 139'-199' 23'''-93''' 139'''-199''' Inter-H-L 130-219' 130''-219''' Inter-H-H 330-330'' -J chain and pentamer Intra-J 13''''-102'''' 72''''-92'''' 110''''-135'''' Inter-H-H 407a-407''b 407b-407''c 407c-407''d 407d-407''e 568a-568''b 568b-568''c 568c-568''d 568d-568''e Inter-H-J 407''a-15'''' 568e-69''''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación IG monomer : 162, 162'', 325, 325'', 388, 388'', 395, 395'', 556, 556'' J chain: 49''''

256 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

pitolisantum 1-{3-[3-(4-chlorophenyl)propoxy]propyl}

pitolisant 1-{3-[3-(4-chlorophényl)propoxy]propyl}pipéridine

pitolisant 1-{3-[3-(4-clorofenil)propoxi]propil}piperidina

C17H26ClNO

N O

Cl

pozaniclinum pozanicline 2-methyl-3-{[(2S)-pyrrolidin-2-yl]methoxy}pyridine

pozanicline 2-méthyl-3-{[(2S)-pyrrolidin-2-yl]méthoxy}pyridine

pozaniclina 2-metil-3-{[(2S)-pirrolidin-2-il]metoxi}piridina

C11H16N2O

H3C N H N O H

racotumomabum # racotumomab immunoglobulin G1-kappa, anti-idiotype anti-[anti- (N-glycolylneuraminic acid (NeuGc, NGNA)-gangliosides GM3) Mus musculus IgM-kappa monoclonal antibody P3], Mus musculus monoclonal antibody; gamma1 heavy chain (1-445) [Mus musculus VH (IGHV1S56*01 - (IGHD)-IGHJ2*01) [8.8.14] (1-121) -IGHG1*01, CH1 E84.2>Q, N-glycosylation sites CH2 N84.4, CH3 N84.4 (122-445)], (223-214’)- disulfide with kappa light chain (1'-214') [Mus musculus V-KAPPA (IGHKV10-96*01 -IGKJ1*01) [6.3.9] (1'-107') -IGKC1*01 (108'-214')]; (225-225'':228-228'':230-230'')-trisdisulfide dimer

racotumomab immunoglobuline G1-kappa, anti-idiotype anti-[anti-(acide N-glycolylneuraminique (NeuGc, NGNA)-gangliosides GM3) anticorps monoclonal IgM-kappa murin P3], Mus musculus anticorps monoclonal; chaîne lourde gamma1 (1-445) [Mus musculus VH (IGHV1S56*01 -(IGHD)-IGHJ2*01) [8.8.14] (1-121) -IGHG1*01, CH1 E84.2>Q, sites de N-glycosylation CH2 N84.4, CH3 N84.4 (122- 445)], (223-214’)-disulfure avec la chaîne légère kappa (1'-214') [Mus musculus V-KAPPA (IGHKV10-96*01 -IGKJ1*01) [6.3.9] (1'-107') -IGKC1*01 (108'-214')]; dimère (225-225'':228-228'':230- 230'')-trisdisulfure

257 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

racotumomab inmunoglobulina G1-kappa, anti-idiotipo anti-[anti-(ácido N-glicolilneuramínico (NeuGc, NGNA)-gangliósidos GM3) anticuerpo monoclonal murino P3 IgM-kappa], anticuerpo monoclonal de Mus musculus; cadena pesada gamma1 (1-445) [Mus musculus VH (IGHV1S56*01 -(IGHD)-IGHJ2*01) [8.8.14] (1-121) -IGHG1*01, CH1 E84.2>Q, posiciones de N-glicosilación CH2 N84.4, CH3 N84.4 (122-445)], (223-214’)-disulfuro con la cadena ligera kappa (1'-214') [Mus musculus V-KAPPA (IGHKV10-96*01 -IGKJ1*01) [6.3.9] (1'-107') - IGKC1*01 (108'-214')]; dímero (225-225'':228-228'':230-230'')- trisdisulfuro

C6476H9922N1712O2048S50

Heavy chain / Chaîne lourde / Cadena pesada QVQLQQSGAE LVKPGASVKL SCKASGYTFT SYDINWVRQR PEQGLEWIGW 50 IFPGDGSTKY NEKFKGKATL TTDKSSSTAY MQLSRLTSED SAVYFCARED 100 YYDNSYYFDY WGQGTTLTVS SAKTTPPSVY PLAPGSAAQT NSMVTLGCLV 150 KGYFPEPVTV TWNSGSLSSG VHTFPAVLQS DLYTLSSSVT VPSSPRPSET 200 VTCNVAHPAS STKVDKKIVP RDCGCKPCIC TVPEVSSVFI FPPKPKDVLT 250 ITLTPKVTCV VVDISKDDPE VQFSWFVDDV EVHTAQTQPR EEQFNSTFRS 300 VSELPIMHQD WLNGKEFKCR VNSAAFPAPI EKTISKTKGR PKAPQVYTIP 350 PPKEQMAKDK VSLTCMITDF FPEDITVEWQ WNGQPAENYK NTQPIMNTNG 400 SYFVYSKLNV QKSNWEAGNT FTCSVLHEGL HNHHTEKSLS HSPGK 445 Light chain / Chaîne légère / Cadena ligera DIQMTQTTSS LSASLGDRVT ISCRASQDIS NYLNWYQQKP DGTVKLLIYY 50 TSRLHSGVPS RFSGSGSGTD YSLTISNLEQ EDIATYFCQQ GNTLPWTFGG 100 GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI 150 DGSERQNGVL NSWTDQDSKD STYSMSSTLT LTKDEYERHN SYTCEATHKT 200 STSPIVKSFN RNEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 148-203 259-319 365-423 22''-96'' 148''-203'' 259''-319'' 365''-423'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 223-214' 223''-214''' Inter-H-H 225-225'' 228-228'' 230-230''

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

ramucirumabum # ramucirumab immunoglobulin G1-kappa, anti-[Homo sapiens vascular endothelial growth factor receptor 2 (VEGFR2, KDR, kinase insert domain receptor, FLK1, CD309) extracellular domain], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-446) [Homo sapiens VH (IGHV3- 21*01(99.00%) -(IGHD)-IGHJ3*02) [8.8.9] (1-116) - IGHG1*03, R120>K (117-446)], (219-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV1-12*01 (85.30%) - IGKJ4*01, E125>D) [6.3.9] (1'-107') -IGKC*01, R1.4>G (108'-214')]; (225-225'':228-228'')-bisdisulfide dimer

ramucirumab immunoglobuline G1-kappa, anti-[Homo sapiens récepteur 2 du facteur de croissance endothélial vasculaire (VEGFR2, KDR, récepteur à domaine insert kinase, FLK1, CD309) domaine extracellulaire], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-446) [Homo sapiens VH (IGHV3-21*01 (99.00%) -(IGHD)-IGHJ3*02) [8.8.9] (1-116) -IGHG1*03, R120>K (117-446)], (219-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-12*01 (85.30%) -IGKJ4*01, E125>D) [6.3.9] (1'-107') -IGKC*01, R1.4>G (108'-214')]; dimère (225-225'':228-228'')-bisdisulfure

258 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

ramucirumab inmunoglobulina G1-kappa, anti-[receptor 2 del factor de crecimiento endotelial vascular de Homo sapiens (conocido como: VEGFR2, KDR, receptor con dominio inserto-kinasa, FLK1, CD309) dominio extracelular], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-446) [Homo sapiens VH (IGHV3-21*01 (99.00%) -(IGHD)-IGHJ3*02) [8.8.9] (1-116) -IGHG1*03, R120>K (117-446)], (219-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-12*01 (85.30%) -IGKJ4*01, E125>D) [6.3.9] (1'-107') -IGKC*01, R1.4>G (108'-214')]; dímero (225-225'':228-228'')-bisdisulfuro

C6374H9896N1692O1996S46

Heavy chain / Chaîne lourde / Cadena pesada EVQLVQSGGG LVKPGGSLRL SCAASGFTFS SYSMNWVRQA PGKGLEWVSS 50 ISSSSSYIYY ADSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARVT 100 DAFDIWGQGT MVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP 150 EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN 200 VNHKPSNTKV DKKVEPKSCD KTHTCPPCPA PELLGGPSVF LFPPKPKDTL 250 MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR 300 VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG QPREPQVYTL 350 PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD 400 GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK 446 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS VSASIGDRVT ITCRASQGID NWLGWYQQKP GKAPKLLIYD 50 ASNLDTGVPS RFSGSGSGTY FTLTISSLQA EDFAVYFCQQ AKAFPPTFGG 100 GTKVDIKGTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 143-199 260-320 366-424 22''-96'' 143''-199'' 260''-320'' 366''-424'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 219-214' 219''-214''' Inter-H-H 225-225'' 228-228''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 296, 296''

regorafenibum regorafenib 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)- 3-fluorophenoxy]-N-methylpyridine-2-carboxamide

régorafénib 4-[4-({[4-chloro-3-(trifluorométhyl)phényl]carbamoyl}amino)- 3-fluorophénoxy]-N-méthylpyridine-2-carboxamide

regorafenib 4-[4-({[4-cloro-3-(trifluorometil)fenil]carbamoil}amino)-3-fluorofenoxi]- N-metilpiridina-2-carboxamida

C21H15ClF4N4O3

H H N N N H O N Cl F O CH3 CF3 O

riferminogenum pecaplasmidum # riferminogene pecaplasmid plasmid DNA vector with a conditional origin of replication (pCOR) expressing a hybrid protein consisting of a secretion from human fibroblast interferon ß fused to the N-terminus of a truncated form of the human fibroblast growth factor-1 (FGF-1) from amino acid 21 to 154 under the control of a cytomegalovirus promoter

259 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

riferminogène pécaplasmide vecteur constitué d'ADN plasmidique avec origine de réplication conditionnelle (pCOR), exprimant une protéine hybride constituée d'un peptide signal de sécrétion de l'interféron ß de fibroblaste humain, fusionnée à l'extrémité N-terminale de la forme tronquée du facteur de croissance des fibroblastes-1 (FGF-1) de l'acide aminé 21 au 154, sous le contrôle d'un promoteur de cytomégalovirus

riferminogén pecaplásmido vector de DNA plasmídico con un origen de replicación condicionado (pCOR) que expresa una proteína híbrida que consiste en el péptido señal de secreción del interferón ß de fibroblastos humanos, fusionado con la región amino terminal de una forma truncada del factor de crecimiento de fibroblastos humano-1 (FGF-1), desde el aminoácido 21 al 154, bajo el control de un promotor de citomegalovirus

robatumumabum # robatumumab immunoglobulin G1-kappa, anti-[Homo sapiens insulin-like growth factor I receptor (IGF-1R, CD221)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-448) [Homo sapiens VH (IGHV3-48*03 (87.80%) -(IGHD)-IGHJ6*01) [8.7.12] (1-118) -IGHG1*01 (119-448)], (221-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV3-20*01 (83.30%) -IGKJ1*01) [6.3.9] (1'-107') - IGKC*01] (108'-214'); (227-227'':230-230'')-bisdisulfide dimer

robatumumab immunoglobuline G1-kappa, anti-[Homo sapiens récepteur du facteur de croissance analogue à l'insuline 1 (IGF-1R, CD221)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-448) [Homo sapiens VH (IGHV3-48*03 (87.80%) -(IGHD)-IGHJ6*01) [8.7.12] (1-118) -IGHG1*01 (119-448)], (221-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-20*01 (83.30%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01] (108'-214'); dimère (227-227'':230-230'')- bisdisulfure

robatumumab inmunoglobulina G1-kappa, anti-[receptor del factor de crecimiento insulínico tipo 1 de Homo sapiens (IGF-1R, CD221)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-448) [Homo sapiens VH (IGHV3-48*03 (87.80%) -(IGHD)-IGHJ6*01) [8.7.12] (1-118) -IGHG1*01 (119-448)], (221-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-20*01 (83.30%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01] (108'-214'); dímero (227-227'':230-230'')- bisdisulfuro

260 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

C6418H9960N1732O1992S42

Heavy chain / Chaîne lourde / Cadena pesada EVQLVQSGGG LVKPGGSLRL SCAASGFTFS SFAMHWVRQA PGKGLEWISV 50 IDTRGATYYA DSVKGRFTIS RDNAKNSLYL QMNSLRAEDT AVYYCARLGN 100 FYYGMDVWGQ GTTVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150 FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200 CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250 TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300 YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350 TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400 SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK 448 Light chain / Chaîne légère / Cadena ligera EIVLTQSPGT LSVSPGERAT LSCRASQSIG SSLHWYQQKP GQAPRLLIKY 50 ASQSLSGIPD RFSGSGSGTD FTLTISRLEP EDFAVYYCHQ SSRLPHTFGQ 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-95 145-201 262-322 368-426 22''-95'' 145''-201'' 262''-322'' 368''-426'' Intra-L 23'-88' 134'-194' 23'''-88''' 134'''-194''' Inter-H-L 221-214' 221''-214''' Inter-H-H 227-227'' 230-230''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 298, 298''

selumetinibum selumetinib 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)- 1-methyl-1H-benzimidazole-6-carboxamide

sélumétinib 5-[(4-bromo-2-chlorophényl)amino]-4-fluoro-N-(2-hydroxyéthoxy)- 1-méthyl-1H-benzimidazole-6-carboxamide

selumetinib 5-[(4-bromo-2-clorofenil)amino]-4-fluoro-N-(2-hidroxietoxi)-1-metil- 1H-benzoimidazol-6-carboxamida

C17H15BrClFN4O3

Br

F Cl

N NH H N OH N O H C 3 O

serlopitantum serlopitant 3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro- 2H-isoindol-2-yl]cyclopent-2-en-1-one

serlopitant 3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5- bis(trifluorométhyl)phényl]éthoxy}-4-(4-fluorophényl)octahydro- 2H-isoindol-2-yl]cyclopent-2-énone

serlopitant 3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluorometil)fenil]etoxi}- 4-(4-fluorofenil)octahidro-2H-isoindol-2-il]ciclopent-2-en-1-ona

261 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

C29H28F7NO2

H O H CH N 3 CF3 O H H H

CF3 F

siltuximabum # siltuximab immunoglobulin G1-kappa, anti-[Homo sapiens interleukin 6 (IL6, IL-6)], chimeric monoclonal antibody; gamma1 heavy chain (1-449) [Mus musculus VH (IGHV5-9-4*01 - (IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120- 449)], (222-213')-disulfide with kappa light chain (1'-213') [Mus musculus V-KAPPA (IGKV4-55*01 –IGKJ2*01) [5.3.9] (1'-106') - Homo sapiens IGKC*01 (107'-213')]; (228-228'':231-231'')- bisdisulfide dimer

siltuximab immunoglobuline G1-kappa, anti-[Homo sapiens interleukine 6 (IL6, IL-6)], anticorps monoclonal chimérique; chaîne lourde gamma1 (1-449) [Mus musculus VH (IGHV5-9-4*01 - (IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120- 449)], (222-213')-disulfure avec la chaîne légère kappa (1'-213') [Mus musculus V-KAPPA (IGKV4-55*01 -IGKJ1*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; dimère (228-228'':231-231'')- bisdisulfure

siltuximab inmunoglobulina G1-kappa, anti-[Homo sapiens interleukina 6 (IL6, IL-6)], anticuerpo monoclonal quimérico; cadena pesada gamma1 (1-449) [Mus musculus VH (IGHV5-9-4*01 -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120- 449)], (222-213')-disulfuro con la cadena ligera kappa (1'-213') [Mus musculus V-KAPPA (IGKV4-55*01 -IGKJ1*01) [5.3.9] (1'-106') - Homo sapiens IGKC*01 (107'-213')]; dímero (228-228'':231-231'')- bisdisulfuro

C6450H9932N1688O2016S50

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGK LLKPGGSLKL SCAASGFTFS SFAMSWFRQS PEKRLEWVAE 50 ISSGGSYTYY PDTVTGRFTI SRDNAKNTLY LEMSSLRSED TAMYYCARGL 100 WGYYALDYWG QGTSVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449

Light chain / Chaîne légère / Cadena ligera QIVLIQSPAI MSASPGEKVT MTCSASSSVS YMYWYQQKPG SSPRLLIYDT 50 SNLASGVPVR FSGSGSGTSY SLTISRMEAE DAATYYCQQW SGYPYTFGGG 100 TKLEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150 NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200 SSPVTKSFNR GEC 213 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427'' Intra-L 23'-87' 133'-193' 23'''-87''' 133'''-193''' Inter-H-L 222-213' 222''-213''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 299, 299''

262 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

sobetiromum sobetirome (4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}- 3,5-dimethylphenoxy)acetic acid

sobétirome acide (4-{[4-hydroxy-3-(1-méthyléthyl)phényl]méthyl}- 3,5-diméthylphénoxy)acétique

sobetiroma ácido (4-{[4-hidroxi-3-(propan-2-il)fenil]metil}- 3,5-dimetilfenoxi)acético

C20H24O4

HO H3C O CO2H

H3C

CH3 CH3

sofiniclinum sofinicline (1S,5S)-3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo[3.2.0]heptane

sofinicline (-)-(1S,5S)-3-(5,6-dichloropyridin-3-yl)- 3,6-diazabicyclo[3.2.0]heptane

sofiniclina (1S,5S)-3-(5,6-dicloropiridin-3-il)-3,6-diazabiciclo[3.2.0]heptano

C10H11Cl2N3

N Cl

H N Cl

N H H

solanezumabum # solanezumab immunoglobulin G1-kappa, anti-[Homo sapiens amyloid-beta (Abeta) peptide soluble monomer], humanized monoclonal antibody; gamma1 heavy chain [humanized VH (Homo sapiens IGHV3-23*04 (87.60%) -(IGHD)-IGHJ4*01) [8.8.5] (1-112) -Homo sapiens IGHG1*01, CH3 K130>del (113-441)], (215-219')-disulfide with kappa light chain (1’-219’) [humanized V-KAPPA (Homo sapiens IGKV2-30*01 (90.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (221-221":224-224")-bisdisulfide dimer

solanezumab immunoglobuline G1-kappa, anti-[Homo sapiens amyloïde-bêta (Abeta) peptide monomère soluble], anticorps monoclonal humanisé; chaîne lourde gamma1 [VH humanisé (Homo sapiens IGHV3-23*04 (87.60%) -(IGHD)-IGHJ4*01) [8.8.5] (1-112) -Homo sapiens IGHG1*01, CH3 K130>del (113-441)], (215-219')-disulfure avec la chaîne légère kappa (1’-219’) [V-KAPPA humanisé (Homo sapiens IGKV2-30*01 (90.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (221-221":224-224")-bisdisulfure

263 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

solanezumab inmunoglobulina G1-kappa, anti-[péptido amiloide-beta (Abeta) monomèrico soluble de Homo sapiens], anticuerpo monoclonal humanizado; cadena pesada gamma1 [VH humanizada (Homo sapiens IGHV3- 23*04 (87.60%) -(IGHD)-IGHJ4*01) [8.8.5] (1-112) -Homo sapiens IGHG1*01, CH3 K130>del (113-441)], (215-219')-disulfuro con la cadena ligera kappa (1’-219’) [V-KAPPA humanizada (Homo sapiens IGKV2-30*01 (90.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (221-221":224-224")- bisdisulfuro

C6396H9922N1712O1996S42

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFTFS RYSMSWVRQA PGKGLELVAQ 50 INSVGNSTYY PDTVKGRFTI SRDNAKNTLY LQMNSLRAED TAVYYCASGD 100 YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT 150 VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK 200 PSNTKVDKKV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISR 250 TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV 300 LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR 350 DELTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF 400 LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP G 441 Light chain / Chaîne légère / Cadena ligera DVVMTQSPLS LPVTLGQPAS ISCRSSQSLI YSDGNAYLHW FLQKPGQSPR 50 LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHVP 100 WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 139-195 256-316 362-420 22''-96'' 139''-195'' 256''-316'' 362''-420'' Intra-L 23'-93' 139'-199' 23'''-93''' 139'''-199''' Inter-H-L 215-219' 215''-219''' Inter-H-H 221-221'' 224-224''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 292, 292''

taberminogenum vadenovecum # taberminogene vadenovec recombinant E1a and E3 deleted (non-replicating), adenovirus (serotype 5) containing a vascular endothelial growth factor – D (VEGF-D) gene driven by a CMV promoter

taberminogène vadénovec adénovirus (sérotype 5) recombinant (non répliquant), régions E1a et E3 supprimées, contenant un gène du facteur de croissance de l'endothélium vasculaire – D (VEGF-D), sous contrôle d'un promoteur de cytomégalovirus (CMV)

taberminogén vadenovec adenovirus recombinante (serotipo 5) (no replicativo) con deleción de los genes E1a y E3, que contiene el factor de crecimiento endotelial vascular – D (VEGF-D) bajo el control de un promotor de citomegalovirus (CMV)

tarafenacinum tarafenacin (3R)-1-azabicyclo[2.2.2]octan-3-yl (3-fluorophenyl)[(3,4,5- trifluorophenyl)methyl]carbamate

tarafénacine (3-fluorophényl)[(3,4,5-trifluorophényl)méthyl]carbamate de (3R)-1-azabicyclo[2.2.2]oct-3-yle

tarafenacina (3-fluorofenil)[(3,4,5-trifluorofenil)metil]carbamato de (3R)-1-azabiciclo[2.2.2]octan-3-ilo

264 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

C21H20F4N2O2

O H F N O N F

F F

telcagepantum telcagepant N-[(3R,6S)-6-(2,3-diflurophenyl)-2-oxo-1-(2,2,2-trifluroethyl)azepan- 3-yl]-4-{2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl}piperidine- 1-carboxamide

telcagépant N-[(3R,6S)-6-(2,3-difluorophényl)-2-oxo-1-(2,2,2-trifluoroéthyl)- azépan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin- 1-yl)pipéridine-1-carboxamide

telcagepant N-[(3R,6S)-6-(2,3-difluorofenil)-2-oxo-1-(2,2,2-trifluoroetil)azepan- 3-il]-4-{2-oxo-2,3-dihidro-1H-imidazo[4,5-b]piridin-1-il}piperidina- 1-carboxamida

C26H27F5N6O3

O NH CF3 N N N O H H N N H O F F

tilivapramum tilivapram 4-[4-(cyclopropylmethoxy)-5-methoxypyridine-2-carboxamido]- 3,5-dichloropyridine 1-oxide

tilivapram 1-oxyde de 4-[4-(cyclopropylméthoxy)-5-méthoxypyridine- 2-carboxamido]-3,5-dichloropyridine

tilivapram 1-óxido de 4-[4-(ciclopropilmetoxi)-5-metoxipiridina-2-carboxamido]- 3,5-dicloropiridina

C16H15Cl2N3O4

H3CO N Cl H N O O N Cl O

265 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

toceranibum toceranib 5-[(5Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]- 2,4-dimethyl-N-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrrole-3-carboxamide

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

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

C22H25FN4O2

H N O H N CH3 F H N N H C 3 O

tozasertibum tozasertib N-[4-({4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol- 3-yl)amino]pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide

tozasertib N-[4-({4-(4-méthylpipérazin-1-yl)-6-[(5-méthyl-1H-pyrazol- 3-yl)amino]pyrimidin-2-yl}sulfanyl)phényl]cyclopropanecarboxamide

tozasertib N-[4-({4-(4-metilpiperazin-1-il)-6-[(5-metil-1H-pirazol- 3-il)amino]pirimidin-2-il}sulfanil)fenil]ciclopropanocarboxamida

C23H28N8OS

CH3 N S N N O N N H HN CH3 N NH

vanutidum cridificarum # vanutide cridificar inactivated diphtheria toxin (carrier) covalently linked to human beta-amyloid protein 42 short fragments: pentadecakis[N6-Lys-(sulfanylacetyl)]-[52-glutamic acid(G>E)]diphtheria toxin Corynebacterium diphtheriae thioether with human beta-amyloid protein 42-(1-7)-peptidylcysteine

vanutide cridificar court fragment de la protéine 42 bêta-amyloïde liée de façon covalente à la toxine diphtérique inactivée (vecteur) : thioéthers entre la protéine 42 bêta-amyloïde humaine- (1-7)peptidylcystéine et la pentadécakis[N6-Lys-(sulfanylacétyl)]- [52-acide glutamique(G>E)]toxine diphtérique Corynebacterium diphtheriae

266 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

vanutida cridificar pequeño fragmento de la proteína 42 beta-amiloide unido covalentemente a la toxina diftérica inactivada (vector) : tioéteres entre la proteína 42 beta-amiloide humana- (1-7)peptidilcisteína y la pentadecakis[N6-Lys-(sulfanilacetil)]-[52-ácido glutámico G>E)]toxina diftérica Corynebacterium diphtheriae

C3215H4916N900O1053S27

GADDVVDSSK SFVMENFSSY HGTKPGYVDS IQKGIQKPKS GTQGNYDDDW 50 KEFYSTDNKY DAAGYSVDNE NPLSGKAGGV VKVTYPGLTK VLALKVDNAE 100 TIKKELGLSL TEPLMEQVGT EEFIKRFGDG ASRVVLSLPF AEGSSSVEYI 150 NNWEQAKALS VELEINFETR GKRGQDAMYE YMAQACAGNR VRRSVGSSLS 200 CINLDWDVIR DKTKTKIESL KEHGPIKNKM SESPNKTVSE EKAKQYLEEF 250 HQTALEHPEL SELKTVTGTN PVFAGANYAA WAVNVAQVID SETADNLEKT 300 TAALSILPGI GSVMGIADGA VHHNTEEIVA QSIALSSLMV AQAIPLVGEL 350 VDIGFAAYNF VESIINLFQV VHNSYNRPAY SPGHKTQPFL HDGYAVSWNT 400 VEDSIIRTGF QGESGHDIKI TAENTPLPIA GVLLPTIPGK LDVNKSKTHI 450 SVNGRKIRMR CRAIDGDVTF CRPKSPVYVG NGVHANLHVA FHRSSSEKIH 500 SNEISSDSIG VLGYQKTVDH TKVNSKLSLF FEIKS 535 Modified residues / Résidus modifiés / Residuos modificados K (-Lys-) O an average of 15 out of 39 lysines are modified environ 15 des 39 lysines sont modifiées aproximadamente 15 de las 39 lisinas están modificadas H S NH

HAsp Ala Glu Phe Arg His Asp N CO H H 2

H

N C H O Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 186-201 461-471

vedolizumabum # vedolizumab immunoglobulin G1-kappa, anti-[Homo sapiens alpha4beta7 (lymphocyte Peyer's patch adhesion molecule 1, LPAM-1), humanized monoclonal antibody; gamma1 heavy chain (1-451) [humanized VH (Homo sapiens IGHV1-3*01 (84.70%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -Homo sapiens IGHG1*01, CH2 L1.2>A, G1>A (122-451)], (224-219')- disulfide with kappa light chain (1'-219') [humanized V-KAPPA (Homo sapiens IGKV2-29*02 (84.00%) -IGKJ2*01, L124>V) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (230-230":233-233")- bisdisulfide dimer

védolizumab immunoglobuline G1-kappa, anti-[Homo sapiens intégrine alpha4bêta7 (molécule 1 d'adhésion des lymphocytes des plaques de Peyer, LPAM-1), anticorps monoclonal humanisé; chaîne lourde gamma1 (1-451) [VH humanisé (Homo sapiens IGHV1-3*01 (84.70%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -Homo sapiens IGHG1*01, CH2 L1.2>A, G1>A (122-451)] , (224-219')- disulfure avec la chaîne légère kappa (1'-219') [V-KAPPA humanisé (Homo sapiens IGKV2-29*02 (84.00%) -IGKJ2*01, L124>V) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (230- 230":233-233")-bisdisulfure

267 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

vedolizumab inmunoglobulina G1-kappa, anti-[ integrina alfa4beta7 de Homo sapiens (conocida como: molécula 1 de adhesión de los linfocitos de las placas de Peyer, LPAM-1), anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-451) [VH humanizado (Homo sapiens IGHV1-3*01 (84.70%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -Homo sapiens IGHG1*01, CH2 L1.2>A, G1>A (122-451)] , (224-219')- disulfuro con la cadena ligera kappa (1'-219') [V-KAPPA humanizada (Homo sapiens IGKV2-29*02 (84.00%) -IGKJ2*01, L124>V) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (230- 230":233-233")-bisdisulfuro

C6528H10072N1732O2042S42

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGAE VKKPGASVKV SCKGSGYTFT SYWMHWVRQA PGQRLEWIGE 50 IDPSESNTNY NQKFKGRVTL TVDISASTAY MELSSLRSED TAVYYCARGG 100 YDGWDYAIDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV 150 KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ 200 TYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELAG APSVFLFPPK 250 PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300 NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP 350 QVYTLPPSRD ELTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP 400 VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG 450 K 451 Light chain / Chaîne légère / Cadena ligera DVVMTQSPLS LPVTPGEPAS ISCRSSQSLA KSYGNTYLSW YLQKPGQSPQ 50 LLIYGISNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCLQGTHQP 100 YTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Intra-H 22-96 148-204 265-325 371-429 22''-96'' 148''-204'' 265''-325'' 371''-429'' Intra-L 23'-93' 139'-199' 23'''-93''' 139'''-199''' Inter-H-L 224-219' 224''-219''' Inter-H-H 230-230'' 233-233''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación 301, 301''

zicronapinum zicronapine 4-[(1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl]- 1,2,2-trimethylpiperazine

zicronapine 4-[(1R,3S)-6-chloro-3-phényl-2,3-dihydro-1H-indén-1-yl]- 1,2,2-triméthylpipérazine

zicronapina 4-[(1R,3S)-6-cloro-3-fenil-2,3-dihidro-1H-inden-1-il]- 1,2,2-trimetilpiperazina

C22H27ClN2

CH3 N Cl H N CH3 CH3

H

268 WHO Drug Information Vol 23, No. 3, 2009 Recommended INN: List 62

AMENDMENTS TO PREVIOUS LISTS MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES MODIFICACIONES A LAS LISTAS ANTERIORES

Recommended International Non Proprietary Names (Rec. INN): List 53 Dénominations communes internationales recommandées (DCI Rec.): Liste 53 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 53 (WHO Drug Information, Vol. 19, No. 1, 2005) p. 83 suprimáse insértese lenalidomide lenalidomida

Recommended International Non Proprietary Names (Rec. INN): List 59 Dénominations communes internationales recommandées (DCI Rec.): Liste 59 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 59 (WHO Drug Information, Vol. 21, No. 2, 2007) p. 45 supprimer insérer bromure d'azixomère bromure d'azoximère

Recommended International Non Proprietary Names (Rec. INN): List 61 Dénominations communes internationales recommandées (DCI Rec.): Liste 61 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 61 (WHO Drug Information, Vol. 23, No. 1, 2009)

p. 52 bafetinibum bafetinib replace the chemical name and the structure by the following bafétinib remplacer le nom chimique et la structure par les suivants bafetinib sustitúyase el nombre químico y la fórmula desarrollada por los siguientes

N-{3-[([4,5'-bipyrimidin]-2-yl)amino]-4-methylphenyl}-4-{[(3S)-3- (dimethylamino)pyrrolidin-1-yl]methyl}-3-(trifluoromethyl)benzamide

N-[3-([4,5'-bipyrimidin]-2-ylamino)-4-méthylphényl]-4-{[(3S)-3- (diméthylamino)pyrrolidin-1-yl]méthyl}-3-(trifluorométhyl)benzamide

N-{3-[([4,5'-bipirimidin]-2-il)amino]-4-metilfenil}-4-{[(3S)-3- (dimetilamino)pirrolidin-1-il]metil}-3-(trifluorometil)benzamida

N N H H N N N N H3C N F3C H O N CH3 CH3

269 Recommended INN: List 62 WHO Drug Information Vol 23, No. 3, 2009

p. 66 levomilnacipranum levomilnacipran replace the structure by the following lévomilnacipran remplacer la structure par la suivante levomilnaciprán sustitúyase la fórmula desarrollada por la siguiente

CH3

O N CH3 H

NH2

# 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.

270