WHO Drug Information Vol 23, No. 3, 2009 World Health Organization WHO Drug Information Contents International Nonproprietary Regulatory Action and News Names Withdrawal of dextropropoxyphene 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 insulin 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-agonists in chronic Directive 222 obstructive pulmonary disease 205 WHO list of recently prequalified Varenicline and bupropion: serious medicinal products 223 mental health events 206 Pain medications 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 monoclonal antibody 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- –mab 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. 195 International Nonproprietary Names WHO Drug Information Vol 23, No. 3, 2009 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 pharmacokinetics and/or immunobio- nonproprietary nature of the INN. Never- logical functions. In particular, glycosyla- theless, this is consistent with