Who drug information vol2

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WHO Drug Information Vol 23, No. 2, 2009

WHO Drug Information

Contents

World Health Organization

Pharmacovigilance FocusBiosimilar medicines and safety: newchallenges for pharmacovigilance 87

Blood and BiomedicinesAvailability, quality and safety of blood

and blood products 95

New Regulatory ChallengesContribution of clinical pharmacologists

to government: opportunities andchallenges 99

Safety and Efficacy IssuesEtanercept: histoplasmosis and invasive

fungal infections 104Zonisamide: metabolic acidosis 104Progressive multifocal leuko-

encephalopathy 105Severe adverse reactions with

intravenous immunoglobulin 105Exanatide: risk of severe pancreatitis

and renal failure 106Benefits of methylphenidate continue to

outweigh risks 106Chromic phosphate P32: acute

lymphocytic leukaemia 107Warning for metoclopramide-containing

drugs 108Metabolic effects of antipsychotics 108Cefaclor and serum sickness-like

reactions in children 108Toremifene: prolongation of QTc interval 109Atomoxetine: risk of psychotic or manic

symptoms 109Lignocaine with chlorhexidrine gel:

anaphylaxis 110Moxifloxacin safety update 110Codeine toxicity in breastfed infants 110Atypical antipsychotics: risk of stroke 111Biphosphonates: atypical stress fractures 112Effects of MRI on implantable drug pumps113

Sodium valproate and fetal malformations113Abacavir: determining risk of heart attack 114Carbamazepine: serious adverse skin

reactions 114Electronic adverse reaction reporting tool 115Intensive monitoring of varenicline 116

Regulatory Action and NewsInfluenza virus vaccines: 2009–2010

season 117Sale of efalizumab suspended 117Efalizumab: voluntary withdrawal 118Oseltamivir: extension of shelf life 118Antiviral medicines in an influenza

pandemic 119European Union and Health Canada:

confidentiality arrangement 119Ixabepilone: withdrawal of application

for marketing authorization 120Peginterferon alfa–2b: withdrawal of

application for marketing authorization 120Levodopa/carbidopa/entacapone:

withdrawal of application forextension of indication 120

Medicines Strategyand PoliciesGood Governance for Medicines

Programme 122

Recent Publications,Information and EventsASEAN: mutual recognition arrangement

for GMP 127Losing artemisinin? 127International drug price indicator guide 128

Proposed InternationalNonproprietary Names: List 101

129

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Pharmacovigilance Focus

Biosimilar medicines andsafety: new challenges forpharmacovigilanceRegulatory experience of approving andmonitoring the safety of biosimilar medi-cines varies across the world. Recently,the European Union (EU) took the lead inestablishing a transparent regulatoryprocess for approving biosimilars. Todate, the EU has approved a number ofbiosimilars such as formulations ofsomatotropin, epoietin and, most recently,filgrastim. The prevailing view amongregulators is that proteins are much morecomplex than small molecule medicinesand it may not be possible to demonstratethe identical nature of two biologicalproducts originating from different manu-facturing sources solely based on qualityinformation.

This has led to the view that follow-onbiological products manufactured bygeneric manufacturers after expiry ofpatent and other exclusivity rights cannotbe approved using the same simplifiedregulatory procedures as applied forsmall molecule-based generic drugs.Generating additional nonclinical andclinical data to demonstrate that thesemedicines have an equivalent, or similar,safety and efficacy profile to the originatorproduct is needed. However, severalparties have raised concerns that suchregulatory procedures may not be enoughto ensure the safety and efficacy of theseproducts. This article gives an overview ofregulatory experience as well as the mainprinciples and issues concerning quality,safety and efficacy of these products.

Biological medicinal products (biopharma-ceuticals) have a successful record intreating many life threatening and chronicdiseases. However, their cost has oftenbeen high, thereby limiting their access topatients, notably in developing countries.More recently, the expiration of patentsand/or data protection for the first majorgroup of innovative biotherapeutics isstimulating development of products“similar” to the original biological productswhich rely for their licensing, in part, ondata from originator products licensed ona full registration dossier.

A variety of terms, such as ‘biosimilars’,‘follow-on protein products’ and ‘subse-quent-entry biologics’ have been used bydifferent jurisdictions to describe theseproducts. The term ‘generic’ medicine isused extensively for chemical, smallmolecule medicinal products that arestructurally and therapeutically equivalentto an originator product whose patentand/or data protection period has expired.

Current situationIn many countries, a regulatory pathwayfor the approval of generic medicines hasbeen established. Since biological medici-nal products consist of large and highlycomplex molecular entities that aredifficult to characterize, the approachestablished for small molecule genericmedicines is not fully appropriate fordevelopment, evaluation and licensing ofbiosimilars — as they are called in theEU. The fine structure of a biotherapeuticmedicine is very sensitive to variousproduction parameters and the fullunderstanding of all processes involved iscomplicated. Thus, it is unlikely that one

* This article does not necessarily reflect the policies and views of the World Health Organiza-tion.

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manufacturer will be able to preciselyreproduce a biotherapeutic medicinemanufactured by another company.Indeed, an increasingly wide range ofbiosimilars are under development oralready licensed in many countries.

As stated, the EU has taken the lead inestablishing a regulatory process forapproving biosimilars and EU legislationnow differentiates between “genericmedicinal products” and “similar biologicalmedicinal products”. It also defines theregulatory approach for EU marketingauthorization of biosimilar medicinalproducts. Both general [1–3] and product-specific guidelines dealing with recom-binant erythropoietin [4], granulocytecolony stimulating factor (G-CSF) [5],human somatotropin [6] and humaninsulin [7] have been issued by theCommittee for Medicinal Products forHuman Use (CHMP) of the EuropeanMedicines Agency (EMEA). Draft guide-lines have also been issued for interferonalfa [8] and low molecular weightheparins [9]. All these guidelines haveone common feature — identifying theneed for at least some clinical data tosupport the approval of biosimilar medici-nal products.

In the USA, there is currently no set ofguidelines comparable to those of the EUfor biosimilars. The Food and DrugAdministration (FDA) has approvedOmnitrope®, a growth hormone biosimilar,but this was done using the abbreviatednew drug application (ANDA) procedurewhich essentially defines biosimilars as“chemical” generic drugs rather thanbiopharmaceuticals [10]. However, thismethod of approval is rather exceptionalas specific US regulatory guidelines forapproval of biosimilars do not currentlyexist. Also, in most other countries acomparative set of guidelines to those ofthe EU is absent.

The need for additional global regulatoryguidelines for evaluation and overall

regulation was formally recognized by theWorld Health Organization (WHO) in2007. Since then, WHO has been work-ing with regulators from many countrieson a draft document that provides guid-ance for the development and evaluationof biological therapeutic products thatmay be subject to abbreviated licensingpathways [11]. The document is expectedto be finalized later in 2009.

Generic medicines and biosimilars:similarities and differencesMultisource (generic) medicines areformulated when patent and other exclu-sivity rights expire. These medicines havean important role to play in public healthas they are well known to the medicalcommunity and usually more affordabledue to competitive availability.

The key requirement for authorization ofgeneric medicines is therapeutic inter-changeability with the originator product.To ensure therapeutic interchangeability,generic products must contain the sameamount of active ingredient and have thesame dosage form and be bioequivalentto the originator product. Bioequivalenceis usually established using comparativein vivo pharmacokinetic studies with theoriginator product (or reference product).A detailed description of how this iscarried out is described in respectiveWHO and national regulatory guidelines[12, 13]. Well-resourced regulatoryauthorities require that a multisource(generic) medicine must meet certainregulatory requirements. In a well estab-lished setting, a generic medicine ingeneral must:

• contain the same active ingredients asthe innovator drug;

• be identical in strength, dosage form,and route of administration;

• have the same use indications;

• be bioequivalent (as a surrogate markerfor therapeutic interchangeability).


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• meet the same batch requirements foridentity, strength, purity and quality, and

• be manufactured under the samestandards of good manufacturingpractice (GMP) required for innovatorproducts.

Traditional generic medicines are small,organic molecules with a well-character-ized structure which can be more easilydefined by their atomic structure thantheir manufacturing processes. In thecase of more complicated generic medi-cines, processes of synthesis are used.For example, biotechnological methodsare applied to produce large moleculemedicines such as antibiotics (for exam-ple, streptomycin). Sometimes, severalmethods of synthesis are combined,including the use of genetically engi-neered microorganisms in fermentation.What makes a difference is how well theresulting active pharmaceutical ingredient(API) can be characterized without riskingunidentified impurities and subtle struc-tural changes resulting in different safetyand efficacy profiles.

The current challenge facing internationaldevelopment of a programme for bio-similars is that there is no way of confirm-ing that the reference product on themarket in one region complies withrequirements in other regions. It is truethat even identifying a global comparatorfor generic “chemical” medicines issometimes very challenging. Above all,the essential characteristics of a bio-similar are not yet perfectly defined. Forexample, some consider that only fullycharacterized proteins with no majordifferences in their structure or impurityprofile can be considered biosimilar.However, EU regulators have accepted adegree of difference provided it can bejustified. For example, Valtropin® (soma-totropin) is expressed from yeast whereasits reference product, Humotrope®, isexpressed from Escherichia coli. This

necessarily implies different host cellimpurities as a minimum but the regulatorhas accepted the product as biosimilar[14]. Differences with other products havebeen justified as being within the range ofnatural variants without major clinicalimpact.

Originator products can go through anumber of variations during productdevelopment and the post marketingperiod. However, it is difficult to ascertainwhether major process variations (e.g.cloning, selection of a suitable cell line,fermentation, purification and formulation)will affect the end product. Thus, a bio-similar may differ significantly from theoriginator product. In principle, some ofthe variations applied by originators canbe more substantial than those applied bygeneric manufacturers. When assessingand accepting variations applied to themanufacture of originator products,regulators can acquire valuable informa-tion for assessing biosimilars.

At present, lack of consistency betweenoriginator epoietins and products manu-factured in countries outside well regu-lated markets (such as the EU and USA)was demonstrated at the World Congressof Nephrology in 2007 [15, 16]. Someproducts were identified as containingadditional basic isoforms — more than4% aggregates and bacterial endotoxincontamination. These findings may affectefficacy, immunogenicity and patientsafety, respectively [16, 17]. Finally, someof these biosimilar products were notapproved under a specific well-definedand transparent regulatory framework.Biopharmaceutical safety and efficacydata are difficult to transcribe into adiscernable format and it is a challengedemonstrating that a biosimilar product isas safe or effective as the originator. It ishoped that rapid advances in science andknowledge obtained from regulatorypractice may make this task easier in thefuture.


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Safety of biosimilars: specificpoints of concernThe two main issues of concern withbiosimilar agents involve variable po-tency/response and immunogenicitythought to be due to one of three mainmechanisms: glycosylation, contamina-tion or changes to three-dimensionalstructure. Immunogenicity is generally theprimary safety concern, but variation inpotency can also raise safety issues inthe case of substitution of the originalmolecule with biosimilars, e.g. variabilityin haemoglobin values seen with originalepoietin [18] and its possible associationwith increased mortality in dialysis pa-tients [19]. The issues of safety andefficacy cannot easily be separated asbinding of an agent by immune systemmolecules will often decrease its clinicaleffect and changes to the shape orstructure of a protein can alter binding toimmune system receptors as well as to itsphysiological target. Therefore, biosimi-lars could induce immune responseswhich may be either clinically irrelevant orcould have severe and potentially lethalconsequences.

The glycosylation of recombinant proteinscan influence degradation, exposure ofantigenic sites and solubility, as well asimmunogenicity. Changes in degradationcan produce novel antigenic epitopes notfound in the parent molecule with poten-tially increased immunogenicity andbiological activity and metabolic half-lifealso affected. The degree of glycosylationdepends primarily on the host cell expres-sion system. For example, recombinantG-CSF expressed in Escherichia coli isnon-glycosylated, whereas that ex-pressed in Chinese hamster ovary cells isglycosylated. Similarly, proteins manufac-tured in yeast cells contain high levels ofmannose sugar groups, rendering themmore prone to degradation and therebydecreasing their half-life. [See references20 and 21 for more details about effectsof immunogenicity.]

Another important factor is potentialcontamination during manufacturing.Impurities in biopharmaceuticals mayderive from chemicals or antibiotics usedduring manufacture or may result frommicrobial or viral contamination. Impuritiessuch as endotoxins or denatured pro-teins, for example, may give a dangersignal to T cells which may then sendactivating signals to B cells leading to animmune response.

An important lesson was learned in thecase of an increasing incidence of anti-body-mediated pure red cell aplasia(PRCA) observed outside the USAbetween 2000 and 2002 which revealedthat a small change in the formulation of awell-established innovator biopharma-ceutical product (epoietin alfa) withextensive patient years experience mayhave significant clinical consequences[22]. The sharp increase in incidenceoccurred primarily among those onEprex®/Erypo®, and coincided withreplacement of human serum albumin asa stabilizer by glycine and polysorbate 80.Subsequent withdrawal of the SC formu-lation of epoietin alfa led to a consider-able decrease in the incidence of PRCAcases. A number of possible mechanismshave been proposed to explain theobserved upsurge of PRCA but it is likelythe modification in formulation played amajor role [23].

Alterations to the three-dimensionalstructure of a protein may also haveimportant effects on immunogenicity.Major sources of such changes includeprotein aggregation (which has beensuggested as one possible explanation ofthe PRCP epidemic described above),oxidation and deamidation. Likely aggre-gation is of particular concern as it maylead to the immune system recognizingthe protein as non-self and mounting aresponse [24]. This is probably becausethe repeating structure of protein aggre-gates more closely resembles the micro-


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bial structures that the immune system isprimed to act against [25]. The processby which the body becomes reactive tothe protein can be very slow: antibodiesto products such as interferon and eryth-ropoietin may be detected for more than ayear after treatment cessation [26].

Clinical safety dataand pharmacovigilanceThe concerns raised above have beenaddressed, as far as possible and in linewith present scientific knowledge, in EUregulatory guidance. For example,erythropoietin is a more complex mole-cule compared to either insulin or growthhormone. The respective guidelinesreflect this complexity and, in order toidentify potential immunogenicity, advo-cate conducting at least two randomizedcontrolled trials confirming safety datacollected over a minimum of 12 monthsfrom at least 300 patients. Within the EUauthorization procedure, the applicantshould present a risk managementprogramme/pharmacovigilance plan inaccordance with current EU legislationand pharmacovigilance guidelines.

In order to further study the safety profileof the biosimilar medicinal product, datafor rare adverse events should be col-lected from a cohort of patients represent-ing all approved therapeutic indications.Specific reference is made to includeassessment of the incidence of PRCAwithin the pharmacovigilance plan forepoietin biosimilars [4]. It is clear that with300 patients PRCA may not be detecteddue to the relatively small number ofpatients involved as compared to therarity of this complication. Consequently,EMEA guidelines for epoietins alsorequire immunogenicity testing andpharmacovigilance programmes tomonitor the efficacy and safety ofbiosimilar products during post-approval.

Nonetheless, some adverse effects maytake more than a year to appear [26] and

even very small changes in manufactur-ing can have major consequences for aproduct’s adverse effects [27]. Pharma-covigilance is thus likely to be a long-termproject for any biosimilar medicine.Overall, routine pharmacovigilance isrecommended for products where nospecial concerns have arisen, whereasadditional pharmacovigilance activitiesand action plans will be required formedicinal products with important estab-lished risks, potential risks or missinginformation.

Spontaneous reporting still remains thecornerstone of pharmacovigilance but hasseveral weaknesses. Often, only theinternational nonproprietary name (INN)is used as the sole product identifier andin the case of several products with thesame INN (originator, plus generics orbiosimilars) it may be difficult to trace theexact manufacturer of the product. Amuch better traceability of products isneeded [28], particularly in the case ofbiosimilars.

Recent developments within the Interna-tional Conference on Harmonization ofTechnical Requirements for Registrationof Pharmaceuticals for Human Use (ICH)raise hopes that a harmonized set ofproduct identifiers will become availablesoon and could improve future traceabil-ity. Recently, the ICH Steering Committeerecognized the benefits of continuing towork with International Standard Develop-ment Organizations in developing harmo-nized electronic messages to transferregulatory information with a view todeveloping harmonized formats forIndividual case safety reports (ICSR) andidentification of medicinal products [29]

Different versions of biopharmaceuticalshave been available in both India andChina for several years [30]. It is impor-tant to note that both India and China areconsidered to have less stringent regula-tory standards than the EU and the USA.


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Unfortunately, both countries have under-developed pharmacovigilance systemsand provide only small number of adversedrug reaction reports to the WHO Interna-tional Programme on Drug Monitoringdatabase managed by the UppsalaMonitoring Centre [31].

ConclusionsThe cost of providing effective therapiesin different disease areas increasesprogressively and biosimilar medicinesmay offer considerable advantages tohard-pressed health-care budgets glo-bally. Regulatory decisions to permitclinical use should be based on rigorousand highly competent case by casescientific assessments and presence ofappropriate systems for pharmacovigi-lance. Clearly this area of rapidly evolvingregulatory science would benefit frombetter cooperation and informationexchange between different regulatorsinternationally. Safety has to come firstand effective pre- and post-marketingsafety monitoring remains the key.

Sufficient regulatory tools are currentlyavailable to ensure safety of biosimilarsbut the proper implementation of thesetools may prove challenging, particularlyoutside well established and resourcedregulatory settings. Even in the EU,applying pharmacovigilance programmeswith uniform excellence across the regionremains a challenge. Pharmacovigilanceis a responsibility that is shared amongactors in the pharmaceutical industry,physicians and pharmacists, with inputfrom appropriately educated and informedpatients. Much better cooperation be-tween all stakeholders is needed toensure that everyone involved fullyunderstands the complex scientificarguments and regulatory decisionsapplying to biosimilar products. Thiswould hopefully lead to safer use andbetter qualitative and quantitative report-ing of suspected adverse reactions.Biosimilar medicines clearly have a future

but patients should not be expected tobear the burden of excessive trial-errorincidents.

References

1. European Medicines Agency. Guideline onSimilar Biological Medicinal Products, CPMP/437/04, October 2005. www.emea.europa. eu/pdfs/human/biosimilar/043704en.

2. European Medicines Agency. Guideline onSimilar Biological Medicinal Products Contain-ing Biotechnology-derived Proteins as DrugSubstance – Non Clinical and Clinical Issues,CHMP/42832/05, February 2006. www.emea.europa.eu/pdfs/human/biosimilar 4283205en.

3. European Medicines Agency. SimilarBiological Medicinal Products ContainingBiotechnology-derived Proteins as ActiveSubstance: Quality Issues, CHMP/49348/05,February 2006. www.emea.europa.eu/pdfs/human/biosimilar/4934805en.

4. European Medicines Agency. AnnexGuideline on Similar Biological MedicinalProducts Containing Biotechnology-derivedProteins as Drug Substance – Non Clinicaland Clinical Issues containing RecombinantHuman Erythtropoietin, CHMP/94526/05,March 2006. www.emea.europa.eu/pdfs/human/biosimilar/9452605en.

5. European Medicines Agency. AnnexGuideline on Similar Biological MedicinalProducts Containing Biotechnology-derivedProteins as Drug Substance –Non Clinical andClinical Issues containing RecombinantGranylocyte Colony-Stimulating Factor,CHMP/313297/05, February 2006. www.emea.europa.eu/pdfs/human/biosimilar/313297/05en.

6. European Medicines Agency. AnnexGuideline on Similar Biological MedicinalProducts Containing Biotechnology-derivedProteins as Drug Substance – Non Clinicaland Clinical Issues containing RecombinantHuman Growth Hormone, CHMP/94528/05,February 2006. www.emea.europa.eu/pdfs/human/biosimilar/9452805en.

7. European Medicines Agency. AnnexGuideline on Similar Biological MedicinalProducts Containing Biotechnology-derived


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Proteins as Drug Substance – Non Clinicaland Clinical Issues. Guidance on SimilarMedicinal Products Containing RecombinantHuman Insulin CHMP/BMWP/32775/05,February 2006. www.emea.europa.eu/pdfs/human/biosimilar/3277505en.

8. European Medicines Agency. Guideline onSimilar Biological Medicinal Products Contain-ing Low-molecular Weight Heparins EMEA/CHMP/BMWP/118264/07. Draft released forconsultation in April 2008. www.emea.europa.eu/pdfs/human/biosimilar/11826407en.

9. European Medicines Agency. Guideline onSimilar Biological Medicinal Products Contain-ing Recombinant Interferone Alpha EMEA/CHMP/BMWP/102046/06. Draft released forconsultation in October 2007. www.emea.europa.eu/pdfs/human/biosimilar/10204606en.

10. Belsey MJ, Harris LM, Das RR et al.Biosimilars: initial excitement gives way toreality. Nat Rev Drug Discov 2006, 5:535–536

11. World Health Organization. Regulatorypathways for biosimilar products. WHO DrugInformation 2008 22(1). www.who.int/druginformation

12. World Health Organization. Multisource(generic) pharmaceutical products: guidelineson registration requirements to establish inter-changeability. In: WHO Expert Committee onSpecifications for Pharmaceutical Prepara-tions. Fortieth Report. Technical ReportSeries, 937, Annex 7, 347–390.

13. European Medicines Agency. Guideline onthe Investigation of Bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1. Draft released forconsultation in July 2008. www.emea.europa.eu/pdfs/human/qwp/140198enrev1.

14. European Medicines Agency. Valtropin.European Public Assessment Report, Revi-sion 1. www.emea.europa.eu/humandocs/Humans/EPAR/valtropin/valtropin.htm.

15. Park SS, Deechongkit S, Patel SK.Analytical comparisons of certain erythropoi-etin products from Asia and Amgen’s epoetinalfa. Abstract M-PO-0592. World Congress ofNephrology, April 21–25, 2007, Rio deJaneiro, Brazil. Available at: http://www.wcn2007.org

16. Singh AK. Gaps in the quality and potentialsafety of Biosimilar epoetins in the developingworld: an international survey. Abstract S-PO-0412. World Congress of Nephrology, April21–25, 2007, Brazil, Rio de Janeiro. Availableat: http://www.wcn2007.org

17. Hermeling S, Schellekens SH, CrommelinDJ et al. Micelle-associated protein in epoetinformulations: a risk factor for immunogenicity?Pharm Res 2003, 20:1903–1907.

18. Berns JS, Elzein H, Lynn RI et al.Hemoglobin variability in epoetin-treatedhemodialysis patients. Kidney Int 200364:1514–1521.

19. Yang W, Israni RK, Brunelli SM, et al.Hemoglobin variability and mortality in ESRD.J Am Soc Nephrol 2007 18:3164–3170.

20. Kessler M, Goldsmith D, Schellekens H.Immunogenicity of biopharmaceuticals.Nephrology Dialysis Transplantation 200621(5:v9-v12). http://ndt.oxfordjournals.org/cgi/content/full/21/suppl_5/v9

21. Biosimilars and biopharmaceuticals: whatthe nephrologists need to know—a positionpaper by the ERA–EDTA Council. NephrologyDialysis Transplantation 2008 23(12):3731–3737 http://ndt.oxfordjournals.org/cgi/content/full/23/12/3731

22. Casadevall H, Nataf J, Viron B et al. Purered-cell aplasia and anti-erythropoietinantibodies in patients treated with recombinanterythropoietin. N Engl J Med 2002 346:469–475.

23. Schellekens H. Immunologic mechanismsof EPO-associated pure red cell aplasia. BestPract Res Clin Haematol 2005 18:473–480.

24. Rosenberg AS. Effects of protein aggre-gates: an immunologic perspective. AAPSJournal 2006 8: E501–E507.

25. Schellekens H. Immunogenicity of thera-peutic proteins: clinical implications and futureprospects. Clin Ther 2002 24:1720–1740.

26. Schellekens H. The first biosimilar epoetin:but how similar is it? Clin J Am Soc Nephrol2008 3:174–178.


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27. Schellekens H. Erythropoietic proteins andantibody-mediated pure red cell aplasia: apotential role for micelles. Nephrol DialTransplant 2004 19:2422.

28. Lamarque V, Merle L. Generics andSubstitution Modalities: Proposed Methods forthe Evaluation of Equivalence, Traceabilityand Pharmacovigilance Reporting. Thérapie2008 63:311–319

29. ICH Steering Committee Press Release.Evolving Science in Drug Safety and Quality,

Brussels, Belgium, Novermber 8–13, 2008,http://www.ich.org/cache/compo/276-254-1.html

30. Frost and Sullivan. Biogenerics demand togo up in Asia. Express Pharma Pulse October7 (2004), Available at: http://www.expresspharmaonline.com/20041007/biogenerics01.

31. The Uppsala Monitoring Centre. http://www.who-umc.org/DynPage.aspx


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Blood and Biomedicines

Availability, quality andsafety of blood and bloodproductsBlood has been collected, stored, tested,and transfused as a therapeutic since thebeginning of the Twentieth century. Untilthe 1950s, activities concentrated onimproving storage of cells and ensuringblood group compatibility. Thereafter,methods were developed for preparingtherapeutic products from human bloodand plasma, for use in treating life-threatening diseases, and to supportcomplex surgical procedures and trans-plantation.

For the past 25 years, efforts havefocused on improving the safety andefficacy of components derived fromblood and plasma, developing andvalidating new methods, and seeking newtherapeutic uses. Blood products such asblood clotting factors and humanimmunoglobulins (polyvalent and specific)are now included in the World HealthOrganization’s (WHO) Model List ofEssential Medicines. This reflects theimportance of blood and blood productsin treating congenital, immune-acquiredlife-threatening diseases, and conditionssuch as bleeding or trauma. In vitrodiagnostic devices for sensitive detectionof infectious disease markers play a rolein successfully screening donor blood andtesting plasma pools prior to fractionation,as well as in clinical diagnosis.

Transmission of infectious diseases byblood (notably HIV, hepatitis B (HBV) andhepatitis C (HCV)) has underscored theimportance of quality systems and effec-tive regulation in the preparation ofplasma as a raw material for use in the

manufacture of medicinal products and insupply of other blood components suchas platelets and red cells.

Developed countries have implementedprocedures, policies and methods toensure the safety, quality and availabilityof all products derived from blood. Thishas facilitated wider access to a compre-hensive range of safe blood products forpatients with bleeding, immunological orother severe diseases. Additionally, goodmanufacturing practices (GMP) havebeen introduced into plasma fractionationcentres and are now also applied in bloodestablishments. Improvements in healthand transfusion safety have been docu-mented by haemovigilance and phar-macovigilance programmes. Conversely,comparable levels of availability, qualityand safety do not yet exist in manydeveloping countries (1).

Equitable and universal access to bloodand blood products of assured qualityand efficacy will contribute to achieve-ment of the UN Millennium DevelopmentGoals relating to reduction of maternaland child mortality, as well as to efforts toprevent HIV, HBV and HCV transmission.

Specific issues requiringactionWastage of blood plasmaSeveral reasons account for the lack ofblood products in developing countries.Plasma collected in developed countriesis restricted and the potential for generat-ing surplus products sufficient to meet theneeds of developing countries is small.Moreover, such products would be tooexpensive. Developing countries musttherefore create their own sustainablesupplies of blood products using blood

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plasma collected by their own bloodestablishments from their own popula-tions. Currently, however, a large percent-age of the plasma collected in developingcountries is categorized as a wastematerial and destroyed. This is becauseappropriate technology and enforcementof GMP are not available. Fractionationcapacity could, however, become avail-able if plasma production complied withinternationally-agreed standards.

Risk of transfusion-transmitteddiseasesIf rigorous standards for donor selection,testing and donation are not applied,blood products and blood transfusionremain potent vectors for transmission ofinfectious diseases. Unfortunately, currentarrangements for blood plasma collection,processing and testing are inadequate ina vast number of developing countries. Inaddition, increasing international mobilityof populations and globalization of theblood industry highlight the need tointroduce and strengthen quality assur-ance regulations.

The history of blood transfusion hasamply demonstrated the risks. Examplesinclude transmission of HIV, HCV andHBV, bacteria, trypanosoma and malarialparasites, as well as emerging and re-emerging diseases. Although worldwideexpansion of human blood plasmacollection and processing of blood prod-ucts has the capacity to save lives,without appropriate control and standardi-zation it can also amplify public healthrisks.

Poor regulation of blood products indeveloping countriesDeveloping countries recognize the needto regulate blood products and assureblood safety. Blood establishmentsshould be subject to inspection and auditby national regulatory authorities andfractionators should demonstrate effectivecontrol and traceability of plasma raw

material. Substantial improvement willprevail through introduction and enforce-ment of appropriate independent andtransparent quality assurance regulationsand inspection procedures.

Cross-border threatsThe risks of disease migration are esca-lating due to changes in habitat, increas-ing mobility of populations, wars andglobal climate change. Pandemic infec-tions may also affect the supply of bloodand blood products in different ways.These factors underscore the need tointroduce and strengthen quality assur-ance regulations in developing countries.The trend towards global regulatoryconvergence favours sharing of bestpractices and the creation of internation-ally agreed regulations. Internationalcoordination, notably in areas such as themanufacture of blood products, is there-fore becoming increasingly important.

WHO activitiesFor more than 50 years, WHO has beenclosely involved in setting quality andsafety standards and training regulatorsin the manufacture and quality control ofbiological and blood products. The overalltechnical responsibility for these activitieslies with the WHO Expert Committee onBiological Standardization (ECBS).Guidelines on the manufacture andquality control of blood and blood prod-ucts have been developed, updated andpromoted by WHO (2–4). They representglobal consensus on the part of manufac-turers, regulators, professional interna-tional societies and national blood pro-grammes with respect to production andquality assurance procedures for bloodand blood products.

International biological reference prepara-tions (5) to assist in establishing thequality and safety of blood products andrelated in vitro diagnostic devices havealso been adopted following validation inglobal coordinated studies. The value of


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reliable internationally agreed referencematerials is that manufacturers, regula-tors and blood establishments cancompare results worldwide despite theincreasing diversity of products.

Public health challenges demonstrate theneed for international collaboration andcooperation and the need to createregulatory networks to support dissemina-tion of regulatory actions, knowledgetransfer and organization of trainingprogrammes. The International Confer-ence on Drug Regulatory Authorities(ICDRA) provides regulatory authorities ofWHO Member States with a forum tomeet and discuss ways to strengthencollaboration. In 2005, the WHO BloodRegulators Network was established inresponse to the request by ICDRAparticipants and the ECBS. The Networkwas set up to foster development ofinternational consensus on effectiveregulatory approaches.

Recognizing the importance of theprovision of safe blood, blood compo-nents and plasma derivatives, the Fifty-eighth World Health Assembly in 2005(Resolution 58.13) expressed its supportfor “full implementation of well organized,nationally coordinated and sustainableblood programmes with appropriateregulatory systems” and stressed the roleof “voluntary, non-remunerated blooddonors from low-risk populations”.

Improving access to bloodand blood productsIn order to ensure the availability of safeblood products in developing countries,Member States should be alerted to therisks of inadequate regulation and guid-ance should be provided on establishingregulatory oversight of blood systems.Efforts should be made to increase thetransfer of validated technology and tobuild capacity with the overall aim ofimproving access to safe, effective andaffordable blood products.

As a first step, up-to-date mechanisms forimplementing and enforcing qualitystandards relating to blood products andblood safety-related in vitro diagnosticdevices will need to be introduced incountries. Activities should be supportedby WHO guidelines for the production ofblood plasma for fractionation, comple-mented with additional guidelines topromote and support implementation ofGMP. Work should also be undertaken toreview existing national regulations forblood products and to support and furtherdevelop technical upgrading of medicinesregulatory authorities. Furthermore,strategies should be sought to share theexpertise and experience already gener-ated in developed countries and todevelop regional regulatory networks.

The dimension and complexity of thesituation requires a multifaceted strategyincorporating input from partners atnational, regional and international levels.WHO is well placed to secure the supportof international and nongovernmentalorganizations, international professionalassociations and other agencies devotedto finding solutions for health problems.

Creating sustainable blood and plasmaprogrammes with appropriate regulatorysystems will ensure both specific andwider public health benefits including:

• optimal use of donated blood plasma;

• safer blood components;

• sustainable and affordable supply ofsafe essential products for the treatmentof congenital diseases, trauma andimmunologically mediated conditions;

• reduction of infectious disease transmis-sion via blood-borne pathogens, bothwithin countries and across nationalborders;

• improved quality and safety of allproducts from blood establishments


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through the enforcement of national(and international) quality assuranceregulations;

• substantial contribution to national/regional public health programmesthrough, for example, improved popula-tion epidemiology for infectious dis-eases such as HIV, HBV and HCV,prevention and control of diseasetransmission, and blood donor healthmonitoring;

• potential application of quality systemsand GMP principles to other medicallaboratory disciplines, and

• inclusion of developing countries in theinternational transfusion community andin activities of associated plasmafractionation industries.

The strategic goal is to improve publichealth by providing safe and effectivemedicine to the world’s population. A risk–benefit analysis must ensure that suffi-cient quantities of the required productsare available at a cost that does not limitaccess.

References

1. Global Database on Blood Safety.http://www.who.int/bloodsafety/global_database/en/

2. World Health Organization. Requirementsfor the collection, processing and qualitycontrol of blood, blood components andplasma derivatives. Technical Report Series,No. 840 (1994).

3. World Health Organization. WHO Recom-mendations for the production, control andregulation of human plasma for fractionation.Technical Report Series, No. 941 (2007).

4. World Health Organization. Guidelines onviral inactivation and removal proceduresintended to assure the viral safety of humanblood plasma products. Technical ReportSeries, No. 924 (2004).

5. World Health Organization. WHO Interna-tional Biological Standards: http://www.who.int/bloodproducts/catalogue/en/index.html


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Regulation and clinicalpharmacology: emergingalliancesAs a function of protecting and promotingpublic health, a government must con-sider the ethical, scientific and develop-mental aspects of medicines. Activities inthese three dimensions are complimen-

tary and provide the means of attainingthe health and wellbeing of citizens.

In a broad sense, the role of regulatoryagencies is multidimensional. The WorldHealth Organization (WHO) proposes thatregulatory goals are achieved throughensuring the safety, efficacy and quality ofmedicines, rational use, and providing

Contribution of clinical pharmacologists to government:opportunities and challenges

New Regulatory Challenges

.Clinical pharmacology is a scientific discipline that focuses on evaluating the effectof medicines in humans. Within a wider context of promoting safety, maximizingefficacy and minimizing side-effects, the work of the clinical pharmacologist is par-ticularly valuable in clinical trials. Other branches of the discipline involve pharma-covigilance, pharmacokinetics, drug metabolism, pharmacoepidemiology and, morerecently, pharmacoeconomics. The clinical pharmacologist collaborates closely withother clinicians, pharmacists, biologists, analytical chemists, statisticians, epidemi-ologists and health economists. The clinical pharmacologist receives training in theevaluation of drug therapy and drug products and this makes the profession valu-able in a number of public activities such as drug approval, post-marketing surveil-lance, drug therapy selection, reimbursement decisions and ethical review of re-search projects.

Faced with the task of regulating increasingly complex medicines and biomedicinesmarkets, many regulatory authorities and health departments in developing coun-tries rely for advice on pharmacists who may have a limited medical background andlack the resources to access and assess information on the latest clinical research.On the other hand, clinical pharmacologists have a rigorous medical and scientifictraining which enables them to evaluate evidence and produce new data throughwell designed studies and interaction with other healthcare professionals. A clinicalpharmacologist can provide the link between government and health care outcomes,serving also as a powerful advocate of evidence-based medicine. They can be in-valuable in addressing current challenges such as assessing new medicines, pro-viding unbiased medicines-related information, contributing to treatment guidelinedevelopment, identifying preventable adverse drug reactions through promoting ra-tional use of medicines and improving prescribing practices. Politicians are oftenunaware of the valuable role that clinical pharmacology can play in improving per-formance of regulatory and health systems through closing the gap between currentmedical practices and latest clinical science.

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appropriate medicines information to thepublic and health professionals (1).Similarly, the European MedicinesAgency (EMEA) coordinates the work ofnational experts and has inter alia thefollowing far reaching responsibilities (2):

“In the context of continuing globaliza-tion, to protect and promote public andanimal health by:

• developing efficient and transparentprocedures to allow rapid access byusers to safe and effective innovativemedicines and to generic and nonpre-scription medicines through a singleEuropean marketing authorization;

• controlling the safety of medicines forhumans and animals, in particularthrough a pharmacovigilance networkand the establishment of safe limits forresidues in food-producing animals;

• facilitating innovation and stimulatingresearch, hence contributing to thecompetitiveness of the EU-basedpharmaceutical industry, and

• mobilizing and coordinating scientificresources throughout the EU to providehigh-quality evaluation of medicinalproducts, to advise on research anddevelopment programmes, to performinspections for ensuring fundamentalGXP (good clinical practice, goodmanufacturing practice and goodlaboratory practice collectively) provi-sions are consistently achieved, and toprovide useful and clear information tousers and healthcare professionals.

The ethical dimensionIn addition to their role in ensuring thesafety, efficacy and quality of medicines,governments are also tasked with theresponsibility of exerting an ethicalinfluence on processes in the develop-ment and marketing of medicines. Theregulatory authority is responsible for

many essential and interrelated activitieswhich underpin the most important role ofthe government in the broader sense: i.e.,to protect the health and wellbeing of itscitizens through ensuring and promotingeffective public health.

Governments and their respective institu-tions are responsible for ensuring basichuman rights of citizens. In the event ofresearch conducted within a country, theyare expected to protect patients and trialparticipants by maintaining effectivesystems for granting clinical researchauthorization and oversight of trials. Thischallenging task involves assessment ofwhether the clinical research planned isbased on scientific principles and consid-erations of safety and whether it will offerthe desired benefits to patients whileidentifying and minimizing any possiblerisks. This task forms the ethical dimen-sion of the government’s role.

Milestones in the currentethical research environmentThe International Covenant on Civil andPolitical Rights (1966) states that ... “noone shall be subjected without his freeconsent to medical or scientific experi-mentation”. These principles were devel-oped with a particular focus on risk/benefit in the World Medical Association’sDeclaration of Helsinki and have beenincorporated into national and interna-tional laws and regulations.

In 1949, the Council for InternationalOrganizations of Medical Sciences(CIOMS) was founded under the aus-pices of WHO and the United NationsEducational, Scientific and CulturalOrganization (UNESCO). The mostimportant of CIOMS publications is itsInternational Ethical Guidelines forBiomedical Research Involving HumanSubjects. The latest version was pub-lished in 2002 (3) and, based on theDeclaration of Helsinki, is designed to beof use in defining the ethics of biomedicalresearch, applying ethical standards in


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local circumstances, and establishing orredefining adequate mechanisms forethical review of research involvinghuman subjects. The Guidelines aretargeted to ethics committees, and reviewboards, sponsors and investigators. TheCIOMS guidelines — to which severalclinical pharmacologists have contributed— also provide the basis for governmentthinking about clinical research, espe-cially in resource poor settings.

Good clinical practice (GCP) is a “stand-ard for the design, conduct, performance,monitoring, auditing, recording, analysisand reporting of clinical trials that pro-vides assurance that the data and re-ported results are credible and accurate,and that rights, integrity and confidential-ity of trial subjects are protected.” Manynational and regional GCP guidelines arebased on, or refer to, the Declaration ofHelsinki, including WHO GCP Guidelinespublished in 1995 (4) and the Interna-tional Conference of Harmonization (ICH)GCP (E6) from 1996 (5).

A priority requirement for the ethicalreview of a scientific study, research orclinical trial involving human subjects issubmission of a research proposal forindependent evaluation by scientific,regulatory and ethical review committees.Nowadays, many governments defineprocedural aspects of the work of theethics committees in detail.

For example, the European Commissionhas laid down strict timelines for process-ing research applications that affect thework of ethical review committees in all27 European Union countries. This canbe perceived as the European Commis-sion’s attempt to facilitate and promoteclinical research. Clinical pharmacologistscan be particularly valuable as membersof the ethical review committee becauseof their extensive knowledge of theeffects of medicines and the related areaof clinical research.

Above all, governments have to ensurethat only effective and safe good qualitymedicines are used to treat their citizens.Nowadays, all medicines are subject tomarketing authorization prior to beingprescribed. Approval is based on assess-ment of quality, safety and efficacy of theproduct. The safety monitoring of medi-cines during their whole life-cycle (frommarketing authorization to potentialwithdrawal from the market) is also a taskfor governments. Usually, these and othermedicines-related regulatory functionsare carried out by specialized govern-mental agencies, such as the Food andDrug Administration (FDA) in the USA orthe European Medicines Agency (EMEA).

Scientific dimensionIt is important for regulators involved inthe evaluation of medicines prior tomarketing to have the best possiblescientific education and background or tobe able to call on expertise which isrelevant to the work in hand. A criticalscientific review of the clinical data willaddress the known and unknown aspectsof an assessment and provide relevantconclusions. The larger regulatory agen-cies possess their own clinical pharma-cology units. For example, the US FDAhas in its Center for Drug Evaluation andResearch (CDER) Office of ClinicalPharmacology. Safety surveillance andpharmacovigilance is also entrusted toregulatory agencies, and here, also,expertise in clinical pharmacology isessential.

Governments, either directly or throughtheir specialized agencies, are alsoinvolved in taking decisions about medi-cines selection for public procurement,developing national treatment guidelinesand proposing inclusion of medicines inreimbursement lists. This work may alsoinvolve composing and updating nationalessential medicines lists as promoted byWHO. The real life performance of drugsfollowing regulatory approval requires a


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cost-effectiveness assessment by highlyqualified specialists using different mod-els and again calls on the expertise of theclinical pharmacologist.

These various activities support therational use of medicines, sometimes alsocalled “quality use” (6). Governmentalinstitutions involved in such activitiesinclude the National Institute for Healthand Clinical Excellence (NICE) in theUnited Kingdom. Activities are based onthe best possible scientific methodologiesand knowledge and are part of thescientific dimension of the Government’sobligation to its citizens. Clinical pharma-cologists are well prepared to meet thechallenges needed in the complex as-sessment of medicines.

Developmental dimensionLastly, governments carry the responsibil-ity of improving the health of their citi-zens. Stimulating the necessary researchand developing research capacities istherefore a regulatory function. Actionshould be directed to facilitating researchin areas where lack of effective or saferhealth care interventions impedes im-provement to public health. Recentexamples provide evidence that privatesector initiatives and funding are insuffi-cient in developing and promoting publichealth through medicines research. Thus,governments may also be involved inproviding financial support to stimulateclinical research in medicines. Clinicalpharmacologists are well positioned tohelp make appropriate judgements on thescientific value of government funding ofresearch proposals.

An important emerging issue is theadoption of electronic patient healthrecords implemented or planned to beimplemented in many countries. Althoughthese may be perceived as mostly admin-istrative tools, they hold scientific poten-tial for monitoring of safety and qualitymedicines therapy. There is already first-

hand evidence that electronic healthrecords can offer added value for phar-macogenetic research and pharmacovigi-lance (7). Clinical pharmacologists shouldbe actively involved in designing elec-tronic patient health records due to theirpotential for future clinical research use,including monitoring of rational use andsafety.

Government efforts to create a researchfriendly environment should include legaland other systems with effective function-ing and well-informed scientific govern-ment backup. Due to the relative lack ofnew therapies and pressure from patientgroups and industry, governments havebeen exorted to grant “early marketapprovals” under certain preconditions.However, effective methodologies forpharmacovigilance and safety studies inthe context of early market access haveyet to be created and tested and clinicalpharmacologists have an important roleto play here (8, 9). Clinical pharmacologyalso contributes to the discipline ofpharmacoepidemiology, which is some-times the only available method to evalu-ate the benefits and risks of long termpharmacotherapy. Similarly, pharmaco-economics attempts to give a financialcost and value to everyday medicines useand contributes to rational reimbursementsystems.

In the implementation of these variousdimensions, governments create varioustools, including laws and regulations,infrastructure and institutions, with sup-porting resource allocations. A keyresource is properly trained specialistswho are capable of taking decisionsbased on the best possible scientificmethodology and evidence. Thesedimensions are interrelated and interde-pendent. Good ethics cannot do withoutgood science and developmental goalscannot be achieved without followingethical principles and a sound sciencebase.


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The clinical pharmacologist is thus aunique specialist and ally who can servethe public best by ensuring that only safeand effective medicines are authorized foruse, as well as facilitating cost effectiveprescribing and improving rational use ofdrugs. In order to meet the needs ofvarious governmental services andensure that the best scientific knowledgeis used to make decisions, clinical phar-macology as a discipline should beharmonized with the objectives andpolicies of governments to ensure abenefit to public health

Equally, governments of emerging econo-mies and developing countries maybenefit hugely from the expertise ofclinical pharmacologists and experiencehas shown that a qualified clinical phar-macologist can make a great difference atcountry level.

References

1. World Health Organization. WHO PolicyPerspective on Medicines No 7, “EffectiveMedicines Regulation: Ensuring Safety,Efficacy and Quality”, November 2003. http://www.who.int/medicines/organization/mgt/PolicyPerspectives.shtml

2. EMEA Mission Statement. http://www.emea.eu.int/mission.htm

3. The Council for International Organizationsof Medical Sciences (CIOMS). InternationalEthical Guidelines for Biomedical ResearchInvolving Human Subjects, Geneva, 2002.http://www.cioms.ch/

4. World Health Organization. Guidelines forgood clinical practice (GCP) for trials onpharmaceutical products. Technical ReportSeries, No. 850, 1995. http://www.who.int/medicines/library/par/ggcp/GGCP.shtml

5. International Conference of Harmonization(ICH) E6: Good Clinical Practice: Consoli-dated Guideline. http://www.ich.org/cache/compo/276–254–1.html

6. Smith AJ, McGettigan P. Quality use ofmedicines in the community: the Australianexperience. Br J Clin Pharmacol (2000) 50(6):515–519.

7. Wang X, Hripcsak G, Markatou M, et al.Active computerized pharmacovigilance usingnatural language processing, statistics andelectronic health records: a feasibility study. JAm Med Inform Assoc (2009).

8. Lesko LJ. Paving the Critical Path: How canClinical Pharmacology Help Achieve theVision? Clinical Pharmacology & Therapeutics(2007) 81:170–177.

9. Massol J, Puech A, Boissel JP. How toanticipate the assessment of the public healthbenefit of new medicines? Therapie. (2007)62(5):427–35.


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Safety and Efficacy Issues

Etanercept: histoplasmosisand invasive fungal infectionsCanada — The manufacturer ofetanercept (Enbrel®) has informedhealthcare professionals of the risk ofinvasive fungal infections, includinghistoplasmosis. Etanercept is indicatedfor the treatment of rheumatoid arthritis,psoriatic arthritis, juvenile idiopathicarthritis, ankylosing spondylitis andplaque psoriasis.

There have been reports of seriouspulmonary and disseminated histoplas-mosis, coccidioidomycosis, blastomycosisinfections, sometimes with fatal out-comes, in patients taking TNF blockers,including etanercept. Histoplasmosis andother invasive fungal infections have notbeen recognized consistently in patientstaking TNF blockers. This has led todelays in instituting appropriate treatment,sometimes resulting in death.

For a patient taking a TNF blocker whopresents with signs and symptoms ofsystemic illness, such as fever, malaise,weight loss, sweats, cough, dyspnoea,and/or pulmonary infiltrates, the health-care professional should ascertain if thepatient has lived or worked in or travelledto areas of endemic mycoses, andappropriate empiric antifungal treatmentmay be initiated while a diagnosticworkup is being performed. As with anyserious infection, the TNF blocker shouldbe stopped until the infection has beendiagnosed and adequately treated.

Prescribers should discuss with patientsand their caregivers the risk for infectionswhile receiving TNF blockers, includinginfections caused by viruses, fungi, orbacteria including tuberculosis (TB).

Reference: Communication from Amgen. 21April 2009 at Health Canada. http://www. hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/index-eng.php

Zonisamide: metabolicacidosisUnited States of America — Followinga review of updated clinical data, theFood and Drug Administration (FDA) hasdetermined that treatment with zonis-amide can cause metabolic acidosis insome patients. Zonisamide (Zonegran®and generics) is indicated as adjunctivetherapy in the treatment of partial sei-zures in adults with epilepsy.

Chronic metabolic acidosis can haveadverse effects on the kidneys and onbones, and can retard growth in children.Patients with predisposing conditions ortherapies, including renal disease, severerespiratory disorders, diarrhoea, surgery,ketogenic diet, or certain other drugs maybe at greater risk for developing meta-bolic acidosis following treatment withzonisamide. The risk of zonisamide-induced metabolic acidosis appears to bemore frequent and severe in youngerpatients. Although not approved by theFDA, zonisamide is sometimes used inchildren. Metabolic acidosis increases therisk for slowed growth in children andcould reduce the overall height that theyachieve.

The FDA recommends that healthcareprofessionals measure serum bicarbo-nate before starting treatment and peri-odically during treatment, even in theabsence of symptoms. If metabolicacidosis develops and persists, consid-eration should be given to reducing thedose or discontinuing zonisamide (using

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WHO Drug Information Vol 23, No. 2, 2009 Safety and Efficacy Issues

dose tapering), and modifying the pa-tient’s antiepileptic treatment as appropri-ate. If the decision is made to continue,then alkali treatment should be consid-ered.

Reference: FDA Alert, 23 February 2009 athttp://www.fda.gov/medwatch

Progressive multifocalleukoencephalopathyUnited Kingdom — Progressivemultifocal leukoencephalopathy (PML) isa rare and usually fatal re-infection of theCNS characterized by progressivedamage and inflammation of the whitematter in the brain, in multiple locations.PML is caused by a type of humanpolyoma virus known as the JC, or JohnCunningham virus. The JC virus iswidespread, with about 70–90% of adultspresenting antibodies.

The virus usually remains latent inhealthy individuals, only causing diseasewhen the immune system is severelycompromised. PML has been studied inpatients with HIV infection, where inci-dence is approximately 5% of the diseasepopulation. PML also occurs in patientswith cancer and those who havereceived kidney or bone-marrow trans-plants. In PML, gradual destruction of themyelin sheath covering nerve axonsleads to impaired transmission of nerveimpulses. PML causes rapidly progres-sive focal neurological deficits including:

• cognitive and behavioural changes;

• paraesthesia;

• visual problems;

• gait abnormalities and loss of limbcoordination, and

• hemiparesis.

The Medicines and Healthcare ProductsRegulatory Agency (MHRA) has previ-

ously identified an association betweenPML and use of some monoclonal anti-bodies such as natalizumab (Tysabri®,used to treat multiple sclerosis) andrituximab (MabThera®, indicated for non-Hodgkin lymphoma and severe activerheumatoid arthritis). An association hasalso now been identified between PMLand efalizumab (Raptiva®).

Up to 6 January 2009, the MHRA hasreceived 19 suspected reports of PML, inthree of which PML was listed as the fatalsuspected reaction.

Reference: Medicines and HealthcareProducts Regulatory Agency, Drug SafetyUpdate, Volume 2, Issue 8 March 2009 athttp://www.mhra.gov.uk/Safetyinformation/

Severe adverse reactions withintravenous immunoglobulinAustralia — Intravenous immunoglobu-lin, normal (human) (IVIG) is used to treata variety of deficiencies and disorderswith an immune (or presumed immune)aetiology. IVIG preparations, includingIntragam P®, Sandoglobulin®, andOctagam®, have been available since the1980s. Use worldwide and in Australiahas more than doubled over the pastdecade (1) partly due to increasing use inoff-label indications.

Nausea and vomiting are most commonlyobserved with IVIG, as are hypersensitiv-ity reactions which may include anaphy-laxis. Those with IgA deficiency have ahigher risk of hypersensitivity to IVIG dueto the presence of IgA antibodies. Lesscommon but also serious reactions areaseptic meningitis, haemolysis andtransfusion-related acute lung injury —one case has been reported in Australiaand one in Canada (2). Recently, HealthCanada highlighted an associationbetween IVIG and thromboembolicevents (3).

To date, the Therapeutic Goods Adminis-tration (TGA) has received 356 reports of

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adverse reactions associated with IVIG:IVIG was the sole suspected agent in90% of reports. Thirty-five per centdescribe serious reactions, includingwhere the outcome was fatal due to:stroke/myocardial infarction, myocardialinfarction, convulsions, hepatic and renalfailure, and respiratory failure respec-tively. In fatal cases, patients generallyhad thrombogenic risk factors such ashypertension, obesity, increasing age, orpast history of stroke.

The TGA has also received substantialnumbers of reports describing pyrexia(58), chills (41), haemolysis or anaemia(32), meningitis (20), neutropenia (12),hepatic disorders (11), and renal failure/impairment (8). In some of the cases, thereactions — particularly those suggestinghypersensitivity — occurred during theIVIG infusion and improved with slowingor stopping the infusion.

Before and during the use of IVIG, anypre-existing thrombogenic risk factorsshould be assessed and all patientsshould be monitored closely duringinfusion. A slow infusion rate of IVIGshould be considered for all patients withrisk factors (as recommended in the PI).

Extracted from the Australian AdverseDrug Reactions Bulletin, Volume 28,Number 2, April 2009 at http://www.tga.gov.au/adr/aadrb/aadr0904.htm

References

1. National Blood Authority. Criteria for theclinical use of intravenous immunoglobulin inAustralia. Australian Health Ministers’ Confer-ence. December 2007.

2. Case Presentation: Intravenous immuneglobulin – suspected association with transfu-sion-related acute lung injury. CanadianAdverse Reactions Newsletter Oct 2008; 18/4.

3. Intravenous immune globulin: myocardialinfarction and cerebrovascular and thromboticadverse reactions. Canadian Adverse Reac-tions Newsletter Jan 2008; 18/1.

Exenatide: risk of severepancreatitis and renal failureUnited Kingdom — Exenatide (Byetta®),an incretin mimetic, is a glucagon-like-peptide-1 analogue that stimulates insulinrelease from pancreatic cells in a glucosedependent manner. Exenatide is indi-cated for treatment of type 2 diabetesmellitus in combination with metformin,with or without sulphonylureas in patientswho have not achieved adequate glycae-mic control on maximally tolerated dosesof these oral therapies.

Exenatide should not be used in patientswith type 1 diabetes or for the treatmentof diabetic ketoacidosis. It should not beused in patients with type 2 diabeteswho require insulin therapy due to cellfailure.

Suspected adverse reaction reports ofnecrotizing and haemorrhagic pancreatitishave been received in association withexenatide. Some of these reports had afatal outcome. If pancreatitis is diag-nosed, exenatide should be permanentlydiscontinued. Reports of renal impair-ment, including acute renal failure andworsened chronic renal failure have alsobeen received. Exenatide is notrecommended for use in patients withend-stage renal disease or severe renalimpairment


Benefits of methylphenidatecontinue to outweigh risksUnited Kingdom — The EMEA’s Com-mittee for Medicinal Products for HumanUse (CHMP) concluded that on the basisof currently available data, the benefits ofmethylphenidate continue to outweigh therisks when used in its licensed indication.Methylphenidate is indicated as part of a


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comprehensive treatment programme forattention deficit/hyperactivity disorder(ADHD) in children aged 6 years or olderand adolescents who are diagnosedaccording to DSM-IV criteria or guidelinesin ICD-10 and when remedial measuresalone are insufficient.

Treatment must be under the supervisionof a specialist in childhood behaviouraldisorders. Patients should be monitoredduring treatment, which should be inter-rupted at least once a year to determinewhether continuation is needed.

Contraindications—methylphenidateshould not be used in patients with:

• Diagnosis or history of severe depres-sion, anorexia nervosa or anorexicdisorders, suicidal tendencies, psychoticsymptoms, mania, schizophrenia,severe mood disorders, or psychopathicor borderline personality disorder.

• Diagnosis or history of severe andepisodic (type I) bipolar (affective)disorder that is not well-controlled.

• Pre-existing cerebrovascular disorders— e.g., cerebral aneurysm and vascularabnormalities, including vasculitis orstroke.

• Unless specialist cardiac advice hasbeen obtained, in pre-existing cardio-vascular disorders, including severehypertension, heart failure, arterialocclusive disease, angina, haemody-namically significant congenital heartdisease, cardiomyopathies, myocardialinfarction, potentially life-threateningarrhythmias, and dysfunction of cardiacion channels

References:

1. EMEA press release at http://www.emea.europa.eu/pdfs/human/referral/methylphenidate/2231509en.pdf;question-and-answer document athttp://www.emea.europa.eu/pdfs/human/

2. Further information on brands ofmethylphenidate available in the UK, seeBNF, p 216 (edn 56; www.bnf.org).

3. Information on DSM-IV criteria is athttp://www.psychiatryonline.com/;information on ICD-10 is athttp://www.cdc.gov/nchs/about/otheract/icd9/abticd10.htm

4. Medicines and Healthcare ProductsRegulatory Agency, Drug Safety Update,Volume 2, Issue 8 March 2009 at http://www.mhra.gov.uk/Safetyinforma tion/

Chromic phosphate P32:acute lymphocytic leukaemiaCanada — Information has been pro-vided on important new safety informationconcerning Chromic phosphate P32suspension (Phosphocol® P32) which isauthorized for intracavitary instillation forthe treatment of peritoneal or pleuraleffusions caused by metastatic disease.

Physicians should be vigilant for signsand symptoms of leukaemia in patientswho have received Phosphocol® P32.The Canadian product monograph will beupdated to include the following warning.

Leukaemia: Phosphocol® P32 mayincrease the risk of leukaemia in certainsituations. Two children (ages 9 and 14)with haemophilia developed acute lym-phocytic leukaemia approximately 10months after intra-articular injections.Phosphocol® P32 is not indicated in thetreatment of haemarthroses.

In addition, the product monograph will beupdated to include post-marketing reportsof radiation injury (necrosis and fibrosis)to the small bowel, caecum, and bladderfollowing peritoneal administration ofPhosphocol® P32.

Reference: Health Canada, Alert dated 25March 2009. at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/index-eng.php


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Warning for metoclopramide-containing drugsUnited States of America — The Foodand Drug Administration (FDA) hasannounced that manufacturers of meto-clopramide, a drug used to treat gastroin-testinal disorders, must add a boxedwarning to labelling about the risk of long-term or high-dose use. Chronic use ofmetoclopramide has been linked totardive dyskinesia even after the drugsare no longer taken.

Metoclopramide works by speeding upthe movement of the stomach muscles,thus increasing the rate at which thestomach empties into the intestines. It isused as a short-term treatment of gastro-oesophageal reflux disease in patientswho have not responded to other thera-pies, and to treat diabetic gastro-paresis.It is recommended that treatment notexceed three months.

Reference: FDA News, 26 February 2009 athttp://www.fda.gov

Metabolic effects ofantipsychoticsNew Zealand — Although schizophreniaitself is associated with several adversemetabolic effects it is now clear that allantipsychotics, and in particular someatypical antipsychotics, are associatedwith adverse effects on weight, bloodglucose, and lipid concentrations. All ofthese adverse effects have long-termconsequences in terms of life expectancy.

While the effects of antipsychotics onweight gain may be responsible for theincreased risk of diabetes and hyperlipi-daemia, a direct effect on glucose me-tabolism may also occur.

Not all atypical antipsychotics are associ-ated with the same level of risk. Clozap-ine and olanzapine are considered tocause adverse metabolic effects more

frequently than other agents. Prescribersare advised to monitor all patients takingantipsychotics for adverse metaboliceffects.

References

1. http://www.bpac.org.nz/magazine/2007/february/antipsychotics.asp

3. Prescriber Update 2009;30(2):12 at http://www.medsafe.govt.nz/profs/PUarticles.asp

Cefaclor and serum sickness-like reactions in childrenAustralia — The association betweencefaclor and serum sickness-like reac-tions (SSLR), particularly in children, haslong been recognized (1). These reac-tions are characterized by a variety ofrashes, which include urticaria or ery-thema multiforme, with or withoutangioedema, accompanied by arthritis/arthralgia, with or without fever.

The reactions are rare but occur moreoften after a second or subsequentcourse of treatment. Onset time is often afew days after cefaclor is commencedand signs and symptoms typically sub-side a few days after the drug is ceased.However, onset may also be delayed andoccur 7–21 days after stopping cefaclor.Children are more susceptible thanadults.

The TGA continues to receive about 10reports per year of cefaclor-related SSLRin children. If cefaclor must be prescribedto a child, the parents/caregivers shouldbe advised to remain alert for the devel-opment of new or worsening symptomsthat might indicate a hypersensitivityreaction to the drug and to contact theirdoctor immediately if there are concerns.



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Reference: ADRAC. Cefaclor in the youngpatient: arthritis and arthralgia <http://www.tga.gov.au/adr/aadrb/aadr9508.htm#cefaclor>. Aust Adv Drug React Bull 1995; 14(3).

Toremifene: prolongationof QTc intervalUnited Kingdom/European Union —The manufacturer of toremifene(Fareston®) has informed healthcareprofessionals of new information onprolongation of the QTc interval related totoremifene. The approved therapeuticindication for toremifene 60 mg/day is thefirst line treatment of hormone dependentmetastatic breast cancer in postmeno-pausal patients.

Both in preclinical investigations and inhumans, changes in cardiac electro-physiology have been observed followingexposure to toremifene, in the form of QTprolongation. Consequently:

• Toremifene is therefore contraindicatedin patients with:

Congenital or documented acquired QTprolongation; electrolyte disturbances,particularly in uncorrected hypokalae-mia; clinically relevant bradycardia;clinically relevant heart failure withreduced left-ventricular ejection fraction;previous history of symptomatic arrhyth-mias.

• Toremifene should not be used concur-rently with other drugs that prolong theQT interval.

• Toremifene should be used with cautionin patients with ongoing proarrhythmicconditions (especially elderly patients)such as acute myocardial ischaemia orQT prolongation as this may lead to anincreased risk for ventricular arrhyth-mias (including Torsade de Pointes) andcardiac arrest.

• If signs or symptoms that may beassociated with cardiac arrhythmiaoccur during treatment with toremifene,treatment should be stopped and anECG should be performed.

Currently, toremifene 20 mg/day and 80mg/day are being studied in prostatecancer indications.

Reference: Communication from OrionPharma UK at http://www.mhra.gov.uk/Safetyinformation/

Atomoxetine: risk of psychoticor manic symptomsUnited Kingdom — Atomoxetine(Strattera®) is a selective noradrenalinereuptake inhibitor, authorized since 2004for use in the treatment of attention-deficit/hyperactivity disorder (ADHD) aspart of a comprehensive treatmentregimen. Continued case reports ofpossible nervous-system and psychiatricadverse effects prompted a review ofdata from all sources resulting in updatedinformation on the risk of new-onset orworsening of serious psychiatric disor-ders, including psychotic reactions,hallucinations, mania, and agitation.

Product information for prescribers hasbeen updated to reflect more fully theemerging safety information. Atomoxetineis associated with treatment-emergentpsychotic or manic symptoms in childrenand adolescents without a history of suchdisorders. If such symptoms occur,consideration should be given to apossible causal role of atomoxetine anddiscontinuation of treatment.

Advice for healthcare professionals:

• At normal doses, atomoxetine can beassociated with emergent psychotic ormanic symptoms (e.g., hallucinations,delusional thinking, mania, or agitation)in children and adolescents without ahistory of psychotic illness or mania.


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• If such symptoms occur, considerationshould be given to a possible causalrole of atomoxetine and discontinuationof treatment.

• It remains possible that atomoxetinemight exacerbate pre-existing psychoticor manic symptoms


Lignocaine with chlorhexidinegel: anaphylaxisUnited Kingdom — Lignocaine 2% gelwith chlorhexidine 0.05% is an anaes-thetic/antiseptic/disinfectant combinationused as a lubricant for urology proce-dures and examination, and as sympto-matic treatment of painful urethritis.

Since 1990, the TGA has received 19reports of suspected adverse reactions tolignocaine with chlorhexidine gel. Elevenof these were of anaphylaxis. Some werelife threatening, but there have been nofatalities.

The MHRA warns of the potential foranaphylaxis or other hypersensitivityreactions with both lignocaine and chlor-hexidine. Users of local anaestheticpreparations should check which prod-ucts contain chlorhexidine and arereminded of the risk of severe allergicreactions to medicines, even whenapplied topically.

Reference: Medicines and HealthcareProducts Regulatory Agency, http://www.mhra.gov.uk/Safetyinforma tion/

Moxifloxacin safety updateSingapore — Moxifloxacin (Avelox® andVigamox®) is a broad-spectrum antibac-terial that is available locally.

In February 2008, the manufacturerinformed healthcare professionals of veryrare liver injuries and serious skin reac-tions associated with moxifloxacin. Thiswas in response to a worldwide review ofserious, including fatal cases of hepato-toxicity and bullous skin reactions such asStevens-Johnson syndrome (SJS) andtoxic epidermal necrolysis (TEN) reportedfor moxifloxacin.

To date, HSA has received 22 localspontaneous adverse drug reactionreports associated with oral moxifloxacin.Patient exposure to moxifloxacin to dateis estimated to be 230 577, according tolocal figures provided by the manufac-turer. In the interpretation of the abovefigures, there is a need to consider thesignificant degree of under-reporting ofadverse reactions as is the case with allspontaneous adverse drug reactionreporting programmes.

References

1. EMEA Press Release. European MedicinesAgency recommends restricting the use of oralmoxifloxacin-containing medicines. http://www.emea. europa.eu/pdfs/human/press/

2. Direct Healthcare Professional Communica-tion regarding moxifloxacin (Avelox®) andserious hepatic and bullous skin reactions.http://www.mhra.gov.uk/

3. HSA Safety News, 19 Mar 2009 at http://www.hsa.gov.sg

Codeine toxicityin breastfed infantsSingapore — Codeine is found in manyprescription and non-prescription painrelievers and cough syrups. Once in-gested, codeine is metabolised by cyto-chrome P450 2D6 (CYP2D6) to its activemetabolite, morphine, which relieves painor cough. Limited evidence suggests thatindividuals with a specific CYP2D6genotype (otherwise known as ultra-rapidmetabolisers) may convert codeine to


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morphine more rapidly and completelythan other people. In nursing mothers,this metabolism can result in higher thanexpected levels of morphine in serum andbreast milk, putting nursing infants atincreased risk for morphine overdose.

Regardless of ethnic variation in theprevalence of ultra-rapid metabolisers, itis important to bear in mind that polymor-phism of CYP2D6 is clinically important.

When prescribing codeine to a nursingmother, physicians should choose thelowest effective dose for the shortestperiod of time.

References

1. FDA Alert. Use of codeine products innursing mothers. http://www.fda.gov/cder/drug/infopage/codeine/default.htm

2. Lancet 2006, Vol 368:704, August 2006

3. FDA Public Health Advisory. Use of codeineby some breastfeeding mothers may lead tolife-threatening side effects in nursing babies.http://www.fda.gov/cder/drug/advisory/codeine.htm

4. FDA News. FDA warning on codeine use bynursing mothers. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01685.html

5. Health Canada Advisory. Use of CodeineProducts by nursing mothers. http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2008/2008_164-eng.php


Atypical antipsychotics:risk of strokeUnited Kingdom — In 2004, the Com-mittee on Safety of Medicines advised ofa clear increase in the risk of strokewith the use of the atypical antipsychoticsrisperidone or olanzapine in elderlypeople with dementia (approximately

three-times increased risk compared withplacebo), and that the magnitude of riskoutweighed any likely benefit of treatingdementia-related behavioural problemswith these drugs. A year later a Europewide review concluded that this risk couldnot be excluded for otherantipsychotics (atypical or typical), andthe product information for all antipsy-chotics was updated to include a classwarning.

In 2005, an analysis of 17 placebo-controlled trials found that atypical antip-sychotics are associated with increasedmortality when used in elderly people withdementia (about 1–2% increased riskcompared with no treatment) (1). Forrisperidone, there is an additional in-crease in the risk when coprescribed withfurosemide.

Subsequently in November 2008, aEuropean assessment of publishedobservational data concluded that asimilar increased risk of death could notbe excluded for the typical (conventional)antipsychotics (2, 3).

In the case of persistent aggression inmoderate to severe Alzheimer disease,where the patient puts themselves orothers at risk of harm, short-term treat-ment with risperidone may be indicated ifthe behaviour has not responded tononpharmacological means. A newanalysis of three randomized control trials(4–6) conducted in behavioural problemsin the elderly showed a clear benefit forthe short-term use of risperidone whenaggression only was considered. Thebalance of risks and benefits for risperi-done use to treat behavioural distur-bances in dementia is only considered tobe positive within its narrow licensedindication: i.e., short-term use for persist-ent aggression in Alzheimer-type demen-tia.


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Advice for healthcare professionals:

• There is a clear increased risk of strokeand a small increased risk of deathwhen antipsychotics (typical or atypical)are used in elderly people with demen-tia.

• The balance of risks and benefitsassociated with risperidone treatmentshould be carefully assessed for everypatient, taking into consideration theknown increased mortality rate associ-ated with antipsychotic treatment in theelderly. Prescribers should carefullyconsider the risk of cerebrovascularevents before treating with risperidoneany patient who has a previous historyof stroke or transient ischaemic attack.Consideration should also be given toother risk factors for cerebrovasculardisease including hypertension, diabe-tes, smoking, and atrial fibrillation.

References

1. Deaths with antipsychotics in elderlypatients with behavioural disturbances. FDAPublic Health Advisory, 11 April 2005. http://www.fda.gov/cder/drug/advisory/

2. Schneeweiss S et al. CAMJ 2007; 176:627–32.

3. Gill SS et al. Ann Intern Med 2007;146: 775–86. See also statement from theEuropean Medicines Agency athttp://www.emea.europa.eu/pdfs/human/opiniongen/Conventional_Antipsychotics_Article5.3-CHMP_Opinion.pdf, accompanyingreport and question-and-answer document athttp://www.emea.europa.eu/pdfs/human/opiniongen/Conventional_%20Antipsychotics_Article5.3-Appendix1-CHMPAR.pdfand http://www.emea.europa.eu/pdfs/human/opiniongen/Conventional_antipsychotics_Article_5.3-Q&A.pdf

4. Katz IR et al. J Clin Psychiatry 1999; 60:107–15.

5. De Deyn PP et al. Neurology 1999; 53:946–55.

6. Brodaty H et al. J Clin Psychiatry 2003; 64:134–43. See also http://www.emea.europa.eu/pdfs/human/referral/Risperdalrisperdal_ bi_en.pdf and http://www.emea.europa.eu/pdfs/human/referral/Risperdal risperdal_annexI_IV_en. pdf, p 48.

7. Medicines and Healthcare ProductsRegulatory Agency, Drug Safety Update,Volume 2, Issue 8 March 2009 at http://www.mhra.gov.uk/Safetyinformation/

Bisphosphonates: atypicalstress fracturesUnited Kingdom — Individual bisphos-phonates have different indications andare used for prophylaxis and treatment ofosteoporosis, treatment of Paget disease;and as part of some cancer regimens,particularly for metastatic bone cancerand multiple myeloma.

Recent evidence from published literaturesuggests that long-term use of alendronicacid may be associated with an increasedrisk of atypical stress fractures (1–3). AEurope wide review of bisphosphonatesand atypical stress fractures has ana-lysed preclinical data, clinical-trial data,postmarketing spontaneous reports ofadverse drug reactions, published litera-ture, and information from other drugregulatory authorities.

Atypical stress fractures of the proximalfemoral shaft have been reported inpatients treated long-term with alendronicacid. Patients who develop stress frac-tures should discontinue alendronic acidand receive no further bisphosphonatetreatment unless the benefits for theindividual clearly outweigh the risk ofharm. An increased risk of atypical stressfractures with other bisphosphonatescannot be excluded

Limited data are available for the otherbisphosphonates in support of a causalassociation with atypical stress fractures.This might reflect their lower usage and


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the limited long-term data that exist forother bisphosphonates. The possibilitythat they may be associated with anincreased risk of atypical stress fracturescannot be excluded.

References

1. Kwek EB et al. Injury 2008; 39: 224–31.

2. Lenart BA et al. N Engl J Med 2008;358: 12.

3. Neviaser AS et al. J Orthop Trauma2008; 22: 346–50.


Effects of MRI on implantabledrug pumpsUnited Kingdom — In December 2008,a medical device alert was issued aboutMRI scanning of patients with implantedMedtronic SynchroMed® drug pumps.These pumps provide baclofen andmorphine therapy but they do not behaveas expected when exposed to the mag-netic field of an MRI scan. Productlabelling states that MRI temporarily stopsthe pump rotor and suspends druginfusion during MRI exposure. The pumpshould resume normal function whenremoved from the MRI field. However,MHRA are aware of risks, includingdelays in drug infusion, after MRI ofpatients implanted with these devices (1).

Healthcare professionals are advised toensure that departmental procedures arein place for MRI scanning of patients withMedtronic SynchroMed® implantabledrug pumps.

References

1. MHRA Safety Warnings. http://www.mhra.gov.uk/Publications/Safety warn-ings/MedicalDeviceAlerts/CON033658.


Sodium valproate and fetalmalformationsAustralia — Sodium valproate is wellknown to cause fetal malformations andis classified as a Pregnancy Category Ddrug (drugs that have caused, are sus-pected to have caused or may be ex-pected to cause an increased incidenceof human fetal malformations or irrevers-ible damage. These drugs may also haveadverse pharmacological effects) (1).Teratogenic risk appears to be dose-dependent and increases markedly atdoses greater than 1100 mg/day in thefirst trimester (2).

Sodium valproate is mainly used to treatepilepsy but it is increasingly beingprescribed to treat psychiatric disorders.

Since 1980, the Therapeutic GoodsAdministration (TGA) has received 72reports of babies born with malformationsfrom mothers taking sodium valproateduring pregnancy, including 18 of spinabifida, four of myelomeningocele and 13of multiple malformations mainly involvingthe CNS. In most of these cases, sodiumvalproate was being used to treat epi-lepsy, but two recent reports describefetal spina bifida and myelomeningocelein babies born to mothers taking sodiumvalproate for bipolar disorder.

One of the cases reported has beendescribed in correspondence to theAustralian and New Zealand Journal ofPsychiatry (3) and serves to remind thatsodium valproate must be used withcaution after careful consideration of therisk-benefit profile in women of child-bearing potential.

Women of child-bearing age prescribedsodium valproate for any indication


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should be informed about the potentialrisks of the drug, including teratogenesis,and should be strongly advised, andperiodically reminded, to maintain ad-equate contraception while taking thisdrug. Routine folic acid supplementationis recommended but efficacy in theprevention of sodium valproate-relatedmalformation is unproven (4).


References

1. ADEC. Prescribing medicines in pregnancy– An Australian categorization of risk of druguse in pregnancy 4th edition (1999). http://www.tga.gov.au/docs/html/medpreg.htm

2. Whitehall J & Smith J. Valproate andbabies. Aust NZ J Psychiatry 2008; 42: 837.

3. Vajda FJ, O’Brien TJ, Hitchcock A, GrahamJ, Cook M, Lander C, Eadie MJ. Criticalrelationship between sodium valproate doseand human teratogenicity: results of theAustralian register of anti-epileptic drugs inpregnancy. J Clin Neurosci 2004; 11: 854-83.

4. Lagrange AH. Folic acid supplementationfor women with epilepsy who might becomepregnant. Nature Clin Pract 2009; 5: 16-17.

Abacavir: determiningrisk of heart attackEuropean Union — The EuropeanMedicines Agency (EMEA) has looked atdata from the D:A:D (Data collection ofAdverse effects of anti-HIV Drugs) study,which suggest an increased risk of heartattack (myocardial infarction) associatedwith the use of abacavir-containingmedicines.

The Agency’s Committee for MedicinalProducts for Human Use (CHMP) con-cluded at its March 2008 meeting that theavailable data do not allow a definitiveconclusion on the association between

the use of abacavir and an increased riskof myocardial infarction to be drawn. Atpresent no changes to the prescribinginformation for abacavir-containingmedicines are required but further infor-mation is needed to determine the risk ofmyocardial infarction.

Abacavir is a nucleoside reverse tran-scriptase inhibitor (NRTI) indicated inantiretroviral combination therapy for thetreatment of human immunodeficiencyvirus (HIV) infection. In the EuropeanUnion, it is available as Ziagen®, incombination with lamivudine as Kivexa®,and in combination with lamivudine andzidovudine as Trizivir®.

Reference: EMEA Press Release, Doc. Ref.EMEA/142888/2008, 2 April 2008. http://www.emea.europa.eu

Carbamazepine: seriousadverse skin reactionsSingapore — Stevens-Johnson syn-drome (SJS) and toxic epidermal necroly-sis (TEN) are life-threatening adverseskin reactions with mortality rates of up tofive and 40% respectively. Drugs aremost often implicated as the suspectedcause of SJS and TEN in adults andelderly persons.

Carbamazepine, indicated for the treat-ment of epilepsy, neuropathic pain andbipolar disorder, is known to be associ-ated with an increased risk of adversecutaneous skin reactions, including SJSand TEN. This risk has been observed inthe local population through relativelyhigher numbers of SJS and TEN reportedin association with the drug over theyears. More recently, studies have beenpublished which demonstrate a plausiblegenetic association with SJS and TENamong Asian patients, in particular, HanChinese and Thais.

Between 2003 and 2008, the HealthSciences Agency (HSA) received 290


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reports of drug-induced SJS and TEN.Other drugs such as allopurinol, pheny-toin and cotrimoxazole were also reportedto be associated with a higher number ofSJS/TEN reports received respectively .

Association observedwith HLA-B*1502 alleleRecently, carbamazepine-induced SJSand TEN have been found to be associ-ated with the HLA-B*1502 allele amongHan Chinese (in Taiwan and Hong Kong)and Thais (1–3).

A European study from the RegiSCARgroup (4) found that out of the 12 patientswith carbamazepine-induced SJS/TEN,all four who were positive for the HLA-B*1502 allele were of Asian origin. Itfurther suggested that the genetic linkmay be specific to patients with Asianancestry such as the Han Chinese.

An analysis of worldwide post-marketingcases reported to the World HealthOrganization (WHO) also pointed to amuch higher reporting rate of SJS/TEN,about 10 times higher in some Asiancountries (5).

Pharmacogenetics initiative by HSAIn an effort to understand the relevance ofgenetic association with adverse drugreactions among the diverse ethnicgroups (Chinese, Malays and Indians) inthe local population, HSA is embarking ona pharmacogenetics-based pharma-covigilance programme together withscientific collaborators from the variouspublic institution hospitals and researchinstitutes (6).

References

1. Epilepsia 2008, 49(12):2087-2091.

2. Pharmacogenet Genomics 2006, 16(4):297-306.

3. Epilepsia 2007, 48(5):1015-1018.

4. Pharmacogenomics J 2006, 6(4), 265-268.


5. http://www.fda.gov/cder/drug/InfoSheets/HCP/carbamazepineHCP.htm


Electronic adverse reactionreporting toolNew Zealand — An electronic adversereaction reporting tool has been launcheddesigned to facilitate the reporting ofadverse drug reactions to the Centre forAdverse Reactions Monitoring (CARM). Ituses an online reporting form pre-popu-lated with patient details from the GPpractice software.

The World Health Organization (WHO)rates New Zealand as having the highestnumber of reports submitted per capitacompared to other countries in theirprogramme. Reports from New Zealandare also rated as being of the highestquality. Despite this, international re-search indicates that at best, only 1 in 10adverse reactions are being reported inNew Zealand.

In addition, research conducted in NewZealand examined the data stored in thepatient management systems of 30general practices. Of the 725 entries inthe medical warnings files that recordedan adverse reaction or allergy to at leastone medicine, only 21 were reported toCARM.

Known barriers to reporting include theabsence of a prompt to initiate reporting,considering that the reaction is alreadywell known, and finally the time requiredto manually fill in adverse reaction forms.The adverse reaction reporting tool hasbeen developed to help overcome thesebarriers.

When the tool is opened it automaticallypre-populates the patient’s medicalhistory, medicine history, and gives the

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reporter the option of including laboratorytest results. If a vaccine is a suspectedmedicine, the tool pre-populates thebatch number, the date of administration,and how the vaccine was given. Once adescription of the reaction is entered, oneclick on the mouse sends an electronicreport to CARM.

Reference: Prescriber Update 2009;30(2):9 athttp://www.medsafe.govt.nz/profs/PUarticles.asp

Intensive monitoringof vareniclineNew Zealand — Varenicline (Champix®)is the newest smoking cessation medi-cine available in New Zealand and hasbeen monitored by the Intensive Medi-cines Monitoring Programme (IMMP)since its introduction in 2007. The IMMPhas recently analysed results for 3389patients who were dispensed a prescrip-tion for varenicline in the first year (1 April2007 to 31 March 2008) of marketing inNew Zealand.

In this interim analysis the IMMP identi-fied a total of 293 reports (for 284 pa-tients) with a total of 538 adverse eventsoccurring while the patient was takingvarenicline. These events have beenidentified from follow-up questionnairessent to doctors in June 2008 and sponta-neous reports submitted to the New

Zealand Pharmacovigilance Centre(NZPhvC). The most frequently reportedadverse events were psychiatric effects,with a total of 169 events (31% of allevents). The most common psychiatricadverse events reported were depression(22 events), insomnia (22), sleep distur-bance (13), fatigue (12), vivid/strangedreams (10), nightmares (10), andanxiety (9). There have also been fourreports of depersonalisation, four reportsof mood swings, four of panic attacks,and two of hypomania/ mood elevation.

The IMMP has identified six reports ofsymptoms following cessation ofvarenicline which appear to be withdrawaleffects.

Prescribers are reminded that patientsmay also experience psychiatric symp-toms such as depression and irritabilityfor many reasons including nicotinewithdrawal.

References

1. Kunac DL, Harrison-Woolrych ML, TatleyMV.. Pharmacovigilance in New Zealand: Therole of the New Zealand PharmacovigilanceCentre in facilitating safer medicines use. NZMedical Journal 2008;1281:76-89

2. Pzifer Inc.(2009).Data sheet for Champixaccessed 30 March 2009 at: www.medsafe.govt.nz/profs/datasheets.

3. Prescriber Update 2009;30(2):9 at http://www.medsafe.govt.nz/profs/PUarticles.asp


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Regulatory Action and News

Influenza virus vaccines:2009–2010 seasonWorld Health Organization — It isrecommended that vaccines for use in the2009–2010 influenza season (northernhemisphere winter) contain the following:

• an A/Brisbane/59/2007 (H1N1)-like virus[A/Brisbane/59/2007 is a current vac-cine virus; A/South Dakota/6/2007 (anA/Brisbane/59/2007-like virus) is acurrent vaccine virus used in live attenu-ated vaccines.]

• an A/Brisbane/10/2007 (H3N2)-like virus[A/Brisbane/10/2007 and A/Uruguay/716/2007 (an A/Brisbane/10/2007-likevirus) are current vaccine viruses].

• a B/Brisbane/60/2008-like virus. [B/Brisbane/33/2008 is a B/Brisbane/60/2008-like virus].

Vaccine viruses (including reassortants)and reagents for use in the laboratorystandardization of inactivated vaccinemay be obtained from:

Immunobiology Section, Office of Labora-tory and Scientific Services, TherapeuticGoods Administration, P.O. Box 100,Woden, ACT 2606, Australia (fax: +61 26232 8564, web site: http://www.tga.gov.au); Division of Virology, National Institutefor Biological Standards and Control,Blanche Lane, South Mimms, Potters Bar,Hertfordshire, EN6 3QG England (fax:+44 1707641050, e-mail: [email protected], web site: http://www.nibsc.ac.uk/fl u_site/index.html); or Division ofProduct Quality, Center for BiologicsEvaluation and Research, Food and DrugAdministration, 1401 Rockville Pike,Rockville,MD, 20892, United States (fax:+1 301 480 9748).

Requests for reference strains for anti-genic analysis should be addressed tothe WHO Collaborating Centre for Refer-ence and Research on Influenza, 10Wreckyn Street, North Melbourne, VIC3051, Australia (fax: +61 3 9342 3939,website: http://www.influenzacentre.org);the WHO Collaborating Centre for Refer-ence and Research on Influenza, Na-tional Institute of Infectious Diseases,Gakuen 4-7-1, Musashi-Murayama,Tokyo 208-0011, Japan (fax: +81 42 5610812 or +81 42 565 2498, web site: http://www.nih.go.jp/niid/index.html); the WHOCollaborating Center for Surveillance,Epidemiology and Control of Influenza,Centers for Disease Control and Preven-tion, 1600 Clifton Road, Mail Stop G16,Atlanta, GA 30333, United States (fax:+1 404 639 0080, web site: http://www.cdc.gov/fl u/); or the WHO Collabo-rating Centre for Reference and Re-search on Influenza, National Institute forMedical Research, The Ridgeway, MillHill, London NW7 1AA, England (fax: +44208 906 4477, email [email protected], web site: http://www.nimr.mrc.ac.uk/wic/.)

Reference: Weekly Epidemiological Record,Vol. 84(9) 65–76, 2009 at http://www.who.int/publications

Sale of efalizumab suspendedSingapore — The Health SciencesAuthority (HSA) has requested theproduct licence holder to suspend salesof efalizumab (Raptiva®) in Singaporewith effect from 26 February 2009 due tothe emergence of new safety issuesassociated with the product.

Raptiva® is available locally as a pre-scription medicine. It contains the active

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ingredient, efalizumab, an immunomo-dulating, humanized monoclonal anti-body, licensed for the treatment of adultpatients with moderate to severe chronicplaque psoriasis who are candidates ofphototherapy or systemic therapy.

HSA’s Pharmacovigilance AdvisoryCommittee has assessed data whichincluded recent adverse reports of pro-gressive multifocal leukoencephalopathy(PML) and the limited place in therapy ofefalizumab in the local setting and con-cluded that the risk versus benefit ofefalizumab is no longer favourable.

The review took into consideration therisks of potentially fatal PML associatedwith efalizumab countered with the factthat it is not a first-line therapy, that it isused in a potentially serious but non-lifethreatening condition, and the availabilityof other treatment options for plaquepsoriasis. Besides PML, efalizumab isalso associated with serious adverseeffects such as Guillain-Barre and Miller-Fisher syndromes, encephalitis, encepha-lopathy, meningitis, sepsis and opportun-istic infections.

PML is a rare neuromuscular diseasecaused by opportunistic infections thatusually leads to severe disability or death.There is no reliable way of knowing whichpatients will develop PML or when thedisease is likely to occur. To date, thereare four worldwide reports of PML (threevirologically confirmed and one sus-pected) associated with the product inpatients who had been continuouslytreated with Raptiva® for three or moreyears. Two of the three confirmed casesresulted in the patient’s death. Locally,the HSA has not received any adversedrug reaction reports associated withRaptiva®.

Reference: HSA Alert, Sales of efalizumab(Raptiva®) suspended. 27 February 2009.http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/safetyinformation/product_safety_alerts.html

Efalizumab: voluntarywithdrawalUnited States of America — The manu-facturer of the psoriasis drug efalizumab(Raptiva®), has announced that it hasbegun a voluntary, phased withdrawal ofthe product from the US market. Thecompany is taking action because of apotential risk of progressive multifocalleukoencephalo-pathy (PML), a rare,serious, progressive neurologic diseasecaused by a virus that affects the centralnervous system. By 8 June 2009, efalizu-mab will no longer be available in theUnited States.

Prescribers are asked not to initiateefalizumab treatment for any new patientsand immediately begin discussing withpatients currently using efalizumab onhow to transition to alternative therapies.

The risk that an individual patient takingRaptiva® will develop PML is rare and isgenerally associated with long-term use.Generally, PML occurs in people whoseimmune systems have been severelyweakened and often leads to an irrevers-ible decline in neurologic function anddeath. There is no known effectivetreatment for PML.

Reference: FDA Statement, 8 April 2009 atwww.fda.gov/medwatch/ and www.gene.com/gene/products.

Oseltamivir: extensionof shelf lifeEuropean Union — The EuropeanMedicines Agency (EMEA) has recom-mended that the shelf life of oseltamivir(Tamiflu®) capsules should be extendedfrom five to seven years. Once formallyapproved by the European Commission,this will apply to all newly manufacturedoseltamivir capsules.

In view of the recent outbreak of the novelinfluenza A/H1N1 virus, the European


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Medicines Agency has also reviewedways to use oseltamivir capsules in caseof a shortage. The Agency’s Committeefor Medicinal Products for Human Use(CHMP) recommended that oseltamivircapsules that are already on the marketmay be used for up to two more yearsafter their current five-year expiry dateduring a declared pandemic. Patientswho have oseltamivir capsules that haverecently expired should not dispose ofthem because they might be neededduring a novel influenza A/H1N1 pan-demic. These recommendations will onlyapply if a pandemic has been declared bythe World Health Organization (WHO).

Reference: Press Release, Doc. Ref. EMEA/284971/2009, 8 May 2009 at http://www.emea.europa.eu/

Antiviral medicines in aninfluenza pandemicEuropean Union — The EuropeanMedicines Agency (EMEA) has givenguidance on the use of oseltamivir(Tamiflu®) in children under one year ofage and use of oseltamivir (Tamiflu®) andzanamivir (Relenza®) in pregnant andbreastfeeding women in the case of adeclared influenza A/H1N1 pandemic bythe World Health Organization (WHO).

Children under the age of oneThe Agency’s Committee for MedicinalProducts for Human Use (CHMP) hasconcluded that during an officially de-clared influenza A/H1N1 pandemic thebenefits of oseltamivir outweigh its risksin the treatment of children under the ageof one. Because there is less evidence tosupport the use of oseltamivir for theprevention of influenza, doctors shouldcarefully consider the benefits and risksfor each patient.

During a pandemic, if oseltamivir isprescribed to children under the age ofone, the recommended dosage is 2 to 3mg per kg body weight.

Pregnant and breastfeeding womenFollowing a review of the available datafor oseltamivir and zanamivir, the CHMPconcluded that the benefits of using thesemedicines in pregnant or breastfeedingwomen outweigh the risks in case of aninfluenza A/H1N1 pandemic.

Reference: Press Release, Doc. Ref. EMEA/285148/2009, 8 May 2009 at http://www.emea.europa.eu/

European Union and HealthCanada: confidentialityarrangementCanada/European Union — The Euro-pean Medicines Agency, the EuropeanCommission and Health Canada, theCanadian regulatory authority for medi-cines, have agreed on an implementationplan for their confidentiality arrangement.

The implementation plan details theprocess for both regular and ad-hocexchanges of information, and describesthe process for monitoring the progress ofthe implementation plan. It also foreseesan exchange programme for staff topromote mutual learning and sharing ofregulatory experience.

The confidentiality arrangement, signed inDecember 2007, allows the parties toshare non-public information on allhuman and veterinary medicines —already authorized or still under review —that fall within the scope of the agree-ment. It also allows the exchange ofinformation on legislation under develop-ment or draft regulatory guidance docu-ments.

The implementation plan with HealthCanada follows largely the plan in placefor implementation of the confidentialityarrangements with the United StatesFood and Drug Administration (FDA). Theregulatory agencies will explore potentialjoint implementation activities with theFDA to avoid duplication of efforts.


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Reference: Press Release, Doc. Ref. EMEA/220316/2009, 8 April 2009 at http://www.emea.europa.eu/

Ixabepilone: withdrawal ofapplication for marketingauthorizationEuropean Union — The EuropeanMedicines Agency (EMEA) has beenformally notified by the product licenceholder of its decision to withdraw theapplication for a centralized marketingauthorization for ixabepilone (Ixempra®),2 mg/ml powder and solvent for concen-trate for solution for infusion. Ixabepilonewas expected to be used to treat locallyadvanced or metastatic breast cancerafter failure of previous cytotoxic chemo-therapy treatments. It was to be used incombination with capecitabine.

The application for the marketing authori-sation for Ixempra was submitted to theAgency on 24 September 2007. On 20November 2008, the Agency’s Committeefor Medicinal Products for Human Use(CHMP) adopted a negative opinion,recommending the refusal of the market-ing authorization. Following this, thecompany requested a re-examination ofthe opinion, which was under review bythe CHMP at the time of the withdrawal.

Reference: EMEA Press Release, Doc. Ref.EMEA/177056/2009, 19 March 2009. http://www.emea.europa.eu

Peginterferon alfa-2b:withdrawal of application formarketing authorizationEuropean Union —The EuropeanMedicines Agency (EMEA) has beenformally notified by the product licenceholder of its decision to withdraw theapplication for a centralized marketingauthorization for the medicine peginter-feron alfa-2b (Cylatron®), 200 micro-grams /0.5 ml, 300 micrograms /0.5 mland 600 micrograms/0.5 ml.


Peginterferon alfa-2b was expected to beused for the adjuvant treatment of pa-tients with stage III melanoma as evi-denced by microscopic, non-palpablenodal involvement.

In its official letter, the company statedthat the withdrawal of the application wasbased on the CHMP’s view that the dataprovided were not sufficient to allow theCommittee to conclude on a positivebenefit-risk balance for Cylatron® at thattime.

Reference: Press Release, 16 March 2009Doc. Ref. EMEA/158824/2009 at http://www.emea.europa.eu/

Levodopa/carbidopa/entacapone: withdrawal ofapplication for extension ofindicationEuropean Union —The EuropeanMedicines Agency (EMEA) has beenformally notified by the product licenceholder of its decision to withdraw itsapplication for an extension of indicationfor the centrally authorized medicinelevodopa/carbidopa/entacapone(Stalevo®) film-coated tablets.

Stalevo® was first authorized in theEuropean Union on 17 October 2003.It is currently authorized for use in pa-tients with Parkinson disease, who arebeing treated with a combination oflevodopa and an inhibitor of dopa decar-boxylase but are having ‘fluctuations’ (awearing-off of the medicine’s effects andre-emergence of symptoms) towards theend of the period between two doses oftheir medication, which cannot be stabi-lized with the standard combinationalone.

In its official letter, the company statedthat the withdrawal of the application wasbased on feedback from the evaluation ofthe application that indicated that the dataprovided were insufficient to support

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approval for this indication. In addition,the company also stated that it is unableto provide additional clinical data to theCHMP within the permitted timeframe.

Stalevo® continues to be authorized forthe currently approved indication.

Reference: Press Release, 10 March 2009Doc. Ref. EMEA/147137/2009 at http://www.emea.europa.eu/


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GGM Activities ReportWHO has defined a model process and along-term strategy for implementing theGood Governance for Medicines (GGM)programme in countries, based on thefollowing three-phase approach.

Phase I: National assessment of trans-parency and potential vulnerability tocorruption of key pharmaceutical systemfunctions. Independent national asses-sors conduct the assessment, and oncompletion a report with the findings andrecommendations for action is produced,providing a baseline to monitor thecountry’s progress over time.

Phase II: Development of a NationalGGM Framework. This involves a nation-wide consultation process among keystakeholders. Countries validate theresults of the assessment and define thebasic components necessary for promot-ing good governance practices in themanagement of their national pharmaceu-tical system.

Phase III: Implementation of the NationalGGM Framework. This phase aims topromote the framework among keypharmaceutical actors and to translate itsrecommendations into action through aset of strategic activities increasing

Corruption is the single greatest obstacle to social and economic development incountries worldwide, undermining democracy and creating unstable governments.With an annual global expenditure estimated at more than US$ 4.4 trillion, the healthsector is a very real target for corruption and other unethical practices.

Corruption in the pharmaceutical sector can take various forms. Whether it is briberyof a government official, falsification of efficacy and safety data, theft in the distribu-tion chain or recruitment of personnel based on favouritism, its impact on public healthand government financial resources can no longer be ignored.

Although hard data on global financial losses due to corruption in the pharmaceuticalsector are lacking, related figures indicate that losses are potentially very high. Forexample, Transparency International estimates that, on average, 10 to 25 % of publicprocurement spending, including in the health sector, is lost due to corruption. Suchabuse can aggravate the global inequalities in access to essential medicines andcan be detrimental to a country’s ability to improve the health of its population.

The Good Governance for Medicines (GGM) programme began in late 2004, in linewith the World Health Organization’s (WHO) Global Medicines Strategy. Its goal is toreduce corruption in the pharmaceutical sector by the application of transparent, ac-countable administrative procedures and by promoting ethical practices. Throughthis initiative, WHO’s objective is to support countries in maintaining efficient health-care systems.

Good Governance for Medicines Programme

Medicines Strategy and Policies

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awareness, strengthening integritysystems and building capabilities forleadership.

GGM technical packageWHO has developed a complete techni-cal package to guide countries in each ofthe three phases of GGM implementation.

Measuring transparency in the publicpharmaceutical sectorThe GGM transparency assessmentinstrument for Phase I measures the levelof transparency in eight key functions ofmedicines regulatory and procurementsystems, and provides both quantitativeand qualitative information. Assessorscollect information through semi-struc-tured interviews of key informants whorepresent different stakeholders, such asgovernment, the private sector, academiaand nongovernmental organizations. Theinformation collected is then converted toa 0 to 10 scale to provide a score ofvulnerability to corruption for each func-tion, from minimally to extremely vulner-able. The basic assumption is that themore transparent any system is, the lessvulnerable to corruption it will be. A first

draft of the instrument was developed in2004 and was regularly refined in light ofthe experience gained by countries. TheEnglish version of the instrument wasfinalized during a global expert consulta-tion in February 2008. The Arabic, Frenchand Spanish translations will be availableshortly to facilitate the future expansion ofthe GGM programme in other countries.

GGM framework for good governancein the pharmaceutical sectorThis GGM framework serves as a PhaseII model for the development of nationalGGM frameworks. At the crux of theargument presented in this document isthat to achieve significant impact effortsto address corruption must include theapplication of two basic strategies:

• Discipline-based strategy – establishinganti-corruption laws, pharmacy practicelaws and regulation, foreseeing ad-equate sanctions for violations of thelaw.

• Values-based strategy – building institu-tional integrity through the promotion ofmoral values and ethical principles.

Values-based strategy Discipline-based strategy

• Framework of moral values & ethical • Established anti-corruption legislation principles:

• Whistle-blowing mechanisms -Justice/fairness -Truth • Sanctions on reprehensible acts -Service to common good - Trusteeship • Established regulations and adminis-

trative procedures• Code of conduct

• Collaboration between anticorruption• Programme for socialization of agencies, CSOs and private sector ethical framework & code of conduct

• Management, coordination and• Promotion of moral leadership evaluation of GGM programme

(Steering Committee & Task Force)

Basic components of the GGM Framework


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Guide for promoting the frameworkfor good governance in thepharmaceutical sectorThere are no “quick fixes” for tacklingcorruption and promoting good govern-ance in the pharmaceutical sector. A long-term strategy is needed that activelycontinues after a country officially adoptsits national GGM framework. Phase IIIconsists of translating the GGM frame-work into action. The guide for Phase IIIrecommends a set of strategic activitiesto socialize the GGM framework, to (i)promote awareness among health profes-sionals and the general public on thepotential for corruption and its impact onhealth system functioning and (ii) buildnational capacity for sustaining goodgovernance in the pharmaceutical sys-tem.

A consultation process for the revision ofthe guide has started, and after furthertesting in countries the revised versionwill be completed in 2009.

Progress in countriesThe GGM programme started in 2004 infour Asian countries: Lao People’s Demo-cratic Republic, Malaysia, the Philippinesand Thailand. Since then the success ofthe programme has exceeded expecta-tions. The number of countries adoptingthe GGM programme globally has in-creased significantly and the programmecurrently operates in 26 countries acrossthe six WHO regions (5).

WHO has developed a training packagefor each of the three phases and theseare provided to countries before the startof each phase. WHO has also estab-lished a monitoring and reporting system,whereby countries report their activities toWHO on a bi-annual basis.

Countries in Phase 1Implementation of the GGM programmestarts after receiving clearance from theMinistry of Health (MoH). Independent

national assessors are selected to con-duct the transparency assessment. WHOprovides technical training workshops forthe assessors on the use of the assess-ment methodology and accompanyingtools.

To date, results indicate that in themajority of countries promotion, selectionand inspection are the functions that arethe most vulnerable to corruption. Com-parison of the findings between countriesshowed some common trends, in both thestrengths and weaknesses. For example,most countries have transparent andcompetitive procurement procedures, witha post-tender mechanism to monitorsuppliers’ performance.

In the selection function, most countrieshad a national essential medicines list,with transparent procedures for theselection process. The common weak-nesses related to the lack of conflict ofinterest guidelines, the absence of aresponsible unit within the medicinesregulatory authorities for monitoringmedicines promotion or the lack ofpublicly available terms of reference forthe committee responsible for overseeingmedicines registration or selection,describing its role and responsibilities.

WHO encourages countries to publish theresults of the national transparencyassessment, although this takes time asthe results need to be validated bynational stakeholders and officiallyapproved by the government beforepublication. By the end of 2008, WHOhad published results from 11 countries.

Countries in Phase IIAssessing the level of transparency andpotential vulnerability to corruption is notan end in itself but rather the beginning ofa long process intended to generate goodgovernance in the pharmaceutical sector.WHO recommends that countries holda national workshop with key stakehold-


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ers shortly after the assessment iscompleted. The objective of such aworkshop is to validate the results of thetransparency assessment and consult onthe key components that need to beincluded in the national GGM frameworkdocument. The workshop is the first keyelement of Phase II.

A national GGM team is then nominatedby the MoH, which is responsible for (i)the development and finalization of theframework document in consultation withall key stakeholders and (ii) the overallmanagement, coordination and evalua-tion of the GGM programme in eachcountry. In some countries, it has been

decided to have a Steering Committee,headed by high-level officials to set thestrategic directions for the GGM pro-gramme and to guide the country team.

Once officially adopted, this documentauthorizes country teams to implementand promote good governance in thepharmaceutical sector.

Countries in Phase IIIGGM frameworks are effective only iftranslated into action. Too often goodpolicy documents are developed but notwidely used. The aim of Phase III is toensure that concrete actions are imple-mented and anti-corruption efforts remain

GGM leadership and network

Global Advisory GroupWHO’s GGM programme is now guided by its Global Advisory Group (GAG) thatprovides overall strategy and policy guidance. It is comprised of a wide range ofstakeholders, including international and bilateral organizations (World Bank, DFID),civil society (Transparency International, Procurement Watch), academia, nationalanti-corruption agencies, ministries of health and the private sector. It meets once ortwice a year.

Global Stakeholders GroupA meeting of the Global Stakeholders Group (GSG) was held in Bangkok, 3 to 5December 2007 with the objective of providing a platform to exchange experiencesin curbing corruption and promoting good governance in the pharmaceutical sector,as well as an opportunity to network with stakeholders. Seventy participants from 25countries, including country officials involved with the implementation of GGM intheir countries as well as a wide range of key stakeholders, attended this two and ahalf day meeting. The theme selected “Transparency for change” aimed to mobilizea “call for action” for all participants to meet the challenges ahead, and ultimately tohelp make quality essential medicines accessible and affordable to all. WHO plansto hold GSG meetings every two years.

GGM human resourcesWHO’s priority in the coming years is to create a global team of “GGM human re-sources” who will be responsible for training and working closely with GGM countryteams, especially from Phase II onwards. This will be essential for the sustainabilityof GGM programmes in countries. The global team will be multilingual (Arabic, Eng-lish, French and Spanish) and its members will be selected on a specific set ofcriteria, such as familiarity with the GGM concepts, and availability to participateactively in GGM activities. WHO will develop a “training of trainers” package andprovide training for this group in 2009.


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sustainable. By the end of 2008, thefollowing four countries were in Phase IIIand planned activities included:

• Bolivia. Training of the national GGMteam, briefing sessions for governmentofficials, production of advocacy materi-als.

• Mongolia. Changing procedures inregulation and supply systems to makethem more transparent, moving towardsa web-based registration and licensingsystem, adoption of a code of conductfor pharmacists and development of aconflict of interest form.

• Philippines. Launching of a GGMnational award for Local GovernmentUnits to decentralize GGM practices tothe provinces.

• Thailand. Introducing the GGM conceptinto university curricula and producingadvocacy materials.

To ensure the sustainability of the GGMprogramme, training the national GGMteam and continuing to work closely withit will be essential. In January 2009 aPhase III training workshop was held forthe first time in Amman for Jordan’snational team. It focused on anti-corrup-tion and pharmaceutical sector legalframeworks, implementation of therecommendations included in the trans-parency assessment (Phase I) and moralleadership capabilities. WHO’s focus inthe coming years will be to build capacityin countries, through a combination ofPhase III training and coaching.

Lessons learnt and the way forwardInterest in the GGM programme has beenhigher than anticipated at global andcountry levels, for a number of reasons.The preventive and constructive ap-proach, namely measuring vulnerability tocorruption and strengthening pharmaceu-

tical systems by increasing transparencyhas appealed to governments. Also, theGGM programme is addressing realconcerns and a deep-rooted issue, whichis increasingly and openly acknowledgedby colleagues in ministries of health,academia, civil society organizations andthe private sector. There appears to be anincreased consciousness that as long ascorruption is not addressed, developmentwork will not be successful. This has ledsenior colleagues in countries to becomeinvolved in the national GGM teams.Momentum for change is increasing.

High-level commitment has proved to bebeneficial, not only for giving this sensi-tive programme the profile it ought tohave, but also for ensuring its sustainabil-ity. Experience has also shown thatpartnering with national anti-corruptionor good governance bodies is extremelyvaluable, together with constant commu-nication and staff training. It is importantto acknowledge that some countries needmore time than others, depending on theirpolitical situation and the availabilityof human resources to carry out GGMactivities.

“Cross-fertilization” between participatingcountries has proved to be probably thebest learning platform and WHO willcontinue its role as a hub in sharinginformation and experiences gained incountries, ensuring systematic evaluationand reflection on how best to increasetransparency and build capacity topromote good governance in the pharma-ceutical sector.

In the next few years WHO will focus onconsolidating the GGM programme incountries and is committed to continuingto provide technical support in this chal-lenging and rewarding area of work.

More information and a list of key GGMpublications is available at http://www.who.int/medicines/ggm or contact [email protected]


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Recent Publications,Information and EventsASEAN: mutual recognitionarrangement for GMPThe Association of Southeast AsianNations (ASEAN) has moved a stepcloser to the realization of its vision of anintegrated regional health care sectorthrough the reduction of technical barriersto trade in pharmaceutical products.

On 10 April 2009, the ASEAN signed aSectoral Mutual Recognition Arrangement(MRA) for good manufacturing practice(GMP) inspection of manufacturers ofmedicinal products (IRMMP) thatwould ensure the safety, quality, efficacyand lower prices of drugs being sold inthe region.

The 14th ASEAN Summit and RelatedSummits report has stated that diver-gences in national product standardsoften act as impediments to trade ingoods. In order to promote deepereconomic integration between economiestowards the realization of the ASEANEconomic Community by 2015 theharmonization of product standards, andmutual recognition of test reports andcertification is necessary.

Inspection reports of manufacturers ofmedical products seeking good manufac-turing practice certifications and/orinspection by authorized agencies willserve as the basis in determining compli-ance with regulatory requirements. Theseinclude the issuance of licences forpharmaceuticals.

The Sectoral Mutual Recognition Ar-rangement will be fully implemented by allASEAN member countries by 1 January2011. Pharmaceuticals must also demon-strate proper compliance with the

Pharmaceutical Inspection CooperationScheme (PIC/S) Guide for MedicinalProducts.

Reference: ASEAN Press Release, 11 April2009 http://www.gov.ph/news/?i=24164

Losing artemisinin?World Health Organization — For manymonths there have been reports fromCambodia of cases of malaria showingresistance to what is now the mainstay ofmalaria treatment – artemisinin combina-tion therapy (ACT) (1, 2)

A programme has now been launchedseeking to contain the spread of artemisi-nin resistance (3). It must be hoped thatthese efforts will achieve some success.The loss of this drug would be calamitousfor malaria control globally.

Since it was first established that artem-isinin could be an effective replacementfor the older malaria treatments, massiveinvestments have been made with theaim of making ACT drugs accessible tothose who need them (4)

The sale of substandard ACTs containinginadequate levels of the active drug andthe use of artemisinin as a monotherapyboth promote the development of resist-ance. It is essential that these practicesshould be halted.

References

1. http://www.tropika.net/svc/review/Chinnock20080509Revartemisin last year.

2. http://blog.tropika.net/tropika/2008/11/03/artemisin-is-resistance-appearing-in-cambodia/

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3. http://www.tropika.net/svc/news/20090302/Chinnock-20090302-News-Artemisinin-resistance

4. http://blog.tropika.net/tropika/2009/03/04/malaria-a-breakthrough-in-artemsinin-produc-tion/

5. News on UNICEF/UNDP/WorldBank/WHO-TDR http://www.who.int/tdr/topmenu/news/

International drug priceindicator guideManagement Sciences for Health hasannounced the availability of the 2008edition of the International Drug PriceIndicator Guide. The Guide provides aspectrum of prices from 25 sources,including pharmaceutical suppliers,international development organizations,and government agencies. The Guideassists supply officers to determine the

probable cost of pharmaceutical productsfor their programmes, allows users tocompare current prices paid to pricesavailable on the international market, orassess the potential financial impact ofchanges to a medicines list, and helps tosupport rational medicine use education.

This edition of the Guide was produced incollaboration with the World HealthOrganization. Development and publica-tion was supported by the UK Departmentfor International Development (DFID) andthe Medicines Transparency Alliance(MeTA).

Reference: Center for PharmaceuticalManagement, Management Sciences forHealth at http://www.msh.org/resource-center/ebookstore

Recent Publications, Information and Events

WHO Drug Information, Vol. 23, No. 2, 2009 Proposed INN: List 101

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International Nonproprietary Names for Pharmaceutical Substances (INN) Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances, the names given in the list on the following pages are under consideration by the World Health Organization as Proposed International Nonproprietary Names. The inclusion of a name in the lists of Proposed International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy. Lists of Proposed (1–96) and Recommended (1–57) International Nonproprietary Names can be found in Cumulative List No. 12, 2007 (available in CD-ROM only). The statements indicating action and use are based largely on information supplied by the manufacturer. This information is merely meant to provide an indication of the potential use of new substances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors will neither be revised nor included in the Cumulative Lists of INNs.

Dénominations communes internationales des Substances pharmaceutiques (DCI) Il est notifié que, conformément aux dispositions de l'article 3 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques les dénominations ci-dessous sont mises à l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes internationales proposées. L'inclusion d'une dénomination dans les listes de DCI proposées n'implique aucune recommandation en vue de l'utilisation de la substance correspondante en médecine ou en pharmacie. On trouvera d'autres listes de Dénominations communes internationales proposées (1–96) et recommandées (1–57) dans la Liste récapitulative No. 12, 2007 (disponible sur CD-ROM seulement). Les mentions indiquant les propriétés et les indications des substances sont fondées sur les renseignements communiqués par le fabricant. Elles ne visent qu'à donner une idée de l'utilisation potentielle des nouvelles substances au moment où elles sont l'objet de propositions de DCI. L'OMS n'est pas en mesure de confirmer ces déclarations ni de faire de commentaires sur l'efficacité du mode d'action ainsi décrit. En raison de leur caractère provisoire, ces informations ne figureront pas dans les listes récapitulatives de DCI.

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI) De conformidad con lo que dispone el párrafo 3 del "Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas", se comunica por el presente anuncio que las denominaciones detalladas en las páginas siguientes están sometidas a estudio por la Organización Mundial de La Salud como Denominaciones Comunes Internacionales Propuestas. La inclusión de una denominación en las listas de las DCI Propuestas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia. Las listas de Denominaciones Comunes Internacionales Propuestas (1–96) y Recomendadas (1–57) se encuentran reunidas en Cumulative List No. 12, 2007 (disponible sólo en CD-ROM). Las indicaciones sobre acción y uso que aparecen se basan principalmente en la información facilitada por los fabricantes. Esta información tiene por objeto dar una idea únicamente de las posibilidades de aplicación de las nuevas sustancias a las que se asigna una DCI Propuesta. La OMS no está facultada para respaldar esas indicaciones ni para formular comentarios sobre la eficacia de la acción que se atribuye al producto. Debido a su carácter provisional, esos datos descriptivos no deben incluirse en las listas recapitulativas de DCI.

Proposed INN: List 101 WHO Drug Information, Vol. 23, No. 2, 2009

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Proposed International Nonproprietary Names: List 101 Comments on, or formal objections to, the proposed names may be forwarded by any person to the INN Programme of the World Health Organization within four months of the date of their publication in WHO Drug Information, i.e., for List 101 Proposed INN not later than 15 November 2009. Publication date: 15 July 2009 Dénominations communes internationales proposées: Liste 101 Des observations ou des objections formelles à l'égard des dénominations proposées peuvent être adressées par toute personne au Programme des Dénominations communes internationales de l'Organisation mondiale de la Santé dans un délai de quatre mois à compter de la date de leur publication dans WHO Drug Information, c'est à dire pour la Liste 101 de DCI Proposées le 15 novembre 2009 au plus tard. Date de publication: 15 juillet 2009 Denominaciones Comunes Internacionales Propuestas: Lista 101 Cualquier persona puede dirigir observaciones u objeciones respecto de las denominaciones propuestas, al Programa de Denominaciones Comunes Internacionales de la Organización Mundial de la Salud, en un plazo de cuatro meses, contados desde la fecha de su publicación en WHO Drug Information, es decir, para la Lista 101 de DCI Propuestas el 15 de Noviembre de 2009 a más tardar. Fecha de publicación: 15 de Julio de 2009.

Proposed INN (Latin, English, French, Spanish) DCI Proposée DCI Propuesta

Chemical name or description: Action and use: Molecular formula Chemical Abstracts Service (CAS) registry number: Graphic formula Nom chimique ou description: Propriétés et indications: Formule brute Numéro dans le registre du CAS: Formule développée Nombre químico o descripción: Acción y uso: Fórmula molecular Número de registro del CAS: Fórmula desarrollada

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

farnesoid X receptor agonist

acide obéticholique acide 6α-éthyl-3α,7α-dihydroxy-5β-cholan-24-oïque agoniste du récepteur du farnésoïde X

ácido obeticólico ácido 6α-etil-3α,7α-dihidroxi-5β-colan-24-oico agonista del receptor de farnesoide X

C26H44O4 459789-99-2

CH3

CH3 H

H

H

H

H3C

CO2H

H

H

OH

H

HHO

H

CH3


131

acidum tiomolibdicum tiomolibdic acid dihydrogen(tetrasulfidomolybdate)

chelating agent

acide tiomolibdique tétrasulfidomolybdate d'hydrogène chélateur

ácido tiomolíbdico dihidrógeno(tetrasulfuromolibdato) quelante

H2MoS4 13818-85-4

HS SHMo

SS

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

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

afacifénacine

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

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

C27H26F3N3O2 877606-63-8

N

HN

H

O

N

OCF3

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

sphingolipidosis therapy (Gaucher's disease)

afégostat (3R,4R,5R)-5-(hydroxyméthyl)pipéridine-3,4-diol traitement des sphingolipidoses (maladie de Gaucher)

afegostat (3R,4R,5R)-5-(hidroximetil)piperidina-3,4-diol tratamiento de la esfingolipidosis (enfermedad de Gaucher)

C6H13NO3 169105-89-9

NHHO

HO

H

H

OH

H


132

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

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

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

aganirsén todo-P-ambo-timidilil-(3′→5′)-2′-desoxi-P-tioadenilil-(3′→5′)-P-tiotimidilil-(3′→5′)-2′-desoxi-P-tiocitidilil-(3′→5′)-2′-desoxi-P-tiocitidilil-(3′→5′)-2′-desoxi-P-tioguanilil-(3′→5′)-2′-desoxi-P-tioguanilil-(3′→5′)-2′-desoxi-P-tioadenilil-(3′→5′)-2′-desoxi-P-tioguanilil-(3′→5′)-2′-desoxi-P-tioguanilil-(3′→5′)-2′-desoxi-P-tioguanilil-(3′→5′)-2′-desoxi-P-tiocitidilil-(3′→5′)-P-tiotimidilil-(3′→5′)-2′-desoxi-P-tiocitidilil-(3′→5′)-2′-desoxi-P-tioguanilil-(3′→5′)-2′-desoxi-P-tiocitidilil-(3′→5′)-2′-desoxi-P-tiocitidilil-(3′→5′)-2′-desoxi-P-tioadenilil-(3′→5′)-P-tiotimidilil-(3′→5′)-2′-desoxi-P-tioguanilil-(3′→5′)-2′-desoxi-P-tiocitidilil-(3′→5′)-P-tiotimidilil-(3′→5′)-2′-desoxi-P-tioguanilil-(3′→5′)-2′-desoxi-P-tiocitidilil-(3′→5′)-P-tiotimidina inhibidor de la angiogénesis

C242H307N91O127P24S24 1146887-67-3 (3'-5')d(P-thio)(T-A-T-C-C-G-G-A-G-G-G-C-T-C-G-C-C-A-T-G-C-T-

G-C-T)


133

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

3-ium] dibromide antinalarial

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

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

C24H42Br2N2O2S2 321915-72-4

NS

CH3

N S

H3CBr

BrHO

OH

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

2-[3-(trifluoromethyl)phenoxy]acetate antidiabetic

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

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

C19H17ClF3NO4 24136-23-0

OO

HN CH3

H

CF3

O

O

Cl

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

cell development regulator

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

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


134

C15H9FN2O3 775304-57-9

CO2HN

ON

F

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

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

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

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

C31H34N6O6 867063-97-6

ON

N

O

O

N

N

CH3

O

O

NNH2

CH3

CH3

O

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

antineoplastic

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

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


135

C31H41NO4 218600-44-3

CH3CH3

CH3

CH3H3C

CH3H3C

O

CO2H

H

NC

O

H

H

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

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

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

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

C159H201N58O82P15S15 1072859-54-1 (3'-5')d(P-thio)(mrC-rT-C-C-C-A-A-C-G-T-G-C-G-mrC-mrC-A)

mrC

H2C

O

N

NO NH2

O

HO

OH

CH3

HH2C

O

N

HNO O

O

HO

OH

CH3

rT

H


136

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

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

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

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

(C16H36N6)x . (C3H6O)y 851373-13-2

NH

NN

HN

HN

NH x

CH2

y

CH2

OH H2C

CH

HO

orouo

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

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

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


137

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

C6376H9874N1722O1992S44 339308-60-0 Heavy chain / Chaîne lourde / Cadena pesada

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

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

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

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

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

1-benzofuran-2-yl)acetate antiarrhythmic

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

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

C27H31I2NO5 335148-45-3

O

O

O

OI

I

N CH3

CH3

O

H3C

HH3C


138

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

2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl}piperidin-4-yl)- 2-methylpropanamide neurokinin NK1 receptor antagonist

burapitant 2-(1-{2-[(2R)-4-{2-[3,5-bis(trifluorométhyl)phényl]acétyl}- 2-(3,4-dichlorophényl)morpholin-2-yl]éthyl}pipéridin-4-yl)- 2-méthylpropanamide antagoniste du récepteur NK1 de la neurokinine

burapitant 2-(1-{2-[(2R)-4-{2-[3,5-bis(trifluorometil)fenil]acetil}- 2-(3,4-diclorofenil)morfolin-2-il]etil}piperidin-4-il)-2-metilpropanamida antagonista del receptor NK1 de neurokinina

C31H35Cl2F5N3O3 537034-22-3

N

CF3

CF3

O

O

N

H2N

Cl

Cl

CH3H3C

O

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

antiarrhythmic

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

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

C14H17N3O4 943134-39-2

N

CO2HHH2N

HNH

O

O

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

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


139

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

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


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

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



davalintidum # davalintide amylin analogue

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


140

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

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

C152H248N50O49S2 863919-85-1 H Lys Cys Asn Thr Ala Thr Cys Val Leu Gly Arg Leu

Ser Gln Glu Leu

Thr

His

Asn

Arg

Thr

Leu

Gly Ser

Gln Thr

Asn

Tyr

Thr

Pro

Tyr

Arg

NH230

10

20

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

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

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

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

C20H15ClFN5O5S2 936500-94-6

NH

NH

S

N

HN

S

F

HN

H3CO

O

O O O

Cl

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

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


141

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

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

C75H124N14O16 681272-30-0

O

NH

HN

HNHN

NH

O

O

O

HH3CCH3

CH3

H

H

HO

H3CCH3O

H3CH

O

H3C

H3C

H

NH

OHN

CH3O

CH3

H H

H

NH

HO

NO

NHO

H3C

H3C H

NH

HO

CH3

H3C

HN

OCH3HO

NH

O CH3

H

H CH3

H3C

H CH3

H

H2N

H

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

anticonvulsant

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

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

C10H7Cl3N4 212778-82-0

N

N

ClNH2

NH2

Cl

Cl


142

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

antiviral

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

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

C14H15IN2O 201349-37-3

N

NH

O

H3C

I

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

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

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

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


143

C1982H3054N560O618S28 944130-77-2 Light chain / Chaîne légère / Cadena ligera

ANAFLEELRP GSLERECKEE QCSFEEAREI FKDAERTKLF WISYSDGDQC 50ASSPCQNGGS CKDQLQSYIC FCLPAFEGRN CETHKDDQLI CVNENGGCEQ 100YCSDHTGTKR SCRCHEGYSL LADGVSCTPT VEYPCGKIPI LEKRNASKPQ 150GR 152

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

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

Modified residues / Résidus modifiés / Residuos modificados

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

4-carboxyGluHO2C

CO2H

CO2H

H NH2

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

(β-Xyl)n-β-Glc→S-52n = 0-2

α-Fuc→S-60

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

R'→3-β-Gal→3-β-Gl-N→2-α-Man→3-

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

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

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

1,3-dihydro-2H-imidazole-2-thione dopamine-β-hydroxylase inhibitor

étamicastat 5-(2-aminoéthyl)-1-[(3R)-6,8-difluoro-3,4-dihydro-2H-chromen-3-yl]-1,3-dihydro-2H-imidazole-2-thione inhibiteur de la dopamine β-hydroxylase

etamicastat 5-(2-aminoetil)-1-[(3R)-6,8-difluoro-3,4-dihidro-2H-cromen-3-il]- 1,3-dihidro-2H-imidazol-2-tiona inhibidores de la dopamina β-hidroxilasa

C14H15F2N3OS 760173-05-5

O

NNH

SF

F H

H2N


144

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

3-sulfonamido)methyl]phenoxy}acetic acid prostaglandin E2 receptor agonist

évatanépag acide 2-{3-[(N-{[4-(tert-butyl)phényl]méthyl}pyridine- 3-sulfonamido)méthyl]phénoxy}acétique agoniste du récepteur de la prostaglandine E2

evatanepag ácido 2-{3-[(N-{[4-(terc-butil)fenil]metil}piridina- 3-sulfonamido)metil]fenoxi}acético agonista del receptor de prostaglandina E2

C25H28N2O5S 223488-57-1

N

S

O CO2H

CH3NH3C CH3

OO

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

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

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

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


145


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

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



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

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

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

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

C29H37N5O3 877130-28-4

O O

OH

N

NNN

CH3

H3C

N

H3C

H3C

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

diagnostic aid

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

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


146

C14H11[18F]N2OS 765922-62-1

N

SHO

NHCH3

18F

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

nootropic agent

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

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

C12H14N2O2 77472-70-9

NNH2

O

Oand enantiomeret énantiomèrey enantiómero

H

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

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

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


147

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


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

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



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

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

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


148

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


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

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



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

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

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

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

C23H33N7O5S 334826-98-1

HN

N

NN

N

SN

N

OO

O

CH3O CH3

OCH3

H3C


149

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

[4-(hydroxycarbamoyl)phenyl]carbamate antineoplastic

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

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

C24H27N3O4 497833-27-9

O NH

NH

OH

O

O

NH3C

H3C

golnerminogenum pradenovecum # golnerminogene pradenovec a replication deficient human adenovirus 5 viral vector deleted in the

E1, E4 and part of the E3 region and expressing a human tumour necrosis factor alpha (TNF-α) gene inserted in the E1 region and under the control of an Egr-1 promoter and the SV40 polyadenylation sequence gene therapy product (antineoplastic)

golnerminogène pradénovec

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

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

957472-14-9

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

1-yl]pyrrolidin-2-yl}methanone antidiabetic

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


150

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

C17H24F2N6O 869490-23-3

HN

NH

N

O

FF

H

NN

N

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

gabamimetic agent

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

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

C9H19NO2 610300-07-7

CO2HH3C

NH2HHH3C

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

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

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


151

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

C148H211N68O53P13S13 868169-64-6 (3'-5')d(3'-amino-3'-deoxy-P-thio)( A G G G T T A G A C A A)pT

HO

HN

O H3C

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

L-threonine-insulin human antidiabetic

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

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

C274H411N65O81S6 844439-96-9

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

Glu Asn Tyr Cys Asn OH

H Phe

Leu

Val

Val

Asn

Cys

Gln His Leu Cys

Gly

Gly Ser

Glu

His Leu Val Glu

Arg Gly Phe Phe Tyr Thr Pro Lys

Ala

OH

Leu Tyr

10

20

10

20

O

N6HN

H CO2HO

HO2C

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

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


152

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

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


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

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



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

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


153

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

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

C6460H(10006-n)124InN1718O2018S48 1011710-99-8

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

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



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

1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate farnesoid X receptor agonist

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

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


154

C25H24F2N2O3 629664-81-9

N

O O

O CH3

CH3

NHH3C

CH3F

F

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

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

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

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

C10H12FN5O3 92562-88-4

HN

N N

N

H2N

O

O

F

HO

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

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


155

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

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


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

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



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

1,3-dicarbonitrile antiviral

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

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


156

C17H18N4O2 473921-12-9 CN

CNO

NN

H3C

HO

H3C

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

antihistaminic

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

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

C20H22N2S 88598-74-7

S

NNH

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

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

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

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

C23H37N5O4S2 910634-41-2

SN

NHN

H3C OHN

S

HN CH3O

CH3H3CH3C

CH3

CH3

O O

or enantiomer(-)-isomer

ou énantiomère(-)-isomère

o enantiómero(-)-isómero


157

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

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

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

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

C39H37F6N3O2 182431-12-5 H

N CF3

N

NH

F3C

O

O

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

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

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

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

C22H26FN3O2 585543-15-3

N NH

CH3

F

NH

O

O

CH3

H3C CH3


158

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

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

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

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

C156H195N49O83P14S14 1072874-90-8 (3'-5')(P-thio)(mC-dC-A-dT-dT-G-T-dC-dA-mC-dA-mC-dT-mC-mC)

mC

H2C

O

N

NO NH2

O

HO

OH

CH3

H

H2C

O

O

HO

OH

H

N N

NN NH2

A

H2C

O

N

HNO O

O

HO

OH

CH3

T

H

H2C

O

O

HO

OH

H

N N

NHN O

H2NG


159

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

2-yl]amino}methyl)benzamide antineoplastic

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

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

C23H20N6O 726169-73-9

NH H

N NNH2

O

N

N

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

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

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

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

C43H64N6O11 736992-12-4

O

HCH3

CH3

OH

H CH3

N

OO

H

HH3C

CH3

CH3

H

O

H3C

OO

N

H

ON

N

N

HCH3

OH3C

N

O

OHCH3

H3C


160

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

1-yl}phenyl)acetamide serotonin receptor agonist

naluzotan N-(3-{4-[4-(1-cyclohexylméthanesulfonamido)butyl]pipérazin- 1-yl}phényl)acétamide agoniste des récepteurs de la sérotonine

naluzotán N-(3-{4-[4-(1-ciclohexilmetanosulfonamido)butil]piperazin- 1-il}fenil)acetamida agonista del receptor de la serotonina

C23H38N4O3S 740873-06-7

N

N

NH

S

NH

CH3

O

OO

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

3-(2,4-difluorophenyl)urea serotonin receptor antagonist

nélotansérine 1-[3-(4-bromo-1-méthyl-1H-pyrazol-5-yl)-4-méthoxyphényl]- 3-(2,4-difluorophényl)urée antagoniste des récepteurs de la sérotonine

nelotanserina 1-[3-(4-bromo-1-metil-1H-pirazol-5-il)-4-metoxifenil]- 3-(2,4-difluorofenil)urea antagonista del receptor de la serotonina

C18H15BrF2N4O2 839713-36-9

HN

HN

FFO

OCH3

NNH3C

Br

ocriplasminum ocriplasmin truncated human plasmin:

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

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


161

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

C1214H1890N338O348S14 1048016-09-6 Truncated heavy chain / Chaîne lourde tronquée/ Cadena pesada truncada

APSFDCGK 550PQVEPKKCPG R 561

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

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

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

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

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

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

C21H26N2O5 868049-49-4

HN

OHH

HN

O

O

HO

OCH3

H3C CH3

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

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

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

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


162

C18H21N3O4S2 426253-04-5

N

CO2HO

H H

H3C

HOH

S

SN

NHCH3

HCH3

H

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

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

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

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


163


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

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

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


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

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

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

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


164


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

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



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

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

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

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

C187H291N45O59 910463-68-2

Glu Gly Thr Phe Thr Ser Asp Val Ser

Leu Glu Gly Gln Ala Ala Lys Glu Phe

Ile Ala Trp Leu Val Arg Gly Arg Gly OH

Ser Tyr

Glu OH

O

7 10

20

30 37

N6

H His NH

CH3H3C

O

OO

O

HO2C

HNO

O

O

NH


165

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

antineoplastic

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

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

C21H20N4 881202-45-5 H

N

NH

HN

N

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

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

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

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

C22H17F4N3O4 910656-27-8

O

O

FNH

NN

O CH3HO CF3

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

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


166

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

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


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

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



sograzepidum sograzepide 1-[(3R)-1-(3,3-dimethyl-2-oxobutyl)-2-oxo-5-(pyridin-2-yl)-

2,3-dihydro-1H-1,4-benzodiazepin-3-yl]- 3-[3-(methylamino)phenyl]urea cholecystokinin receptor antagonist

sograzépide 1-[(3R)-1-(3,3-diméthyl-2-oxobutyl)-2-oxo-5-(pyridin-2-yl)- 2,3-dihydro-1H-1,4-benzodiazépin-3-yl]- 3-[3-(méthylamino)phényl]urée antagoniste des récepteurs des cholécystokinines

sograzepida 1-[(3R)-1-(3,3-dimetil-2-oxobutil)-2-oxo-5-(piridin-2-il)-2,3-dihidro- 1H-1,4-benzodiazepin-3-il]-3-[3-(metilamino)fenil]urea antagonista de los receptores de las colecistoquininas


167

C28H30N6O3 155488-25-8

N

N

NH

H

O

H3C CH3

CH3

N

O

NH

HNCH3

O

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

adenosine receptor agonist

sonédénoson 2-[2-(4-chlorophényl)éthoxy]-9-β-D-ribofuranosyl-9H-purin-6-amine agoniste du récepteur de l’adénosine

sonedenosón 2-[2-(4-clorofenil)etoxi]adenosina agonista del receptor de la adenosina

C18H20ClN5O5 131865-88-8

OHO

N

N N

N

NH2

O

OH OH

Cl

sothrombomodulinum alfa # sothrombomodulin alfa soluble mutated human thrombomodulin

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

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

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


168

C2181H3278N616O706S49 151638-93-6 EPQPGGSQCV EHDCFALYPG PATFLNASQI CDGLRGHLMT VRSSVAADVI 50

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

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

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

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

inhibitor of amyloid fibril deposition

tafamidis acide 2-(3,5-dichlorophényl)-1,3-benzoxazole-6-carboxylique inhibition du dépôt de fibrilles amyloïdes

tafamidis ácido 2-(3,5-diclorofenil)-1,3-benzoxazol-6-carboxílico inhibidor del depósito de fibrillas de amiloide

C14H7Cl2NO3 594839-88-0

N

O CO2HCl

Cl

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

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

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

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


169

C2580H3918N680O727S17 37228-64-1 EFARPCIPKS FGYSSVVCVC NATYCDSFDP PTFPALGTFS RYESTRSGRR 50

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

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

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

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

β-Man→4-β-Gl-N→4−

R→6−β-Gl-N→peptide

α-Man→3−

α-Man→6−

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

tanexabanum tanexaban N-[2-hydroxy-6-(4-methoxybenzamido)phenyl]-4-(4-methyl-

1,4-diazepan-1-yl)benzamide blood-coagulation factor Xa inhibitor

tanexaban N-[2-hydroxy-6-(4-méthoxybenzamido)phényl]-4-(4-méthyl- 1,4-diazépan-1-yl)benzamide inhibiteur du facteur Xa de coagulation sanguine

tanexabán N-[2-hidroxi-6-(4-metoxibenzamido)fenil]-4-(4-metil-1,4-diazepan- 1-il)benzamida inhibidor del factor Xa de coagulación sanguínea

C27H30N4O4 365462-23-3

HN

NH

O

O

OCH3

N

NH3C

HO

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

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

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


170

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

C21H14F6O5 867257-26-9

O O

OH

O

O

CH3

CF3

CF3

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

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

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

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

C30H43Cl2N5O8 432037-57-5

N O O

O

NH

NH

NNC

O

Cl OO

OO

H3C

Cl

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

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

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


171

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


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

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



tipapkinogenum sovacivecum # tipapkinogene sovacivec an attenuated recombinant vaccinia virus (derived from the Modified

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

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

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

1052105-48-2


172

torezolidum torezolid (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-

5-(hydroxymethyl)-1,3-oxazolidin-2-one antibiotic

torézolid (5R)-3-{3-fluoro-4-[6-(2-méthyl-2H-tétrazol-5-yl)pyridin-3-yl]phényl}-5-(hydroxyméthyl)-1,3-oxazolidin-2-one antibiotique

torezolid (5R)-3-{3-fluoro-4-[6-(2-metil-2H-tetrazol-5-il)piridin-3-il]fenil}- 5-(hidroximetil)-1,3-oxazolidina-2-ona antibiótico

C17H15FN6O3 856866-72-3

N

OHHO

F

O

N

N NN

NCH3

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

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

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

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


173

C971H1511N267O306S26 α subunit: 847420-37-5 β subunit: 847420-38-6

Alpha subunit / Sous-unité alpha / Subunidad alfa

APDVQDCPEC TLQENPFFSQ PGAPILQCMG CCFSRAYPTP LRSKKTMLVQ 50KNVTSESTCC VAKSYNRVTV MGGFKVENHT ACNCSTCYYH KS 92

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

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

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

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

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

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

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

C25H36N4O5S 866933-46-2

N

HN

N

NS

CH3

H3C CH3

O

OOHH

O O

H

H

H

CH3

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

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

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

zaurategrast ácido (2S)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-il)amino]- 3-{4-[(2,7-naftiridin-1-il)amino]fenil}propanoico antiinflamatorio no esteroide


174

C26H25BrN4O3 455264-31-0

NH

O

OH

HN

H

N

N

Br

O


175

Names for Radicals and Groups Some substances for which a proposed international nonproprietary name has been established may be used in the form of salts or esters. The radicals or groups involved may be of complex composition and it is then inconvenient to refer to them in a systematic chemical nomenclature. Consequently, shorter nonproprietary names for some radicals and groups have been devised or selected, and they are suggested for use with the proposed international nonproprietary names. Dénominations applicables aux radicaux et groupes Certaines substances pour lesquelles une dénomination commune internationale proposée a été établie sont parfois utilisées sous forme de sels ou d'esters. Les radicaux ou groupes correspondants sont alors quelques fois si complexes qu'il est malcommode de les désigner conformément à la nomenclature chimique systématique. Des dénominations communes abrégées ont donc été formées ou choisies pour certains d'entre eux et il est suggéré de les employer avec les dénominations communes internationales proposées. Denominaciones para Radicales y Grupos Ciertas sustancias para las cuales hay establecidas una denominación común internacional pueden usarse en forma de sales o de ésteres. Los radicales o grupos correspondientes pueden llegar a tener una composición tan compleja que resulte incómodo referirse a ellos mediante la nomenclatura química sistemática. Las siguientes denominaciones comunes abreviadas han sido ideadas o elegidas para algunos de estos radicales y grupos y se sugiere que se empleen con las denominaciones comunes internacionales propuestas. valactas valactate (2S)-2-[(2S)-2-amino-3-methylbutanoyloxy]propanoate valactate (2S)-2-[(2S)-2-amino-3-méthylbutanoyloxy]propanoate valactato (2S)-2-[(2S)-2-amino-3-metilbutanoiloxi]propanoato C8H14NO4

O

O

O

H CH3

H2N

O

HCH3

H3C

# 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/


176

AMENDMENTS TO PREVIOUS LISTS MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES

MODIFICACIONES A LAS LISTAS ANTERIORES Proposed International Non Proprietary Names (Prop. INN): List 91 Dénominations communes internationales proposées (DCI Prop.): Liste 91 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 91 (WHO Drug Information, Vol. 18, No. 2, 2004) p. 171 suprimáse insértese lenalidomide lenalidomida Proposed International Non Proprietary Names (Prop. INN): List 97 Dénominations communes internationales proposées (DCI Prop.): Liste 97 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 97 (WHO Drug Information, Vol. 21, No. 2, 2007) p. 138 supprimer insérer bromure d'azixomère bromure d'azoximère Proposed International Non Proprietary Names (Prop. INN): List 98 Dénominations communes internationales proposées (DCI Prop.): Liste 98 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 98 (WHO Drug Information, Vol. 21, No. 4, 2007) p. 331 delete/supprimer/suprimáse insert/insérer/insértese deforolimusum ridaforolimusum deforolimus ridaforolimus

déforolimus ridaforolimus deforolimus ridaforolimus

Proposed International Non Proprietary Names (Prop. INN): List 99 Dénominations communes internationales proposées (DCI Prop.): Liste 99 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 99 (WHO Drug Information, Vol. 22, No. 2, 2008)

p. 123- 124

delete/supprimer/suprimáse insert/insérer/insértese

afutuzumab obinutuzumab afutuzumab obinutuzumab

afutuzumab obinutuzumab

afutuzumab obinutuzumab


177

p. 125 bafetinibum bafetinib replace the chemical name, the CAS registry number and the structure by the

following bafétinib remplacer le nom chimique, le numéro de registre du CAS et la structure par

les suivants bafetinib sustitúyase el nombre químico, el número de registro del CAS 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

859212-16-1

NHN

HN

OCH3

F3C

N

NN

H3C

CH3H

N

N

p. 141 levomilnacipranum levomilnacipran replace the structure by the following

lévomilnacipran remplacer la structure par la suivante levomilnaciprán sustitúyase la fórmula desarrollada por la siguiente

NO CH3

CH3

NH2

H

Proposed International Non Proprietary Names (Prop. INN): List 100 Dénominations communes internationales proposées (DCI Prop.): Liste 100 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 100 (WHO Drug Information, Vol. 22, No. 4, 2008) p. 317 canosimibum canosimibe replace the chemical name by the following

canosimibe remplacer le nom chimique par le suivant canosimiba sustitúyase el nombre químico por el siguiente

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


178

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

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

p. 327 suprimáse insértese ingenol mebutato mebutato de ingenol

p. 327 laninamivirum laninamivir replace the chemical name by the following

laninamivir remplacer le nom chimique par le suivant

laninamivir sustitúyase el nombre químico por el siguiente

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

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

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


179

Annex 1

PROCEDURE FOR THE SELECTION OF RECOMMENDED INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES1

The following procedure shall be followed by the World Health Organization (hereinafter also referred to as “WHO”)

in the selection of recommended international nonproprietary names for pharmaceutical substances, in accordance with resolution WHA3.11 of the World Health Assembly, and in the substitution of such names. Article 1 - Proposals for recommended international nonproprietary names and proposals for substitution of such names shall be submitted to WHO on the form provided therefore. The consideration of such proposals shall be subject to the payment of an administrative fee designed only to cover the corresponding costs of the Secretariat of WHO (“the Secretariat”). The amount of this fee shall be determined by the Secretariat and may, from time to time, be adjusted. Article 2 - Such proposals shall be submitted by the Secretariat to the members of the Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations designated for this purpose, such designated members hereinafter referred to as “the INN Expert Group”, for consideration in accordance with the “General principles for guidance in devising International Nonproprietary Names for Pharmaceutical Substances”, annexed to this procedure2. The name used by the person discovering or first developing and marketing a pharmaceutical substance shall be accepted, unless there are compelling reasons to the contrary. Article 3 - Subsequent to the examination provided for in article 2, the Secretariat shall give notice that a proposed international nonproprietary name is being considered. a) Such notice shall be given by publication in WHO Drug Information3

and by letter to Member States and to national and regional pharmacopoeia commissions or other bodies designated by Member States.

i) Notice shall also be sent to the person who submitted the proposal (“the original applicant”) and other persons known to be concerned with a name under consideration.

b) Such notice shall:

i) set forth the name under consideration; ii) identify the person who submitted the proposal for naming the substance, if so requested by such person; iii) identify the substance for which a name is being considered; iv) set forth the time within which comments and objections will be received and the person and place to whom they should be directed; v) state the authority under which WHO is acting and refer to these rules of procedure.

c) In forwarding the notice, the Secretariat shall request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the proposed name during the period it is under consideration by WHO. Article 4 - Comments on the proposed name may be forwarded by any person to WHO within four months of the date of publication, under article 3, of the name in WHO Drug Information.

1 See Annex 1 in WHO Technical Report Series, No. 581, 1975. The original text was adopted by the Executive Board in resolution EB15.R7 and amended in resolutions EB43.R9 and EB115.R4.

2 See Annex 2.

3 Before 1987, lists of international nonproprietary names were published in the Chronicle of the World Health Organization.


180

Article 5 - A formal objection to a proposed name may be filed by any interested person within four months of the date of publication, under article 3, of the name in WHO Drug Information.

Such objection shall:

i) identify the person objecting;

ii) state his or her interest in the name; iii) set forth the reasons for his or her objection to the name proposed. Article 6 - Where there is a formal objection under article 5, WHO may either reconsider the proposed name or use its good offices to attempt to obtain withdrawal of the objection. Without prejudice to the consideration by WHO of a substitute name or names, a name shall not be selected by WHO as a recommended international nonproprietary name while there exists a formal objection thereto filed under article 5 which has not been withdrawn. Article 7 - Where no objection has been filed under article 5, or all objections previously filed have been withdrawn, the Secretariat shall give notice in accordance with subsection (a) of article 3 that the name has been selected by WHO as a recommended international nonproprietary name. Article 8 - In forwarding a recommended international nonproprietary name to Member States under article 7, the Secretariat shall: a) request that it be recognized as the nonproprietary name for the substance; and b) request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the name and to prohibit registration of the name as a trademark or trade name. Article 9 a) In the extraordinary circumstance that a previously recommended international nonproprietary name gives rise to errors in medication, prescription or distribution, or a demonstrable risk thereof, because of similarity with another name in pharmaceutical and/or prescription practices, and it appears that such errors or potential errors cannot readily be resolved through other interventions than a possible substitution of a previously recommended international nonproprietary name, or in the event that a previously recommended international nonproprietary name differs substantially from the nonproprietary name approved in a significant number of Member States, or in other such extraordinary circumstances that justify a substitution of a recommended international nonproprietary name, proposals to that effect may be filed by any interested person. Such proposals shall be submitted on the form provided therefore and shall: i) identify the person making the proposal;

ii) state his or her interest in the proposed substitution; and iii) set forth the reasons for the proposal; and

iv) describe, and provide documentary evidence regarding the other interventions undertaken in an effort to resolve the situation, and the reasons why these other interventions were inadequate.

Such proposals may include a proposal for a new substitute international nonproprietary name, devised in accordance with the General principles, which takes into account the pharmaceutical substance for which the new substitute international nonproprietary name is being proposed. The Secretariat shall forward a copy of the proposal, for consideration in accordance with the procedure described in subsection (b) below, to the INN Expert Group and the original applicant or its successor (if different from the person bringing the proposal for substitution and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations). In addition, the Secretariat shall request comments on the proposal from:

i) Member States and national and regional pharmacopoeia commissions or other bodies designated by Member States (by including a notice to that effect in the letter referred to in article 3(a), and

ii) any other persons known to be concerned by the proposed substitution.


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The request for comments shall:

i) state the recommended international nonproprietary name that is being proposed for substitution (and the proposed substitute name, if provided);

ii) identify the person who submitted the proposal for substitution (if so requested by such person);

iii) identify the substance to which the proposed substitution relates and reasons put forward for substitution; iv) set forth the time within which comments will be received and the person and place to whom they should be directed; and v) state the authority under which WHO is acting and refer to these rules of procedure.

Comments on the proposed substitution may be forwarded by any person to WHO within four months of the date of the request for comments. b) After the time period for comments referred to above has elapsed, the Secretariat shall forward any comments received to the INN Expert Group, the original applicant or its successor and the person bringing the proposal for substitution. If, after consideration of the proposal for substitution and the comments received, the INN Expert Group, the person bringing the proposal for substitution and the original applicant or its successor all agree that there is a need to substitute the previously recommended international nonproprietary name, the Secretariat shall submit the proposal for substitution to the INN Expert Group for further processing. Notwithstanding the foregoing, the original applicant or its successor shall not be entitled to withhold agreement to a proposal for substitution in the event the original applicant or its successor has no demonstrable continuing interest in the recommended international nonproprietary name proposed for substitution.

In the event that a proposal for substitution shall be submitted to the INN Expert Group for further processing, the INN Expert Group will select a new international nonproprietary name in accordance with the General principles referred to in article 2 and the procedure set forth in articles 3 to 8 inclusive. The notices to be given by the Secretariat under article 3 and article 7, respectively, including to the original applicant or its successor (if not the same as the person proposing the substitution, and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations), shall in such event indicate that the new name is a substitute for a previously recommended international nonproprietary name and that Member States may wish to make transitional arrangements in order to accommodate existing products that use the previously recommended international nonproprietary name on their label in accordance with national legislation.

If, after consideration of the proposal for substitution and the comments received in accordance with the procedure described above, the INN Expert Group, the original applicant or its successor and the person bringing the proposal for substitution do not agree that there are compelling reasons for substitution of a previously recommended international nonproprietary name, this name shall be retained (provided always that the original applicant or its successor shall not be entitled to withhold agreement to a proposal for substitution in the event that the original applicant or its successor has no demonstrable continuing interest in the recommended international nonproprietary name proposed to be substituted). In such an event, the Secretariat shall advise the person having proposed the substitution, as well as the original applicant or its successor (if not the same as the person proposing the substitution, and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations), Member States, national and regional pharmacopoeia commissions, other bodies designated by Member States, and any other persons known to be concerned by the proposed substitution that, despite a proposal for substitution, it has been decided to retain the previously recommended international nonproprietary name (with a description of the reason(s) why the proposal for substitution was not considered sufficiently compelling).


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ANNEX 2

GENERAL PRINCIPLES FOR GUIDANCE IN DEVISING INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES1

1. International Nonproprietary Names (INN) should be distinctive in sound and spelling. They should not be inconveniently long and should not be liable to confusion with names in common use. 2. The INN for a substance belonging to a group of pharmacologically related substances should, where appropriate, show this relationship. Names that are likely to convey to a patient an anatomical, physiological, pathological or therapeutic suggestion should be avoided. These primary principles are to be implemented by using the following secondary principles: 3. In devising the INN of the first substance in a new pharmacological group, consideration should be given to the possibility of devising suitable INN for related substances, belonging to the new group. 4. In devising INN for acids, one-word names are preferred; their salts should be named without modifying the acid name, e.g. “oxacillin” and “oxacillin sodium”, “ibufenac” and “ibufenac sodium”. 5. INN for substances which are used as salts should in general apply to the active base or the active acid. Names for different salts or esters of the same active substance should differ only in respect of the name of the inactive acid or the inactive base. For quaternary ammonium substances, the cation and anion should be named appropriately as separate components of a quaternary substance and not in the amine-salt style. 6. The use of an isolated letter or number should be avoided; hyphenated construction is also undesirable. 7. To facilitate the translation and pronunciation of INN, “f” should be used instead of “ph”, “t” instead of “th”, “e” instead of “ae” or “oe”, and “i” instead of “y”; the use of the letters “h” and “k” should be avoided. 8. Provided that the names suggested are in accordance with these principles, names proposed by the person discovering or first developing and marketing a pharmaceutical preparation, or names already officially in use in any country, should receive preferential consideration. 9. Group relationship in INN (see General principle 2) should if possible be shown by using a common stem. The following list contains examples of stems for groups of substances, particularly for new groups. There are many other stems in active use.2 Where a stem is shown without any hyphens it may be used anywhere in the name. Latin English -acum -ac anti-inflammatory agents, ibufenac derivatives -adolum -adol } analgesics -adol- -adol-} -astum -ast antiasthmatic, antiallergic substances not acting primarily as antihistaminics -astinum -astine antihistaminics -azepamum -azepam diazepam derivatives bol bol steroids, anabolic -cain- -cain- class I antiarrhythmics, procainamide and lidocaine derivatives -cainum -caine local anaesthetics 1

In its Twentieth report (WHO Technical Report Series, No. 581, 1975), the WHO Expert committee on Nonproprietary Names for Pharmaceutical Substances reviewed the general principles for devising, and the procedures for selecting, INN in the light of developments in pharmaceutical compounds in recent years. The most significant change has been the extension to the naming of synthetic chemical substances of the practice previously used for substances originating in or derived from natural products. This practice involves the use of a characteristic “stem” indicative of a common property of the members of a group. The reason for, and the implications of, the change are fully discussed. The guiding principles were updated during the 13th consultation on nonproprietary names for pharmaceutical substances (Geneva, 27-29 April 1983) (PHARM S/NOM 928 13 May 1983, revised 18 August 1983).

2 A more extensive listing of stems is contained in the working document WHO/PSM/QSM/2006.3 which is regularly updated and can be requested from the INN Programme, WHO, Geneva.


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cef- cef- antibiotics, cefalosporanic acid derivatives -cillinum -cillin antibiotics, 6-aminopenicillanic acid derivatives -conazolum -conazole systemic antifungal agents, miconazole derivatives cort cort corticosteroids, except prednisolone derivatives -coxibum -coxib selective cyclo-oxygenase inhibitors -entanum -entan endothelin receptor antagonists gab gab gabamimetic agents gado- gado- diagnostic agents, gadolinium derivatives -gatranum -gatran thrombin inhibitors, antithrombotic agents gest gest steroids, progestogens gli gli antihyperglycaemics io- io- iodine-containing contrast media -metacinum -metacin anti-inflammatory, indometacin derivatives -mycinum -mycin antibiotics, produced by Streptomyces strains -nidazolum -nidazole antiprotozoal substances, metronidazole derivatives -ololum -olol β-adrenoreceptor antagonists -oxacinum -oxacin antibacterial agents, nalidixic acid derivatives -platinum -platin antineoplastic agents, platinum derivatives -poetinum -poetin erythropoietin type blood factors -pril(at)um -pril(at) angiotensin-converting enzyme inhibitors -profenum -profen anti-inflammatory substances, ibuprofen derivatives prost prost prostaglandins -relinum -relin pituitary hormone release-stimulating peptides -sartanum -sartan angiotensin II receptor antagonists, antihypertensive (non-peptidic) -vaptanum -vaptan vasopressin receptor antagonists vin- vin- } vinca-type alkaloids -vin- -vin-}

ANNEXE 1

PROCEDURE A SUIVRE EN VUE DU CHOIX DE DENOMINATIONS COMMUNES INTERNATIONALES RECOMMANDEES POUR LES SUBSTANCES

PHARMACEUTIQUES1

L’Organisation mondiale de la Santé (également désignée ci-après sous l’appellation « OMS ») observe la procédure exposée ci-dessous pour l’attribution de dénominations communes internationales recommandées pour les substances pharmaceutiques, conformément à la résolution WHA3.11 de l’Assemblée mondiale de la Santé, et pour le remplacement de telles dénominations. Article 1 - Les propositions de dénominations communes internationales recommandées et les propositions de remplacement de telles dénominations sont soumises à l’OMS sur la formule prévue à cet effet. L’examen de telles propositions est soumis au paiement d’une taxe administrative destinée uniquement à couvrir les coûts correspondants assumés par le Secrétariat de l’OMS (« le Secrétariat »). Le montant de cette taxe est déterminé par le Secrétariat et peut être modifié de temps à autre. Article 2 - Ces propositions sont soumises par le Secrétariat aux experts désignés à cette fin parmi les personnalités inscrites au Tableau d’experts de la Pharmacopée internationale et des Préparations pharmaceutiques, ci-après désignés sous l’appellation « le Groupe d’experts des DCI » ; elles sont examinées par les experts conformément aux « Directives générales pour la formation de dénominations communes internationales pour les substances pharmaceutiques » reproduites ci-après2.

La dénomination acceptée est la dénomination employée par la personne qui découvre ou qui, la première, fabrique et lance sur le marché une substance pharmaceutique, à moins que des raisons majeures n’obligent à s’écarter de cette règle.

1 Voir annexe 1 dans OMS, Série de Rapports techniques, N° 581, 1975. Le texte original a été adopté par le Conseil exécutif dans sa résolution EB15.R7 et amendé dans ses résolutions EB43.R9 et EB115.R4.

2 Voir annexe 2.


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Article 3 - Après l’examen prévu à l’article 2, le Secrétariat notifie qu’un projet de dénomination commune internationale est à l’étude. a) Cette notification est faite par une insertion dans WHO Drug Information1 et par l’envoi d’une lettre aux Etats Membres et aux commissions nationales et régionales de pharmacopée ou autres organismes désignés par les Etats Membres.

i) Notification est également faite à la personne qui a soumis la proposition (« le demandeur initial ») et à d’autres personnes portant à la dénomination mise à l’étude un intérêt notoire.

b) Cette notification contient les indications suivantes :

i) dénomination mise à l’étude;

ii) nom de l’auteur de la proposition tendant à attribuer une dénomination à la substance, si cette personne le demande ;

iii) définition de la substance dont la dénomination est mise à l’étude ;

iv) délai pendant lequel seront reçues les observations et les objections à l’égard de cette dénomination ; nom et adresse de la personne habilitée à recevoir ces observations et objections ;

v) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement.

c) En envoyant cette notification, le Secrétariat demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété sur la dénomination proposée pendant la période au cours de laquelle cette dénomination est mise à l’étude par l’OMS. Article 4 - Des observations sur la dénomination proposée peuvent être adressées à l’OMS par toute personne, dans les quatre mois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3). Article 5 - Toute personne intéressée peut formuler une objection formelle contre la dénomination proposée dans les quatre mois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3). Cette objection doit s’accompagner des indications suivantes :

i) nom de l’auteur de l’objection ; ii) intérêt qu’il ou elle porte à la dénomination en cause ; iii) raisons motivant l’objection contre la dénomination proposée. Article 6 - Lorsqu’une objection formelle est formulée en vertu de l’article 5, l’OMS peut soit soumettre la dénomination proposée à un nouvel examen, soit intervenir pour tenter d’obtenir le retrait de l’objection. Sans préjudice de l’examen par l’OMS d’une ou de plusieurs appellations de remplacement, l’OMS n’adopte pas d’appellation comme dénomination commune internationale recommandée tant qu’une objection formelle présentée conformément à l’article 5 n’est pas levée. Article 7 - Lorsqu’il n’est formulé aucune objection en vertu de l’article 5, ou que toutes les objections présentées ont été levées, le Secrétariat fait une notification conformément aux dispositions du paragraphe a) de l’article 3, en indiquant que la dénomination a été choisie par l’OMS en tant que dénomination commune internationale recommandée. Article 8 - En communiquant aux Etats Membres, conformément à l’article 7, une dénomination commune internationale recommandée, le Secrétariat : a) demande que cette dénomination soit reconnue comme dénomination commune de la substance considérée ; et b) demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété sur cette dénomination et interdire le dépôt de cette dénomination comme marque ou appellation commerciale. 1

Avant 1987, les listes de dénominations communes internationales étaient publiées dans la Chronique de l’Organisation mondiale de la Santé.


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Article 9 - a) Dans le cas exceptionnel où une dénomination commune internationale déjà recommandée donne lieu à des erreurs de médication, de prescription ou de distribution ou en comporte un risque démontrable, en raison d’une similitude avec une autre appellation dans la pratique pharmaceutique et/ou de prescription, et où il apparaît que ces erreurs ou ces risques d’erreur ne peuvent être facilement évités par d’autres interventions que le remplacement éventuel d’une dénomination commune internationale déjà recommandée, ou dans le cas où une dénomination commune internationale déjà recommandée diffère sensiblement de la dénomination commune approuvée dans un nombre important d’Etats Membres, ou dans d’autres circonstances exceptionnelles qui justifient le remplacement d’une dénomination commune internationale recommandée, toute personne intéressée peut formuler une proposition dans ce sens. Cette proposition est présentée sur la formule prévue à cet effet et doit s’accompagner des indications suivantes :

i) nom de l’auteur de la proposition ;

ii) intérêt qu’il ou elle porte au remplacement proposé ;

iii) raisons motivant la proposition ; et

iv) description, faits à l’appui, des autres interventions entreprises pour tenter de régler le problème et exposé des raisons pour lesquelles ces interventions ont échoué.

Les propositions peuvent comprendre une proposition de nouvelle dénomination commune internationale de remplacement, établie conformément aux Directives générales, compte tenu de la substance pharmaceutique pour laquelle la nouvelle dénomination commune internationale de remplacement est proposée. Le Secrétariat transmet une copie de la proposition pour examen, conformément à la procédure exposée plus loin au paragraphe b), au Groupe d’experts des DCI et au demandeur initial ou à son successeur (s’il s’agit d’une personne différente de celle qui a formulé la proposition de remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles). De plus, le Secrétariat demande aux entités et personnes ci-après de formuler des observations sur la proposition :

i) les Etats Membres et les commissions nationales et régionales de pharmacopée ou d’autres organismes désignés par les Etats Membres (en insérant une note à cet effet dans la lettre mentionnée à l’article 3.a), et

ii) toutes autres personnes portant au remplacement proposé un intérêt notoire. La demande d’observations contient les indications suivantes : i) dénomination commune internationale recommandée pour laquelle un remplacement est proposé (et la dénomination de remplacement proposée, si elle est fournie) ; ii) nom de l’auteur de la proposition de remplacement (si cette personne le demande) ; iii) définition de la substance faisant l’objet du remplacement proposé et raisons avancées pour le remplacement ; iv) délai pendant lequel seront reçus les commentaires et nom et adresse de la personne habilitée à recevoir ces commentaires ; et v) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement. Des observations sur la proposition de remplacement peuvent être communiquées par toute personne à l’OMS dans les quatre mois qui suivent la date de la demande d’observations. b) Une fois échu le délai prévu ci-dessus pour la communication d’observations, le Secrétariat transmet les observations reçues au Groupe d’experts des DCI, au demandeur initial ou à son successeur et à l’auteur de la proposition de remplacement. Si, après avoir examiné la proposition de remplacement et les observations reçues, le Groupe d’experts des DCI, l’auteur de la proposition de remplacement et le demandeur initial ou son successeur reconnaissent tous qu’il est nécessaire de remplacer la dénomination commune internationale déjà recommandée, le Secrétariat soumet la proposition de remplacement au Groupe d’experts des DCI pour qu’il y donne suite.


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Nonobstant ce qui précède, le demandeur initial ou son successeur n’est pas habilité à refuser son accord à une proposition de remplacement au cas où il ne peut être démontré qu’il porte un intérêt durable à la dénomination commune internationale recommandée qu’il est proposé de remplacer.

Dans le cas où une proposition de remplacement est soumise au Groupe d’experts des DCI pour qu’il y donne

suite, le Groupe choisit une nouvelle dénomination commune internationale conformément aux Directives générales mentionnées à l’article 2 et selon la procédure décrite dans les articles 3 à 8 inclus. La notification faite par le Secrétariat en vertu de l’article 3 et de l’article 7, respectivement, y compris au demandeur initial ou à son successeur (si ce n’est pas la même personne que celle qui a proposé le remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles), doit dans un tel cas indiquer que la nouvelle dénomination remplace une dénomination commune internationale déjà recommandée et que les Etats Membres peuvent souhaiter prendre des mesures transitoires pour les produits existants qui utilisent la dénomination commune internationale déjà recommandée sur leur étiquette conformément à la législation nationale.

Si, après examen de la proposition de remplacement et des observations communiquées conformément à la

procédure exposée plus haut, le Groupe d’experts des DCI, le demandeur initial ou son successeur et l’auteur de la proposition de remplacement ne s’accordent pas sur le fait qu’il y a des raisons impératives de remplacer une dénomination commune internationale déjà recommandée, cette dernière est conservée (étant entendu toujours que le demandeur initial ou son successeur n’est pas habilité à refuser son accord à une proposition de remplacement au cas où il ne peut être démontré qu’il porte un intérêt durable à la dénomination commune internationale recommandée qu’il est proposé de remplacer). Dans un tel cas, le Secrétariat informe l’auteur de la proposition de remplacement, ainsi que le demandeur initial ou son successeur (s’il s’agit d’une personne différente de celle qui a formulé la proposition de remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles), les Etats Membres, les commissions nationales et régionales de pharmacopée, les autres organismes désignés par les Etats Membres et toutes autres personnes portant un intérêt notoire au remplacement proposé que, malgré une proposition de remplacement, il a été décidé de conserver la dénomination commune internationale déjà recommandée (avec une brève description de la ou des raisons pour lesquelles la proposition de remplacement n’a pas été jugée suffisamment impérative).

ANNEXE 2

DIRECTIVES GENERALES POUR LA FORMATION DE DENOMINATIONS COMMUNES INTERNATIONALES APPLICABLES AUX SUBSTANCES

PHARMACEUTIQUES1 1. Les dénominations communes internationales (DCI) devront se distinguer les unes des autres par leur consonance et leur orthographe. Elles ne devront pas être d’une longueur excessive, ni prêter à confusion avec des appellations déjà couramment employées. 2. La DCI de chaque substance devra, si possible, indiquer sa parenté pharmacologique. Les dénominations susceptibles d’évoquer pour les malades des considérations anatomiques, physiologiques, pathologiques ou thérapeutiques devront être évitées dans la mesure du possible. Outre ces deux principes fondamentaux, on respectera les principes secondaires suivants : 3. Lorsqu’on formera la DCI de la première substance d’un nouveau groupe pharmacologique, on tiendra compte de la possibilité de former ultérieurement d’autres DCI appropriées pour les substances apparentées du même groupe. 1

Dans son vingtième rapport (OMS, Série de Rapports techniques, N° 581, 1975), le Comité OMS d’experts des Dénominations communes pour les Substances pharmaceutiques a examiné les directives générales pour la formation des dénominations communes internationales et la procédure à suivre en vue de leur choix, compte tenu de l’évolution du secteur pharmaceutique au cours des dernières années. La modification la plus importante a été l’extension aux substances de synthèse de la pratique normalement suivie pour désigner les substances tirées ou dérivées de produits naturels. Cette pratique consiste à employer des syllabes communes ou groupes de syllabes communes (segments-clés) qui sont caractéristiques et indiquent une propriété commune aux membres du groupe des substances pour lequel ces segments-clés ont été retenus. Les raisons et les conséquences de cette modification ont fait l’objet de discussions approfondies. Les directives ont été mises à jour lors de la treizième consultation sur les dénominations communes pour les substances pharmaceutiques (Genève, 27-29 avril 1983) (PHARM S/NOM 928, 13 mai 1983, révision en date du 18 août 1983).


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4. Pour former des DCI des acides, on utilisera de préférence un seul mot. Leurs sels devront être désignés par un terme qui ne modifie pas le nom de l’acide d’origine : par exemple «oxacilline» et «oxacilline sodique», «ibufénac» et «ibufénac sodique». 5. Les DCI pour les substances utilisées sous forme de sels devront en général s’appliquer à la base active (ou à l’acide actif). Les dénominations pour différents sels ou esters d’une même substance active ne différeront que par le nom de l’acide inactif (ou de la base inactive). En ce qui concerne les substances à base d’ammonium quaternaire, la dénomination s’appliquera de façon appropriée au cation et à l’anion en tant qu’éléments distincts d’une substance quaternaire. On évitera de choisir une désignation évoquant un sel aminé. 6. On évitera d’ajouter une lettre ou un chiffre isolé ; en outre, on renoncera de préférence au trait d’union. 7. Pour simplifier la traduction et la prononciation des DCI, la lettre « f » sera utilisée à la place de « ph », « t » à la place de « th », « e » à la place de « ae » ou « oe », et « i » à la place de « y » ; l’usage des lettres « h » et « k » sera aussi évité. 8. On retiendra de préférence, pour autant qu’elles respectent les principes énoncés ici, les dénominations proposées par les personnes qui ont découvert ou qui, les premières, ont fabriqué et lancé sur le marché les préparations pharmaceutiques considérées, ou les dénominations déjà officiellement adoptées par un pays. 9. La parenté entre substances d’un même groupe (voir Directive générale 2) sera si possible indiquée dans les DCI par l’emploi de segments-clés communs. La liste ci-après contient des exemples de segments-clés pour des groupes de substances, surtout pour des groupes récents. Il y a beaucoup d’autres segments-clés en utilisation active. 1 Les segments-clés indiqués sans trait d’union pourront être insérés n’importe où dans une dénomination. Latin Français -acum -ac substances anti-inflammatoires du groupe de l’ibufénac -adolum -adol } analgésiques -adol- -adol- }

-astum -ast antiasthmatiques, antiallergiques n’agissant pas principalement en tant qu’antihistaminiques -astinum -astine antihistaminiques -azepamum -azépam substances du groupe du diazépam bol bol stéroïdes anabolisants -cain- -caïn- antiarythmiques de classe I, dérivés du procaïnamide et de la lidocaïne -cainum -caïne anesthésiques locaux cef- céf- antibiotiques, dérivés de l’acide céphalosporanique -cillinum -cilline antibiotiques, dérivés de l’acide 6-aminopénicillanique -conazolum -conazole agents antifongiques systémiques du groupe du miconazole cort cort corticostéroïdes, autres que les dérivés de la prednisolone -coxibum -coxib inhibiteurs sélectifs de la cyclo-oxygénase -entanum -entan antagonistes du récepteur de l’endothéline gab gab gabamimétiques gado- gado- agents diagnostiques, dérivés du gadolinium -gatranum -gatran antithrombines, antithrombotiques gest gest stéroïdes progestogènes gli gli antihyperglycémiants io- io- produits de contraste iodés -metacinum -métacine substances anti-inflammatoires du groupe de l’indométacine -mycinum -mycine antibiotiques produits par des souches de Streptomyces -nidazolum -nidazole substances antiprotozoaires du groupe du métronidazole -ololum -olol antagonistes des récepteurs β-adrénergiques -oxacinum -oxacine substances antibactériennes du groupe de l’acide nalidixique -platinum -platine antinéoplasiques, dérivés du platine -poetinum -poétine facteurs sanguins de type érythropoïétine -pril(at)um -pril(ate) inhibiteurs de l’enzyme de conversion de l’angiotensine -profenum -profène substances anti-inflammatoires du groupe de l’ibuprofène prost prost prostaglandines

1

Une liste plus complète de segments-clés est contenue dans le document de travail WHO/PSM/QSM/2006.3 qui est régulièrement mis à jour et qui peut être demandé auprès du programme des DCI, OMS, Genève.


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-relinum -réline peptides stimulant la libération d’hormones hypophysaires -sartanum -sartan antagonistes d’un récepteur de l’angiotensine II, antihypertenseurs (non peptidiques) -vaptanum -vaptan antagonistes du récepteur de la vasopressine vin- vin- } alcaloïdes du type vinca -vin- -vin- }

ANEXO 1

PROCEDIMIENTO DE SELECCIÓN DE DENOMINACIONES COMUNES INTERNACIONALES RECOMENDADAS PARA SUSTANCIAS FARMACÉUTICAS1

La Organización Mundial de la Salud (OMS) seguirá el procedimiento que se expone a continuación tanto para seleccionar denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas, de conformidad con lo dispuesto en la resolución WHA3.11, como para sustituir esas denominaciones. Artículo 1 - Las propuestas de denominaciones comunes internacionales recomendadas y las propuestas de sustitución de esas denominaciones se presentarán a la OMS en los formularios que se proporcionen a estos efectos. El estudio de estas propuestas estará sujeto al pago de una tasa destinada a sufragar los costos de administración que ello suponga para la Secretaría de la OMS («la Secretaría»). La Secretaría establecerá la cuantía de esa tasa y podrá ajustarla periódicamente. Artículo 2 - Estas propuestas serán sometidas por la Secretaría a los miembros del Cuadro de Expertos en Farmacopea Internacional y Preparaciones Farmacéuticas encargados de su estudio, en adelante designados como «el Grupo de Expertos en DCI», para que las examinen de conformidad con los «Principios generales de orientación para formar denominaciones comunes internacionales para sustancias farmacéuticas», anexos a este procedimiento.2 A menos que haya poderosas razones en contra, la denominación aceptada será la empleada por la persona que haya descubierto o fabricado y comercializado por primera vez esa sustancia farmacéutica. Artículo 3 - Tras el examen al que se refiere el artículo 2, la Secretaría notificará que está en estudio un proyecto de denominación internacional. a) Esa notificación se hará mediante una publicación en Información Farmacéutica OMS3

y el envío de una carta a los Estados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismos designados por los Estados Miembros.

i) La notificación será enviada también a la persona que haya presentado la propuesta («el solicitante inicial») y a otras personas que tengan un interés especial en una denominación objeto de estudio.

b) En esa notificación se incluirán los siguientes datos: i) la denominación sometida a estudio; ii) la identidad de la persona que ha presentado la propuesta de denominación de la sustancia, si lo pide esa persona; iii) la identidad de la sustancia cuya denominación está en estudio; iv) el plazo fijado para recibir observaciones y objeciones, así como el nombre y la dirección de la persona a quien deban dirigirse; y v) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento.

1 Véase el anexo 1 en OMS, Serie de Informes Técnicos, Nº 581, 1975. El texto vigente fue adoptado por el Consejo Ejecutivo en su resolución EB15.R7 y modificado en las resoluciónes EB43.R9 y EB115.R4.

2 Véase el anexo 2.

3 Hasta 1987 las listas de DCI se publicaban en la Crónica de la Organización Mundial de la Salud.


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c) Al enviar esa notificación, la Secretaría solicitará de los Estados Miembros la adopción de todas las medidas necesarias para impedir la adquisición de derechos de patente sobre la denominación propuesta, durante el periodo en que la OMS la tenga en estudio. Artículo 4 - Toda persona puede formular a la OMS observaciones sobre la denominación propuesta dentro de los cuatro meses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3. Artículo 5 - Toda persona interesada puede presentar una objeción formal a una denominación propuesta dentro de los cuatro meses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3. Esa objeción deberá acompañarse de los siguientes datos:

i) la identidad de la persona que formula la objeción; ii) las causas que motivan su interés por la denominación; y iii) las causas que motivan su objeción a la denominación propuesta.

Artículo 6 - Cuando se haya presentado una objeción formal en la forma prevista en el artículo 5, la OMS podrá reconsiderar el nombre propuesto o utilizar sus buenos oficios para intentar lograr que se retire la objeción. La OMS no seleccionará como denominación común internacional una denominación a la que se haya hecho una objeción formal, presentada según lo previsto en el artículo 5, que no haya sido retirada, todo ello sin perjuicio de que la Organización examine otra denominación o denominaciones sustitutivas. Artículo 7 - Cuando no se haya formulado ninguna objeción en la forma prevista en el artículo 5, o cuando todas las objeciones presentadas hayan sido retiradas, la Secretaría notificará, conforme a lo dispuesto en el párrafo a) del artículo 3, que la denominación ha sido seleccionada por la OMS como denominación común internacional recomendada. Artículo 8 - Al comunicar a los Estados Miembros una denominación común internacional, conforme a lo previsto en el artículo 7, la Secretaría: a) solicitará que esta denominación sea reconocida como denominación común para la sustancia de que se trate; y b) solicitará a los Estados Miembros que adopten todas las medidas necesarias para impedir la adquisición de derechos de patente sobre la denominación, y prohíban que sea registrada como marca de fábrica o como nombre comercial. Artículo 9 a) En el caso excepcional de que, debido a su semejanza con otra denominación utilizada en las prácticas farmacéuticas y/o de prescripción, una denominación común internacional recomendada anteriormente ocasione errores de medicación, prescripción o distribución, o suponga un riesgo manifiesto de que esto ocurra, y parezca que tales errores o potenciales errores no sean fácilmente subsanables con otras medidas que no sean la posible sustitución de esa denominación común internacional recomendada anteriormente; en el caso de que una denominación común internacional recomendada anteriormente difiera considerablemente de la denominación común aprobada en un número importante de Estados Miembros, o en otras circunstancias excepcionales que justifiquen el cambio de una denominación común internacional recomendada, cualquier persona interesada puede presentar propuestas en este sentido. Esas propuestas se presentarán en los formularios que se proporcionen a estos efectos e incluirán los siguientes datos:

i) la identidad de la persona que presenta la propuesta;

ii) las causas que motivan su interés en la sustitución propuesta;

iii) las causas que motivan la propuesta; y

iv) una descripción, acompañada de pruebas documentales, de las otras medidas que se hayan adoptado con el fin de resolver la situación y de los motivos por los cuales dichas medidas no han sido suficientes.

Entre esas propuestas podrá figurar una relativa a una nueva denominación común internacional sustitutiva,

formulada con arreglo a los Principios generales y que tenga en cuenta la sustancia farmacéutica para la que se proponga la nueva denominación común internacional sustitutiva.

La Secretaría enviará al Grupo de Expertos en DCI y al solicitante inicial o a su sucesor (en el caso de que sea


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una persona diferente de la que ha presentado la propuesta de sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales) una copia de la propuesta, para que sea examinada de conformidad con el procedimiento descrito en el párrafo b) infra. Además, la Secretaría solicitará observaciones sobre la propuesta:

i) a los Estados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismos designados por los Estados Miembros (ello se hará incluyendo una notificación a tal efecto en la carta a la que se refiere el párrafo a) del artículo 3), y

ii) a cualquier persona que tenga un interés especial en la sustitución propuesta.

Al solicitar que se formulen estas observaciones se facilitarán los siguientes datos: i) la denominación común internacional recomendada que se propone sustituir (y la denominación sustitutiva propuesta, si se ha facilitado);

ii) la identidad de la persona que ha presentado la propuesta de sustitución (si lo pide esa persona); iii) la identidad de la sustancia a la que se refiere la sustitución propuesta y las razones para presentar la propuesta de sustitución; iv) el plazo fijado para recibir observaciones, así como el nombre y la dirección de la persona a quien deban dirigirse; y

v) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento.

Toda persona puede formular a la OMS observaciones sobre la sustitución propuesta dentro de los cuatro meses siguientes a la fecha en que se realizó la solicitud de observaciones. b) Una vez agotado el mencionado plazo para la formulación de observaciones, la Secretaría enviará todos los comentarios recibidos al Grupo de Expertos en DCI, al solicitante inicial o a su sucesor, y a la persona que haya presentado la propuesta de sustitución. Si después de examinar la propuesta de sustitución y las observaciones recibidas, el Grupo de Expertos en DCI, la persona que haya presentado la propuesta de sustitución y el solicitante inicial, o su sucesor, están de acuerdo en la necesidad de sustituir la denominación común internacional recomendada anteriormente, la Secretaría remitirá la propuesta de sustitución al Grupo de Expertos en DCI para que la tramite. No obstante lo anterior, el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta de sustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuya sustitución se propone.

En caso de que la propuesta de sustitución sea presentada al Grupo de Expertos en DCI para que la tramite, este grupo seleccionará una nueva denominación común internacional de conformidad con los Principios generales a los que se refiere el artículo 2 y al procedimiento establecido en los artículos 3 a 8 inclusive. En ese caso, en las notificaciones que la Secretaría ha de enviar con arreglo a los artículos 3 y 7, respectivamente, incluida la notificación al solicitante inicial o a su sucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales), se indicará que la nueva denominación sustituye a una denominación común internacional recomendada anteriormente y que los Estados Miembros podrán, si lo estiman oportuno, adoptar disposiciones transitorias aplicables a los productos existentes en cuya etiqueta se utilice, con arreglo a la legislación nacional, la denominación común internacional recomendada anteriormente que se haya sustituido.

En caso de que, después de haber estudiado la propuesta de sustitución y los comentarios recibidos de conformidad con el procedimiento descrito anteriormente, el Grupo de Expertos en DCI, el solicitante inicial o su sucesor y la persona que haya presentado la propuesta de sustitución no lleguen a un acuerdo sobre la existencia de razones poderosas para sustituir una denominación común internacional recomendada anteriormente, esta denominación se mantendrá (siempre en el entendimiento de que el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta de sustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuya sustitución se propone). En ese caso, la Secretaría comunicará a la persona que haya propuesto la sustitución, así como al solicitante inicial o a su sucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto


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con las asociaciones industriales), a los Estados Miembros, a las comisiones nacionales y regionales de las farmacopeas o a otros organismos designados por los Estados Miembros y a cualquier otra persona que tenga interés en la sustitución propuesta, que, pese a la presentación de una propuesta de sustitución, se ha decidido mantener la denominación común internacional recomendada anteriormente (con una descripción de la o las razones por las que se ha considerado que la propuesta de sustitución no estaba respaldada por razones suficientemente poderosas).

ANEXO 2

PRINCIPIOS GENERALES DE ORIENTACIÓN PARA FORMAR DENOMINACIONES COMUNES INTERNACIONALES PARA SUSTANCIAS FARMACÉUTICAS1

1. Las denominaciones comunes internacionales (DCI) deberán diferenciarse tanto fonética como ortográficamente. No deberán ser incómodamente largas, ni dar lugar a confusión con denominaciones de uso común. 2. La DCI de una sustancia que pertenezca a un grupo de sustancias farmacológicamente emparentadas deberá mostrar apropiadamente este parentesco. Deberán evitarse las denominaciones que puedan tener connotaciones anatómicas, fisiológicas, patológicas o terapéuticas para el paciente. Estos principios primarios se pondrán en práctica utilizando los siguientes principios secundarios: 3. Al idear la DCI de la primera sustancia de un nuevo grupo farmacológico, deberá tenerse en cuenta la posibilidad de poder formar DCI convenientes para las sustancias emparentadas que se agreguen al nuevo grupo. 4. Al idear DCI para ácidos, se preferirán las de una sola palabra; sus sales deberán denominarse sin modificar el nombre del ácido: p. ej. «oxacilina» y «oxacilina sódica», «ibufenaco» y «ibufenaco sódico». 5. Las DCI para las sustancias que se usan en forma de sal deberán en general aplicarse a la base activa o al ácido activo. Las denominaciones para diferentes sales o esteres de la misma sustancia activa solamente deberán diferir en el nombre del ácido o de la base inactivos. En los compuestos de amonio cuaternario, el catión y el anión deberán denominarse adecuadamente por separado, como componentes independientes de una sustancia cuaternaria y no como sales de una amina. 6. Deberá evitarse el empleo de letras o números aislados; también es indeseable el empleo de guiones. 7. Para facilitar la traducción y la pronunciación, se emplearán de preferencia las letras «f» en lugar de «ph», «t» en lugar de «th», «e» en lugar de «ae» u «oe», e «i» en lugar de «y»; se deberá evitar el empleo de las letras «h» y «k». 8. Siempre que las denominaciones propuestas estén de acuerdo con estos principios, recibirán una consideración preferente las denominaciones propuestas por la persona que haya descubierto las sustancias, o que fabrique y comercialice por primera vez una sustancia farmacéutica, así como las denominaciones ya adoptadas oficialmente en cualquier país. 9. El parentesco entre sustancias del mismo grupo se pondrá de manifiesto en las DCI (véase el Principio 2) utilizando una partícula común. En la lista que figura a continuación se indican ejemplos de partículas para grupos de sustancias, en particular para grupos nuevos. Existen muchas otras partículas que se usan habitualmente.2 Cuando una partícula aparece sin guión alguno, puede utilizarse en cualquier lugar de la palabra. 1 En su 20º informe (OMS, Serie de Informes Técnicos, Nº 581, 1975), el Comité de Expertos de la OMS en Denominaciones Comunes para las Sustancias Farmacéuticas revisó los Principios generales para formar denominaciones comunes internacionales (DCI), y su procedimiento de selección, a la luz de las novedades registradas en los últimos años en materia de compuestos farmacéuticos. El cambio más importante había consistido en hacer extensivo a la denominación de sustancias químicas sintéticas el método utilizado hasta entonces para las sustancias originadas en productos naturales o derivadas de éstos. Dicho método conlleva la utilización de una «partícula» característica que indica una propiedad común a los miembros de un grupo. En el citado informe se examinan en detalle las razones y consecuencias de este cambio. Los Principios generales de orientación se actualizaron durante la 13ª consulta sobre denominaciones comunes para sustancias farmacéuticas (Ginebra, 27 a 29 de abril de 1983) (PHARM S/NOM 928, 13 de mayo de 1983, revisado el 18 de agosto de 1983). 2 En el documento de trabajo WHO/PSM/QSM/2006.3, que se actualiza periódicamente y puede solicitarse al Programa sobre Denominaciones Comunes Internacionales, OMS, Ginebra, figura una lista más amplia de partículas.


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Latin Español -acum -aco antiinflamatorios derivados del ibufenaco -adolum -adol ) analgésicos -adol- -adol- ) -astum -ast antiasmáticos, sustancias antialérgicas cuya acción principal no es la antihistamínica -astinum -astina antihistamínicos -azepamum -azepam derivados del diazepam bol bol esteroides anabolizantes -cain- -caína- antiarrítmicos de clase I, derivados de procainamida y lidocaína -cainum -caína- anestésicos locales cef- cef- antibióticos, derivados del ácido cefalosporánico -cillinum - cilina antibióticos derivados del ácido 6-aminopenicilánico -conazolum -conazol antifúngicos sistémicos derivados del miconazol cort cort corticosteroides, excepto derivados de prednisolona -coxibum -coxib inhibidores selectivos de ciclooxigenasa -entanum -entán antagonistas del receptor de endotelina gab gab gabamiméticos gado- gado- agentes para diagnóstico derivados de gadolinio -gartranum -gatrán inhibidores de la trombina antitrombóticos gest gest esteroides progestágenos gli gli hipoglucemiantes, antihiperglucémicos io- io- medios de contraste iodados -metacinum -metacina antiinflamatorios derivados de indometacina -mycinum -micina antibióticos producidos por cepas de Streptomyces -nidazolum -nidazol antiprotozoarios derivados de metronidazol -ololum -olol antagonistas de receptores β-adrenérgicos -oxacinum -oxacino antibacterianos derivados del ácido nalidíxico -platinum -platino antineoplásicos derivados del platino -poetinum -poetina factores sanguíneos similares a la eritropoyetina -pril(at)um -pril(at) inhibidores de la enzima conversora de la angiotensina -profenum -profeno antiinflamatorios derivados del ibuprofeno prost prost prostaglandinas -relinum -relina péptidos estimulantes de la liberación de hormonas hipofisarias -sartanum -sartán antihipertensivos (no peptídicos) antagonistas del receptorde angiotensina II -vaptanum -vaptán antagonistas del receptor de vasopresina vin- vin- ) alcaloides de la vinca -vin- -vin- )

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