WHO Drug Information · WHO Drug Information Vol. 23, No. 4, 2009 International Nonproprietary...

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WHO Drug Information Vol. 23, No. 4, 2009

WHO Drug Information

Contents

World Health Organization

International NonproprietaryNamesINN identifiers for biological products 273

Safety and Efficacy IssuesRituximab: multifocal leuko-

encephalopathy 282Darbepoetin alfa: risk of stroke 282Vigabatrin and movement disorders 283Alendronate: risk of low-energy femoral

shaft fracture 283Ceftriaxone and calcium containing

solutions 284Etravirine: severe skin and hyper-

sensitivity reactions 285Oseltamivir phosphate: dosing risk 285Safety signal: hyponatraemia 286Clopidogrel and omeprazole: reduced

effectiveness 286Bisphosphonates: osteonecrosis of

the jaw 287Intravenous promethazine: serious

tissue injuries 287Cyproterone: risk of meningiomas 288Gadolinium-containing contrast agents 289Cesium chloride: cardiac risks 290Washout or taper when switching

antidepressants 290Zanamivir inhalation powder must

not be nebulized 291Pandemrix®: risk of fever 291Weekly pandemic pharmacovigilance

updates 292

Biomedicines and VaccinesInternational biological standards:

2009 update 292

International HarmonizationICH Implementation: Quality Working

Groups 295ICH Pharmacopoeial Discussion Group 296

Prequalification of MedicinesProgrammePrequalification of quality control

laboratories 300

Pharmacovigilance FocusA/H1N1 vaccination safety: PaniFlow®

surveillance tool 305

Regulatory Action and NewsInfluenza vaccines for 2010 southern

hemisphere winter 306Romidepsin: approved for cutaneous

T-cell lymphoma 306Orciprenaline sulphate: withdrawal 306Artemisinin antimalarials: not for

use as monotherapy 307Vitespen: withdrawal of marketing

authorization application 307Aripiprazole: withdrawal of application

for extension of indication 307Substandard and counterfeit medicines:

USAID–USP Agreement 308Vandetinib: withdrawal of marketing

authorization application 308

Consultation DocumentInternational Pharmacopoeia

Artesunate 309Artesunate tablets 313

Recent Publications,Information and EventsIllegal weight-loss medicines and

dietary supplements 318Southern Med Review 318

Proposed InternationalNonproprietary Names List 102 319

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WHO Drug Information Vol. 23, No. 4, 2009World Health Organization

Announcement

The 14th International Conference of Drug

Regulatory Authorities (ICDRA) will be hosted by

the Health Sciences Authority, Singapore, in

collaboration with the World Health Organization

The ICDRA will take place in Singapore

from 30 November to 3 December 2010

Updated information is available at:http://www.icdra2010.sg

http://www.who.int/medicines/icdra

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International NonproprietaryNamesINN identifiers forbiological productsThe International Nonproprietary Names(INN) Programme was created by WHOin the 1950s with the intention of provid-ing convenient common names forpharmaceutical substances. At the time ofits origin, as well as during its laterdevelopment, the INN Programme wasinherently linked to progress in drugresearch and its success was reliant onthe ability to deal appropriately with eachnew group of medicinal products thatentered into therapeutic use. In the1980s, the development of biotechnologyproducts based on recombinant tech-niques led to highly novel therapeuticagents, thus creating a new need foradaptation of the INN system. Thepresent article describes the ways thatthe INN Programme has responded to thechallenges that arose in connection withthis evolution.

Basic rules for the INN system set thelimits within which all INN can be con-structed. They include the need to prop-erly define the substance or product thatis named, to indicate in the name thepharmacological or therapeutic class towhich the substance or product belongsby use of the INN stem system and,finally, to shape the name in a mannerwhich facilitates its use by prescribers.(These issues are summarized on page274.)

In its initial phase, the INN Programmewas designed to cover only single chemi-

cal substances of well-defined structurealthough other groups of non-homo-genous established products, includingfrom natural sources, were also consid-ered. When substances which hadalready been named by the INN Pro-gramme became available through newbiotechnological processes, earlierdecisions on naming non-homogenousproducts had an influence on definingand naming novel products. Practicesrecognized in naming and defining twospecific product groups: low molecularweight heparins and insulins stronglyinfluenced this approach. (A discussionof these practices is found on page 274and 275.)

Specific approaches are needed whenformulating definitions and, in particular,for creating suitable INN for biotechno-logical products. These approaches havebeen under active consideration by theINN Programme since the 1980s andwere finally formulated in a 1994 INNguideline (1). Until now, 45 INN withGreek letter identifiers have been se-lected for glycosylated biological prod-ucts.

Application of the guidelines in naming ofindividual groups of biological productscontaining carbohydrate residues in theirstructure is described on pages 275–277.Difficulties that relate to the use of Greekletter identifiers in naming of interferonsare presented on page 279. The namingof monoclonal antibodies (mAbs), animportant group of glycoproteins obtainedby biotechnology, is not considered in thisdocument as issues related to mAbnames have been discussed separatelyat recent INN meetings and are alsoreviewed in two issues of WHO DrugInformation (2). Related documents of

* Professor Witold Wieniawski,Counsellor,Polish Pharmaceutical Society, Poland andMember, WHO INN Expert Group.

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interest are also available on the INNwebsite including a document on INN forbiological and biotechnology substances(3), documents relating to biologicals andmAbs (4) and an INN document onbiosimilars (5).

Creating INNIn the selection of INN, two separateissues are considered which influence thefinal shape of the name: (i) the way inwhich the substance is identified, and (ii)the structure of the name.

In the case of individual chemical sub-stances, the identification process isbased on chemical names established bythe International Union of Pure andApplied Chemistry (IUPAC). The chemicaldesignation is further supported by agraphic formula.

In the case of products obtained by bio-technology, the identification process ismore complicated because such productsusually form a mixture (the word “com-plex” is sometimes used) of several (ormore) individual substances of similarstructure and activity. The use of theseproducts occurs without separation intoindividual active components. Definitionof such products is complicated and ismade individually for each product group.Formulation of definitions has progressedin line with analytical methods thatincreasingly allow a highly precise de-scription of the structure of individualcomponents. Examples of such changesoccurring for individual groups are pre-sented later.

Creation of INN for single chemicalsubstances involves selection of anappropriate stem indicating the expectedactivity (or the decision to select an INNoutside the stem system) followed byadditional elements (usually the prefix) tocreate a distinctive name. When an INN

is selected for an active moiety, while asalt or an ester are employed in practice,an INNM system is used to create suit-able two-word names.

However, creating INN for productsobtained by biotechnology is a more com-plex process. While the selection of basicstems (-ase, -mab, -micin, -mycin,-poetin, etc.) can be carried out accordingto the normal INN system, the naming ofindividual components of each seriesrequires specific decisions on the extentof supplementary information to beincluded in the name. Those issues mayvary for individual groups, but the follow-ing remarks apply to all situations.

General rules for the construction of INNoffer only a few options for introducingelements of additional information. Inone-word names this can be done byinsertion of specific infixes (or prefixes).Otherwise, inclusion of a second or eventhird word is necessary as in the case ofINNM names. This approach is also usedwhen describing complexes with metalsor radioactive elements. The second-word approach is used frequently forbiological products when the second wordconsists of a spelled out Greek letter.

Other identifiers widely used in scientifictexts like numerals (Arabic or Roman),single letters (Latin alphabet), or singleGreek letters in the original script, areprecluded in INN. The reason for this ruleis that such elements of names couldlead to confusion and mistakes whenused on a medical prescription, asnumerals are used also to describe thedose (or concentration) or the number ofdosage units. Single letters may also beconfused, especially in handwriting.

The rules indicated above are alsoapplied when selecting names for biologi-cal products with a glycoprotein structure.This can sometimes create additionaldifficulties, and is described later.

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Selecting INN for natural andsemisynthetic products

INN for LMW heparinsLow molecular weight (LMW) heparinsare products obtained from naturalheparin by chemical reaction leading todepolymerization and various changes instructure. Natural heparin is a sulfatedpolysaccharide (polyuronic acid), which isa mixture of components differing in chainlength. LMW heparins also form mixturesof individual components that may differin chain length and other structuralfeatures because they are produced froma natural heterogenous material byprocesses that do not warrant full homo-geneity of the final product.

In 1983, when the first INN request for aLMW heparin was made, the INN ExpertGroup held prolonged discussions onwhether this type of biological productshould be included in INN system. It wasconcluded finally that selecting INN forsuch products would serve a usefulpurpose, and the stem -parin was se-lected for the group. The first name in theseries was enoxaparin published in 1984.(The name was later modified to enoxa-parin sodium.) The next group of requestsfor LMW heparins was given the INNnadroparin calcium, parnaparin sodium,reviparin sodium and tinzaparin sodium.Since then, a further eight INN containingthe -parin stem have been selected.

As can be seen, individual members ofthe group are distinguished by using INNcontaining a common stem (-parin) anddifferent prefixes. Individual products aredefined in a rather complicated mannerby description of manufacturing process,information on the structure of compo-nents and indication of molecular mass.

INN for insulinsInsulin serves as an example of theapproach for naming a group of relatedpeptides by using a parent name (insulin)

followed (or preceded) by another word(or words) which is indicative of changesin the structure of the parent compound.

Insulin as such was never listed as anINN, being considered a well-establishedname. Between 1956 and 1958, INNwere given to 6 insulin preparations:insulin zinc suspension (crystalline) and(amorphous), protamine zinc insulininjection, etc. The definition for eachproduct described its preparation.

The first insulin obtained in 1982 byrecombinant technology was given theINN insulin human, defined as “a proteinhaving the normal structure of the naturalantidiabetic principle produced by thehuman pancreas”. In this case the secondword in the name served a dual purpose,to link the actual structure of the productwith that of a natural product, followingthe pattern established in the case ofbeef insulin and pork insulin.

The two-word approach was maintainedfor six further INN for modified insulinsproduced by biotechnology: insulinargine, insulin lispro, etc. containingmodifications in the amino-acidsequences, but in these cases the sec-ond word serves to indicate a structuralchange. The substances are defined bydescribing their chemical structure.

INN for erythropoietinsThe first request for erythropoietin pro-duced by biotechnology was made in1988 by a US manufacturer. The requestindicated that the substance was pro-duced by “human clone λHEPOFL13protein moiety”. The manufacturer’sproposal to select erythropoietin as anINN was modified to eripoetin and thisname was considered to be suitableprovided that the product correspondedto the natural endogenous substance. Itwas also agreed that -poetin would beconsidered in the future as a stem for allerythropoietin type blood factors. Later in

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1988 a second request for an INN forerythropoietin produced by biotechnologywas received from another manufacturer.

However, during evaluation, the mainproblem that emerged concerning therecombinant form was that erythropoietinis a glycoprotein and that the activity ofthe substance depends strongly on thedegree of glycosylation, as erythropoietinwithout the carbohydrate moiety is notactive in vivo. Additionally, the recom-binant forms differ in the type and degreeof glycosylation and neither one is identi-cal to the endogenous substance. Litera-ture published on the subject confirmedthat N-glycosylation is cell specific andsite specific creating different glycoformsdepending on the cell line used in themanufacturing process. It was also knownthat erythropoietin has three N-glycosyla-tion sites at Asn24, Asn38 and Asn83 andone O-glycosylation site at Ser126. It wasalso known that carbohydrate moieties atN-terminals are quite complex (antennarystructure).

On the basis of these arguments, the INNGroup decided in 1989 to consider eachrequest as representing a differentproduct and to give an individual INN (6).Subsequently, the INN guideline adoptedin 1994 (1) states that the Greek letterwould serve to differentiate betweencompounds of the same amino acidsequence as human erythropoietin,which vary in the glycosylation pattern.INN for products with different amino acidsequence would be named using the-poetin stem and a random prefix (seedarbepoetin alfa).

Between 1992 and 2007, six other INNwere selected for erythropoietins pro-duced by biotechnology: epoetin gamma,epoetin delta, epoetin epsilon, epoetinzeta (in Spanish dseta), epoetin theta (inSpanish zeta), epoetin kappa, andepoetin omega. In 2001, darbepoetin alfawas selected for an erythropoietin with amodified amino acid chain.

Definitions for all epoetins include infor-mation that the product is a 1-165-erythropoietin and contains a glycoformidentifier expressed as α, β and γ, etc.In addition, definitions of epoetin alfa,epoetin beta, epoetin gamma, epoetinepsilon and epoetin omega also indicatethe designation “human cloneλHEPOFL13 protein moiety” describingthe gene coding of the amino acidsequence for human erythropoietin(HEPOFL being an abbreviation forHuman Erythropoietin Fetal Liver source).

Definitions for three other epoetinsinclude gene codes which are not in linewith symbols used in regular gene no-menclature and are seemingly sugges-tions from manufacturers. The definitionof epoetin delta contains the expression“human HMR4396” where the designationHMR4396 is the manufacturer’s code. Asimilar situation occurred in the case ofepoetin kappa. In the case of epoetinzeta, the definition contains the expres-sion “human clone B03XA01” where thedesignation B03XA01 is an ATC code foranti-anaemic preparations. It may beappropriate to later delete these designa-tions from the definitions.

INN for enzymesINN for enzymes obtained from naturalsources were usually selected to corre-spond to enzyme names established bythe Nomenclature Committee of theInternational Union of Biochemistry andMolecular Biology. In those cases theirstructure was not further defined, but inthe majority of cases the origin of theproduct was indicated. Recently, ECnumbers have been added to the defini-tions.

The following examples show approachesthat were used in this group of products.INN urokinase (published in 1966) wasdefined originally as “plasminogen activa-tor isolated from human urine”, but thedefinition was changed in 1982 to “plas-

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minogen activator isolated from humansources” to take account of the fact thatthe product started to be produced byhuman kidney cell culture in vitro. Peni-cillinase was defined as an enzymeobtained by fermentation from cultures ofBacillus cereus. Kallidinogenase wasdefined as an enzyme isolated from thepancreas or urine of mammals. Sfericasewas defined as alkaline Bacillus spheri-cus proteinase.

In the 1990s, the situation progressedfurther when some specific enzymes thatare glycoproteins started to be producedby biotechnology. The INN Group consid-ered it necessary to indicate the glyco-form by using the Greek letter system anda few examples are given here. INNdornase alfa, selected in 1993, wasdefined as “deoxyribonuclease (humanclone 18-1 protein moiety)”. Algluco-sidase alfa was defined as “humanlysosomal prepro-α-glucosidase-(57-952)-peptide 199-arginine-223-histidinevariant”. Bucelipase alfa was defined as“human bile-salt-activated lipase (choles-terol esterase, EC 3.1.1.13), glycoformalfa (recombinant hBSSL)”.

The use of Greek letters as identifierswas useful in the case of INN forα-galactosidase. Agalsidase alfa wasselected for a product isolated fromrecombinant human cell line and INNagalsidase beta for a product obtainedfrom a Chinese Hamster Ovary (CHO)cell line. The same approach was usedfor conestat alfa which was selected in2007 for a specific C1 esterase inhibitor(serine protease inhibitor).

A rather different situation occurred in thegroup of plasminogen activators. Initialdiscussion on these products was held inApril 1985 (7). The first request for atissue plasminogen activator was made in1985 for a recombinant product for whichalteplase was finally selected in 1988.Another one, for urokinase-type recom-

binant plasminogen activator followed, forwhich saruplase was selected in 1987.During the period 1985–1987 discussionswere centred on the suitability of treatingthese products as enzymes by using the-ase suffix, and the issue of glycosylationwas not considered. Finally, two stems forplasminogen activators: -teplase (fortissue-type) and -uplase (for urokinase-type) were established in 1987 (8).

As this decision was made before thesystem of glycoform identifiers wasintroduced, subsequent INN containing-plase stems were selected without thisidentifier, as in the majority of cases theINN were given for products with modifi-cations in the amino acid chain. In somedefinitions the notion that the product is aglycoprotein was included in the defini-tion. Silteplase was defined as “N-[N 2-(N-glycyl-N-alanyl)-L-arginyl)plas-minogen activator (human tissue-typeprotein moiety reduced), glycoform”. Asimilar remark was made in the definitionfor nateplase where “glycoform β” ismentioned.

However, the absence of a glycosylationidentifier later created a specific difficultyin the group of urokinase-type plasmino-gen activators. Nasaruplase was definedas “prourokinase (enzyme-activating)(human clone pA3/pD2/pF1) proteinmoiety)”. This definition was later modi-fied by adding “glycosylated”. At the sametime saruplase — defined originally as“prourokinase (enzyme-activating) (hu-man clone pUK4/pUK18 protein moietyreduced) — had to be changed by addi-tion of “non-glycosylated”. In 2001, whenanother request was made for recom-binant prourokinase produced by anothercell line, nasaruplase beta was selected,defined as “prourokinase (enzyme-activating) human (clone pUK4/pUK18protein moiety), glycosylated (murine cellline SP2/0)”. The use of a Greek letteridentifier permitted a better separation ofproducts differing in glycosylation pat-terns.

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INN for other glycosylatedbiologicalsProduction of biological products identicalor analogous to natural proteins or glyco-proteins by recombinant technology wasalso applied to other types of products.The naming system used for creating INNfor these products is similar to thatalready discussed.

Blood coagulation factorsand related productsIn the group of blood coagulation factors(substances that are glycoproteins), thefirst INN requests for products obtainedby biotechnology were made in 1993 forthree products: blood coagulation factorVIIA, blood coagulation factor VIII and forblood coagulation factor VIII with amodified (truncated) amino acid structure.

The main issue centred on whether toretain the established descriptive namesfor products obtained by biotechnology orswitch to the INN approach of one-wordnames composed of a suitable stem anda random prefix. The option that wasfinally accepted is reflected in the follow-ing policy statements:

• New names will only be given to prod-ucts produced by recombinant biotech-nology, but not to plasma derivedproducts.

• Suitable stems will be created, glyco-sylation pattern may be reflected byaddition of a Greek letter (spelled out).

• The distinction between natural andmodified amino acid sequence will beindicated by using different prefixes.

This system was referred to as the“epoetin approach” (1).

INN eptacog alfa (activated) was selectedin 1994 and defined as “blood coagula-tion factor VII (human clone λHVII2463protein moiety). Moroctocog alfa was

defined as “(1-724)-(1637–1648)-bloodcoagulation factor VIII (human reduced)with 1649-2332- blood coagulation factorVIII (human reduced)”. Octocog alfa wasdefined as “blood coagulation factor VIII(human), glycoform α”. Other INN in theblood coagulation factor group includeberoctocog alfa, eptacog alfa pegol(activated), nonacog alfa, and vatrepta-cog alfa (activated).

INN were also selected for two bloodcoagulation cascade inhibitors: drotre-cogin alfa (activated) and taneptacoginalfa, and for five further products relatedto blood coagulation processes: thrombinalfa. antithrombin alfa, troplasminogenalfa, thrombomodulin alfa, and so-thrombomodulin alfa.

InterleukinsThe first INN in this group, teceleukin,was selected in 1985 for N-L-methionyl-interleukin-2 obtained by biotechnology.Subsequently, aldesleukin was selectedin 1990 and celmoleukin in 1991 forinterleukin-2 derivatives with modifica-tions in the amino acid chain. Althoughnatural interleukin-2 is a glycoprotein, theissue of glycosylation was not discussedat that time.

In 1994, the situation changed when arequest was received for a derivative ofinterleukin-6. For this product, atexakinalfa was selected and defined as “1-(1-L-alanyl-l-proline)interleukin-6 (humanclone HGF-15 protein moiety reduced),cyclic (54->50), (73->83)-bis(disulfide)”.

The formal decision to publish INN forglycosylated interleukins with a Greekletter in accordance with the generalpolicy of naming glycosylated proteinswas later confirmed in 1995 (10).

Following this decision, edodekin alfa wasselected in 1998 for interleukin-12 andadargileukin alfa in 2003 for partiallyglycosylated modified interleukin-2.

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Tadekinig alfa was selected in 2004 forinterleukin-18 binding protein.

Pituitary and placentalglycoprotein hormonesPreparations produced from human post-menopausal urine containing a mixture offollicle-stimulating pituitary hormone(FSH) and luteinizing hormone (LH) havebeen manufactured since the 1960s andpINN menotrophin and follotrophin(human) were selected in 1963 and 1965.These INN were later withdrawn, as theirdefinitions were considered not suitable.However, the issue was revisited in 1987when urofollitropin was selected for aproduct defined as “a preparation ofmenopausal gonadotrophin extractedfrom human urine but possessing neglig-ible LH activity”.

In 1991, a request was received forhuman FSH produced by recombinanttechnology followed by a request forhuman LH also produced by biotechnol-ogy. After discussion, follitropin alfa andlutropin alfa were suggested as INN, withGreek letters indicating glycosylation.This proposal was however contested,because natural pituitary hormonescontain two amino acid chains in theirstructure that were designated by bio-chemists as α and β subunits and thesedesignations were widely used in thescientific literature. Although members ofthe INN Expert Group considered that theuse of Greek letters in INN may lead toconfusion, they conceded that such riskwas minor (9).

The arguments against this selection maybe of some relevance for scientists, butINN are intended primarily for use byhealth professionals such as physiciansand pharmacists and not for scientistsspecialized in this area. As a result,follitropin alfa and lutropin alfa wereselected as well as follitropin beta.Corifollitropin alfa was selected as a

fusion protein composed of FSH and 118-145-chorionic gonadotropin (human βsubunit). Recently, varfollitropin alfa wasselected as FSH with amino acid modifi-cations in both subunits.

Other INN selected in this group forglycoprotein hormones obtained bybiotechnology are thyrotropin alfa (thyro-tropin releasing hormone) and chorio-gonadotropin alfa (human chorionicgonadotropin).

Other glycoproteinsThe Greek letter system was also em-ployed for several other glycoproteinsobtained by recombinant technology:dibotermin alfa and eptotermin alfa wereselected for bone morphogenic proteins,ismomultin alfa was selected for cartilageglycoprotein 39, and talactoferrin alfa wasselected for human lactoferrin.

INN for interferons: difficulties withGreek letter identifiersWhen discussing the use of Greek letteridentifiers to indicate possible differencesin the glycosylation pattern of glycopro-teins it is necessary to mention also thecase of INN interferon nomenclature,since, in the naming system used for thisgroup of products, the Greek letters havea different meaning. A short review of thispeculiar situation is thus necessary.

The INN interferon was selected in 1962and defined as “a protein formed by theinteraction of animal cells with virusescapable of conferring on animal cellsresistance to virus infection”. The defini-tion corresponded to the level of scientificknowledge at that time. Later develop-ments have shown that this designationalso covered substances produced bydifferent types of cells. Three types ofinterferons were established: leukocyteinterferon, fibroblast interferon andimmune interferon, each type corres-ponding to a group of substances.


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In 1982, the first INN request for leuko-cyte interferon produced by recombinanttechnology was received, followed in1983 by a request for a fibroblast inter-feron. During discussions concerninginterferon nomenclature, several optionswere considered. One was to create astem -feron, but this was rejected due toconflicts with established trademarks forinterferon preparations. Another approachwas to follow designations currently usedin biochemical literature: INF-a (forleukocyte interferons), INF-b (for fibro-blast interferons) and INF-l (for immuneinterferons). The latter approach wasprovisionally agreed in April 1982 (10)together with the decision to spell out theGreek letter. This approach to interferonnomenclature was finally approved in1984 (11) when interferon alfa, interferonbeta and interferon gamma were selectedwith appropriate definitions.

The general definition for interferon alfaintroduced the possibility of indicatingprotein variants in the name by hyphen-ated addition of an Arabic number. In thecase of interferon alfa-2 further possibilityof distinguishing substances that differ inamino acid composition at specificpositions of the amino acid chain couldbe made by the addition of a small caseLatin letter. The system was published inINN list PL52. Using this system inter-feron alfacon-1 was selected in 1997,peginterferon alfa-2a and peginterferonalfa-2b in 2000 and albinterferon alfa-2bin 2008.

In interferon nomenclature, the Greekletter acquired a separate meaning, as itnow identified the type of substance. Thenomenclature also uses single letters andnumbers, which is against normal INNpractice. These differences are due to adecision by the INN Programme to followthe system established by the InterferonNomenclature Committee [later renamedNomenclature Committee of the Interna-tional Society for Interferon and Cytokine

Research (ISICR)]. In the 1980s,interferons were considered to be a highlyimportant field of therapeutic progress,and the INN Programme considered thatit was preferable to follow biochemicalinterferon nomenclature extensively usedat that time, and thereby ignoring diver-gence with established rules for creatingINN.

ConclusionAs shown, the INN Programme hasskilfully responded to the demand forselection and naming of new groups oftherapeutic products and, in particular,those manufactured by recombinanttechnology. The INN system has foundways for naming these products eitherby linkage to customary names for olderbiological products and/or creatingappropriate names for newer membersof each series.

The INN Programme has also beenchallenged with developing appropriateways for defining products composed ofmixtures of closely related componentsand to gradually upgrade the definitionsin response to the enormous progress inelucidation of the structure of biologicalsubstances.

This daunting task has required the useof individual approaches while taking intoaccount the specificity of each group. Tothe extent possible, a common style ofcoining INN nomenclature has evolved,especially for products with the glycopro-tein structure, where the use of Greekletter identifiers is now firmly establishedand is confirmed by the use of theseidentifiers in 45 INN to date.

References

1. Report of the Twenty-fourth INN Consulta-tion held in 1994. (See also reference 3: items3.4 and 4.8.)

2. World Health Organization. WHO DrugInformation, 22(2) (2008) and 23(3) (2009).


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3. World Health Organization. http://www.who.int/medicines/services/inn/CompleteBioRevDoc%2008-11-07_2_.pdf

4. World Health Organization. http://www.who.int/medicines/services/inn/publica-tion/en/index.html

5. World Health Organization. http://www.who.int/medicines/services/inn/BiosimilarsINN_Report.pdf

6. Report of the Twentieth INN Consultationheld in April 1990.


7. Report of the Fifteenth INN Consultationheld in April 1985.

8. Report of the Seventeenth INN Consultationheld in 1987.

9. Report of the Twenty-fifth INN Consultationheld in April 1995.

10. Report of the Twelfth INN Consultationheld in April 1982.

11. Report of the Fourteenth INN Consultationheld in 1984.

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Safety and Efficacy Issues

Rituximab: multifocalleuko-encephalopathyCanada — Healthcare professionalshave been informed of important newsafety information regarding the use ofrituximab (Rituxan®) and progressivemultifocal leuko-encephalopathy (PML).

Rituximab is authorized for the treatmentof B-cell non-Hodgkin lymphoma (NHL),previously untreated B-cell chroniclymphocytic leukaemia (B-CLL), stage Bor C, and rheumatoid arthritis in combina-tion with methotrexate to reduce signsand symptoms in adult patients withmoderate to severe rheumatoid arthritiswho have had an inadequate response orintolerance to one or more tumour necro-sis factor (TNF) inhibitor therapies.

This is the first case of PML in a patientwith rheumatoid arthritis who has notbeen previously treated with other potentbiologic immunomodulating therapies.Previously, two fatal cases of confirmedPML were reported in patients withrheumatoid arthritis treated with rituxi-mab.

Physicians should consider PML in anypatient being treated with rituximab whopresents with new onset neurologicmanifestations (i.e., cognitive impairment,motor deficit, speech and vision impair-ment) and should be immediately referredfor neurological consultation.

PML is a rare, progressive, demyelinatingdisease of the central nervous systemthat usually leads to death or severedisability. PML is caused by activation ofthe JC virus. JC virus resides in latentform in 40–80% of healthy adults. The

factors leading to activation of the latentinfection are not fully understood. PMLhas been reported in HIV-positive pa-tients, immunosuppressed cancer pa-tients, transplantation patients andpatients with auto-immune diseases,including RA. There are no known inter-ventions that can reliably prevent oradequately treat PML.

Reference: Communication dated 21 October2009 from Hoffmann-La Roche Limited athttp://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/rituxan_5_hpc-cps-eng.php

Darbepoetin alfa:risk of strokeUnited States of America — A study hasbeen published in the New EnglandJournal of Medicine raising safety con-cerns about darbepoetin alfa and the riskof stroke. Additionally, among patientswith a history of cancer, 60 of 188 pa-tients taking darbepoetin alfa died com-pared to 37 of 160 on placebo.

Anaemia is associated with an increasedrisk of cardiovascular and renal eventsamong patients with type 2 diabetes andchronic kidney disease. Althoughdarbepoetin alfa can effectively increasehaemoglobin levels, its effect on clinicaloutcomes in these patients has beeninadequately tested.

The study involved 4038 patients withdiabetes, chronic kidney disease, andanaemia. Primary end points were thecomposite outcomes of death or a cardio-vascular event (nonfatal myocardialinfarction, congestive heart failure, stroke,or hospitalization for myocardial ischemia)and of death or end-stage renal disease.

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During the study, death or a cardiovas-cular event occurred in 632 patientsassigned to darbepoetin alfa and 602patients assigned to placebo. Death orend-stage renal disease occurred in 652patients assigned to darbepoetin alfa and618 patients assigned to placebo. Fatalor nonfatal stroke occurred in 101 patientsassigned to darbepoetin alfa and 53patients assigned to placebo. There wasonly a modest improvement in patient-reported fatigue in the darbepoetin alfagroup as compared with the placebogroup.

Furthermore, the use of darbepoetin alfain patients with diabetes, chronic kidneydisease and moderate anaemia who werenot undergoing dialysis did not reduce therisk of either of the two primary compositeoutcomes (either death or a cardiovascu-lar event or death or a renal event) andwas associated with an increased risk ofstroke. For many persons involved inclinical decision making, this risk willoutweigh the potential benefits.

Reference: TREAT Investigators. A Trial ofDarbepoetin Alfa in Type 2 Diabetes andChronic Kidney Disease. New EnglandJournal of Medicine 2009; 361:2019–2032

Vigabatrin and movementdisordersUnited Kingdom — Vigabatrin (Sabril®)is an anti-epileptic indicated, in combina-tion with other anti-epileptics, for thetreatment of patients with resistant partialepilepsy (with or without secondarygeneralization) who have not respondedto or who are intolerant of all otherappropriate drug combinations. Vigabatrinis also indicated as monotherapy in thetreatment of infantile spasms (Westsyndrome).

Researchers in Finland first raisedconcerns about a risk of movementdisorders (including dystonia, dyskinesia,and hypertonia) and brain abnormalities

on MRI (interpreted as cytotoxic oedema)associated with the use of vigabatrin,after they received reports of theseadverse drug reactions from a Finnishhealthcare professional.

A Europe-wide review completed in July2009 involving experts in paediatricneurology from the UK assessed theevidence available on this issue, includingpreclinical data, clinical data, reportedcases of adverse drug reactions, andrelevant published literature.

Clinical trial data (1) for vigabatrin ininfantile spasms provide evidence ofbrain MRI abnormalities at all doses, butin particular in young infants treated withhigh doses (≥125 mg/kg/day). These MRIabnormalities were transient, seemed tobe dose dependent, and in most patientsresolved even if treatment with vigabatrincontinued.

The review concluded that it is not possi-ble to correlate the MRI findings with themovement disorders based on the currentdata. Therefore, the two events of move-ment disorders and brain MRI abnormali-ties will be independently described in theupdated product information for vigabatrinto reflect these new data. If new move-ment disorders occur during treatmentwith vigabatrin, consideration should begiven to dose reduction or a gradualdiscontinuation of treatment in consulta-tion with specialist advice.

Reference: Medicines and HealthcareProducts Regulatory Agency. Drug SafetyUpdate, Volume 3, Issue 4 November 2009.

Alendronate: risk of low-energy femoral shaft fractureNew Zealand — A number of publishedcase reports have described atypical lowenergy stress fractures of the sub-trochanteric and proximal femoral shaftin patients taking alendronate long-term(1–3). In some cases, the patient experi-

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enced prodromal pain in the affected areaweeks to months before a completefracture occurred.

Prescribers should consider the risk ofatypical stress fractures in alendronate-treated patients reporting pain of thesubtrochanteric or proximal femoral shaft.It is important to note that the reportedalendronate-associated fractures werefrequently bilateral; therefore the contra-lateral femur should be examined if afracture is suspected.

Factors which may increase the risk offractures include: vitamin D deficiency,malabsorption, glucocorticoid use, previ-ous stress fracture, lower extremityarthritis or fracture, extreme or increasedexercise, diabetes mellitus, and chronicalcohol abuse.

It is important to note that atypical stressfractures have also been reported inpatients not taking bisphosphonates. Inaddition, it is possible that other bisphos-phonates may be associated with anincreased risk of atypical stress fractures.Medsafe advises that the interruption ofbisphosphonate therapy in patients withatypical stress fractures should only beconsidered following an individual risk-benefit assessment.

References

1. Kwek EB, Goh K, Koh JSB, Png MA et al.An emerging pattern of subtrochanteric stressfractures: A long-term complication of alendro-nate therapy. Injury 2008;39: 224–231.

2. Lenart BA, Lorich DG, Lane JM. Atypicalfractures of the femoral diaphysis in post-menopausal women taking alendronate. NewEngland Journal of Medicine 2008;358(12):1304–6.

3. Neviaser AS, Lane JM, Lenart BA et al. Lowenergy femoral shaft fractures associated withalendronate use. Journal of OrthopaedicTrauma 2008;22:346–50.

4. Prescriber Update 2009;30(4):25 November2009 at http://www.medsafe.nz

Ceftriaxone and calciumcontaining solutionsCanada — Healthcare professionalshave been informed of updated prescrib-ing information for ceftriaxone when usedwith calcium-containing solutions via theintravenous (IV) route. This new safetyinformation is based on the results of tworecent in vitro studies that showed anincreased risk of ceftriaxone-calciumprecipitates in neonatal plasma.

The following are new recommendations:

• Ceftriaxone is contraindicated in neo-nates if they require (or are expected torequire) treatment with calcium-contain-ing intravenous solutions, includingcontinuous calcium-containing infusionssuch as parenteral nutrition, because ofthe risk of precipitation of ceftriaxone-calcium.

• In patients other than neonates, ceftriax-one and calcium-containing solutionsmay be administered sequentially toone another if the infusion lines arethoroughly flushed between infusionswith a compatible fluid.

• Diluents containing calcium, such asRinger solution or Hartmann solution,are not to be used to reconstituteceftriaxone vials or to further dilute areconstituted vial for intravenous admin-istration because a precipitate can form.Ceftriaxone must not be administeredsimultaneously with calcium-containingintravenous solutions, including continu-ous calcium-containing infusions suchas parenteral nutrition via a Y-site,because precipitation of ceftriaxone-calcium can occur.

Ceftriaxone is a long-acting broad spec-trum cephalosporin antibiotic for paren-

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teral use. Ceftriaxone is indicated for thetreatment of lower respiratory tractinfections, urinary tract infections, bac-terial septicaemia, skin and skin structureinfections, bone and joint infections, intra-abdominal infections, and meningitiswhen caused by susceptible organisms.Ceftriaxone is also indicated for uncompli-cated gonorrhoea and for prophylaxis ofpatients undergoing certain surgicalprocedures.

Reference: Health Advisory dated 15 October2009 at http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/rituxan_5_hpc-cps-eng.php

Etravirine: severe skin andhypersensitivity reactionsCanada — Healthcare professionalshave been informed of important safetyinformation regarding severe skin reac-tions in patients receiving combinationtherapy including etravirine (Intelence®)tablets. Specifically, there have beenpostmarketing reports of severe hyper-sensitivity reactions sometimes accompa-nied by hepatic failure, and a fatality dueto toxic epidermal necrolysis.

Severe, potentially life-threatening andfatal skin reactions have been reported.These include cases of Stevens-Johnsonsyndrome, toxic epidermal necrolysis anderythema multiforme. Hypersensitivityreactions were characterized by rash,constitutional findings, and sometimesorgan dysfunction, including hepaticfailure.

Discontinue etravirine immediately ifsigns or symptoms of severe skin reac-tions or hypersensitivity reactions develop(including severe rash or rash accompa-nied by fever, general malaise, fatigue,muscle or joint aches, blisters, orallesions, conjunctivitis, facial oedema,hepatitis, eosinophilia). Clinical statusincluding liver transaminases should bemonitored and appropriate therapy

initiated. Delay in stopping etravirinetreatment after the onset of severe rashmay result in a life-threatening reaction.

Cases within clinical and postmarketingexperience illustrate the importance ofvigilance and familiarity with the signsand symptoms of severe skin rash andhypersensitivity reactions. In Phase IIIclinical trials, Grade 3 and 4 rashes werereported in 1.3 % of subjects receivingetravirine compared to 0.2 % of placebosubjects. A total of 2 % of HIV-1-infectedpatients receiving etravirine discontinuedfrom Phase III trials due to rash. Rashoccurred most commonly during the firstsix weeks of therapy.

Reference: Communication dated 15 October2009 from Janssen-Ortho Inc. at http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/rituxan_5_hpc-cps-eng.php

Oseltamivir phosphate:dosing riskCanada — The manufacturer of oselta-mivir (Tamiflu®) has informed healthcareprofessionals of important dosing andadministration information regardingpowder for oral suspension.

Oseltamivir is a viral neuraminidaseinhibitor authorized for use in the treat-ment and prevention of uncomplicatedacute illness due to influenza infection inadults and children above one year ofage who have been symptomatic for nomore than two days or have come inclose contact with an infected individual.Health Canada has also issued an InterimOrder in July 2009 expanding use ofTamiflu® as a treatment or prophylaxis forchildren less than one year of age forinfection caused by the pandemic H1N12009 virus.

When dispensing commercially manufac-tured oseltamivir powder for oral suspen-sion (12 mg/mL), pharmacists shouldensure that the units of measure on theprescription instructions match the dosing

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device provided (e.g., a device graduatedin mg for a prescription in mg).

Reference: Communication from the manu-facturer dated 13 October 2009 at http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof

Safety signal: hyponatraemiaNew Zealand — The Centre for AdverseReactions Monitoring (CARM) hasexamined recent reports of hyponatrae-mia in its database.

Hyponatraemia, defined as plasmasodium < 135 mmol/L, is caused by arange of medicines and clinical condi-tions. Medicine-related hyponatraemiaoccurs most often in the elderly early inthe course of treatment. The mechanismis most often a syndrome of inappropriateantidiuretic hormone secretion or renalloss.

Medicines most often implicated in recentreports to CARM are selective serotoninor noradrenaline reuptake inhibitors(SSRIs/SNRIs) and thiazide diuretics.Other medicines reported more than oncein 2007 and 2008 were anticanceragents, proton pump inhibitors, sodiumvalproate and ACE inhibitor/diureticcombinations. Carbamazepine has alsobeen frequently implicated in the data-base.

Serious hyponatraemia (plasma sodium< 120 mmol/L) can lead to confusion,convulsions and serious neurologicaldamage. Examination of serious sympto-matic reports to CARM revealed that inmost cases more than one hyponatrae-mic medicine was implicated. The reportsthat CARM has received support currentadvice that plasma sodium should bemeasured shortly after starting potentiallyhyponatraemic medicines, especiallySSRIs or diuretics. Measurements shouldbe repeated both before and after addinganother hyponatraemic medicine. If thereis mild persistent hyponatraemia theaddition of further medicines or the

development of clinical conditions thatcan decrease plasma sodium may lead toa more profound and symptomaticreaction.

Reference: Prescriber Update 2009;30(4):23November 2009 at http://www.medsafe.nz

Clopidogrel and omeprazole:reduced effectivenessUnited States of America — The Foodand Drug Administration (FDA) is alertinghealthcare professionals to new safetyinformation concerning an interactionbetween clopidogrel (Plavix®), an anti-clotting medication, and omeprazole(Prilosec/Prilosec OTC®), a proton pumpinhibitor (PPI). New data show that whenclopidogrel and omeprazole are takentogether, the effectiveness of clopidogrelis reduced. Patients at risk for heartattacks or strokes who use clopidogrel toprevent blood clots will not get the fulleffect of this medicine if they are alsotaking omeprazole.

Omeprazole inhibits the drug metaboliz-ing enzyme CYP2C19 which is responsi-ble for the conversion of clopidogrel intoits active metabolite. New studies com-pared the active metabolite and its effecton platelets in clopidogrel plus ome-prazole versus clopidogrel alone. Theeffect of clopidogrel on platelets wasreduced by as much as 47% in peoplereceiving clopidogrel and omeprazoletogether.

Other drugs that are potent inhibitors ofthe CYP2C19 enzyme would be expectedto have a similar effect and should beavoided in combination with clopidogrel.These include: cimetidine, fluconazole,ketoconazole, voriconazole, etravirine,felbamate, fluoxetine, fluvoxamine, andticlopidine. Since the level of inhibitionamong other PPIs varies, it is unknown towhat extent other PPIs may interfere withclopidogrel. However, esomeprazole, aPPI that is a component of omeprazole,

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inhibits CYP2C19 and should also beavoided in combination with clopidogrel.

Separating the dose of clopidogrel andomeprazole in time will not reduce druginteraction. Other drugs to avoid incombination with clopidogrel becausethey may have a similar interactioninclude: esomeprazole, cimetidine,fluconazole, ketoconazole, voriconazole,etravirine, felbamate, fluoxetine, fluvox-amine, and ticlopidine.

Reference: Food and Drug Administration,Medwatch, 17 November 2009 at http://www.fda.gov/Drugs/Drug Safety

Bisphosphonates:osteonecrosis of the jawUnited Kingdom — The risk of osteo-necrosis of the jaw is greater for patientsreceiving intravenous bisphosphonatesfor cancer than for patients receiving oralbisphosphonates for osteoporosis orPaget disease. All patients with cancershould have a dental check-up beforebisphosphonate treatment. During treat-ment, patients should be encouraged tomaintain good oral hygiene, receiveroutine dental check-ups, and report anyoral symptoms such as dental mobility,pain, or swelling

Individual bisphosphonates with differentindications can be used for:

• Prophylaxis and treatment of osteo-porosis.

• Treatment of Paget disease.

• As a component of some cancer regi-mens, particularly for metastatic bonecancer and multiple myeloma.

A Europe-wide review has been com-pleted on the risk of osteonecrosis of thejaw (ONJ) in association with the use ofbisphosphonates. The review includeddata from the published literature, data

provided by Marketing AuthorizationHolders (experimental and preclinicalstudies, clinical trials, and postmarketingreports) and guidelines. The review alsoincorporated advice from a group ofexperts representing all areas of medicinewhere bisphosphonates are used, den-tistry and bone surgery, and representa-tives of patient organizations.

The European Medicines Agency’sCommittee for Medicinal Products forHuman Use (CHMP) reached conclusionson four main areas: definition and diagno-sis of ONJ related to bisphosphonates,possible underlying pathophysiologicalmechanism(s), risk stratification, and riskminimization.

A patient may be considered to haveONJ related to bisphosphonates if allof the following three characteristicsare present:

• Exposed or necrotic bone in the maxillo-facial region that has persisted for morethan 8 weeks.

• No history of irradiation of the jaw.

• Current or previous treatment with abisphosphonate.

Reference: Medicines and HealthcareProducts Regulatory Agency. Drug SafetyUpdate, Volume 3, Issue 4 November 2009 athttp://www.mhra.gov.uk

Intravenous promethazine:serious tissue injuriesNew Zealand — Promethazine injectionis highly caustic to the intima of bloodvessels and surrounding tissues (1).Reports from the United States describeserious tissue reactions including throm-bosis, nerve damage, tissue necrosis andgangrene in patients who have receivedintravenous promethazine. In rare cases,surgical intervention such as skin graft,fasciectomy or amputation has been

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required (1, 2). In New Zealand, prometh-azine injection is approved for the treat-ment of vomiting, allergic reactions(including anaphylaxis) and to inducesedation.

After reviewing the published literature,assessing New Zealand case reports,and consulting with healthcare profes-sionals, Medsafe has concluded thatthere remains a clinical need for intrave-nous promethazine in New Zealand.However, Medsafe recommends thatintravenous promethazine should only beused if the benefits clearly outweigh therisks in each patient. This may includeemergency situations (such as treatmentof anaphylaxis) or situations whereintramuscular or oral administration iscontraindicated.

To maximize safe use, Medsafe hasoffered the following advice:

• Deep intramuscular injection is thepreferred route of administration ofpromethazine injection.

• Promethazine must not be administeredsubcutaneously or intra-arterially.

• An alternative medicine should beconsidered if intravenous administrationis required.

• Promethazine should be administeredthrough large patent veins. Veins in thehand and wrist should be avoided ifpossible (1).

• If intravenous administration is required,the maximum recommended concentra-tion is 25 mg/mL and the maximumrecommended rate of administration is25 mg/minute. Further dilution andadministration over 10–15 minutes mayreduce the risks even further (1).

• The injection should be stopped immedi-ately if pain or a burning sensationoccurs.

• Patients should be advised to seekmedical assistance if pain, a burningsensation, swelling or blistering occursat any time after the administration ofintravenous promethazine.

The New Zealand data sheet for prometh-azine is currently being updated in linewith this advice (4).

References

1. Grissiner M. Preventing serious tissue injurywith intravenous promethazine (Phenergan®).P&T 2009;34(4):175-176.

2. FDA. Information for Health Professionals –Intravenous Promethazine and Severe TissueInjury, Including Gangrene. 16 September2009 at http://www.fda.gov/Drugs.

3. Prescriber Update 2009;30(4):23 November2009 at http://www.medsasfe.nz

4. Data sheet at http://www.medsafe. co.nz/profs/Datasheet/dsform.asp

Cyproterone: riskof meningiomasUnited Kingdom — Cyproterone acetateis a derivative of progesterone, and hasprogestagenic, antiandrogenic, andantigonadotrophic effects. High-dosepreparations available in the UK includeCyprostat-50® and Cyprostat-100®,which are indicated for use in the treat-ment of prostate cancer. Cyproteroneacetate is also available as Androcur-50®, which is indicated for the control oflibido in men with severe hypersexualityor sexual deviation (or both). In some EUcountries, Androcur-50® is used for thetreatment of androgenization in women.

Lower-dose cyproterone acetate isavailable for use in women as co-cyprindiol (Dianette®) in combination with35 micrograms ethinylestradiol for thetreatment of severe acne that is refractoryto prolonged antibiotic therapy, and formoderately severe hirsutism.

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Meningiomas are the most commonintracranial tumours, with an annualincidence of six per 100 000 in thegeneral population. Multiple meningiomasaccount for approximately 1–10 % of allcases. Though histologically benign, theycan have serious consequences. Thepotential role of sex hormones in thedevelopment of meningiomas has beenpostulated: approximately 70% of menin-giomas express progesterone receptorsand about 30% express oestrogenreceptors (1). The occurrence of (multi-ple) meningiomas has been reported inassociation with longer-term use (years)of cyproterone acetate at doses of 25 mg/day or higher.

Up to September 2009, 36 cases ofmeningioma, of which 19 describedmultiple meningioma, have been reportedworldwide in association with high-dosecyproterone acetate. Nine cases werediscussed in a published case series, (2)and 27 cases are unpublished casereports. Duration of treatment with cypro-terone acetate ranged from 4 to 27 yearsand in all but one case it was prescribedat doses higher than 25 mg per day.Thirty-one of the cases were from France(which compared with other countries hasextensive use of high-dose cyproteroneacetate). None of the reported cases hada fatal outcome.

Advice for healthcare professionals:

• Patients with existing meningioma or ahistory of meningioma must not beprescribed cyproterone acetate at dosesof 25 mg per day or higher.

• This advice does not apply to medicinesthat contain low-dose cyproteroneacetate such as co-cyprindiol(Dianette®).

References

1. Blitshteyn S et al. J Clin Oncol 2008; 26:279–82.

2. Froelich S et al. Endocrine Abstracts.Proceedings of the 10th EuropeanCongress of Endocrinology; Berlin,Germany. 2008; 16:158. http://www.endocrineabstracts.org

3. Drug Safety Update. Volume 3 Issue 3,October 2009 at http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON059804

Gadolinium-containingcontrast agentsEuroean Union — The European Medi-cines Agency (EMEA) has adopted a setof recommendations aimed at minimizingthe risk of nephrogenic systemic fibrosis(NSF) with gadolinium-containing contrastagents in patients at risk of developingthe condition.

Gadolinium-containing contrast agentsare used in patients undergoing magneticresonance imaging (MRI) or magneticresonance angiography (MRA) scans.The Agency’s Committee for MedicinalProducts for Human Use (CHMP) re-viewed these agents because of theassociation between the use of gado-linium-containing contrast agents andNSF, a rare, serious and sometimes life-threatening condition that is characterizedby formation of connective tissues in theskin, joints, muscles and internal organs,in patients with severe kidney problems.

Based on currently available data, andwith risk minimization measures in place,the CHMP considers that the balance ofbenefits and risks of these agents isacceptable.

References

1. European Medicines Agency makesrecommendations to minimise risk of nephro-genic systemic fibrosis with gadolinium-containing contrast agents. Press Release,Doc. Ref. EMEA/CHMP/739818/2009, 20November 2009 at www.emea.europa.eu


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2. Question-and-answer document.

3. A public statement on the associationbetween gadolinium-containing contrastagents and the NSF. February 2007. http://www.emea.europa.eu/pdfs/human/press/pus/4974107en.pdf

Cesium chloride: cardiac risksCanada — Use of stable cesium com-pounds (non-radioactive form of cesiumsalts, primarily cesium chloride) may posea risk of life-threatening heart problems.Cesium, primarily in the form of cesiumchloride, is promoted on the Internet toprevent various forms of cancer and as aself-administered cancer treatment.

While use of radioactive cesium in radia-tion treatment for cancer is authorized inCanada, Health Canada has not author-ized any health products containingstable cesium compounds for oral orintravenous use, including cesium chlo-ride. However, numerous Internet sitespromote the oral use of cesium chlorideas an alternative to chemotherapy.

Health Canada is aware of three cases ofserious cardiac arrhythmias (irregularheartbeat) in Canadian consumers whotook oral cesium chloride. These patientsalso experienced decreased or loss ofconsciousness.

Reference: Medeffect Health Advisory, 10September 2009 at http://hc-sc.gc.ca

Washout or taper whenswitching antidepressantsAustralia — Antidepressants are indi-cated for the treatment of major depres-sive disorders and may be indicated alsofor anxiety disorders, obsessive compul-sive disorder, premenstrual dysphoricdisorder and/or chronic pain. They in-clude:


• Selective serotonin reuptake inhibitors(SSRI)

• Tricyclic antidepressants

• Noradrenergic and 5HT1-serotonergicreceptor agonists

• Serotonin and noradrenaline reuptakeinhibitors (SNRI)

• Noradrenaline reuptake inhibitors

• St John’s Wort (Hypericum perforatum)

These drugs have various mechanisms ofaction but they share a number of similarproperties which may predispose indi-viduals to suffer from adverse effects dueto interactions when switching antidepres-sants even if they are of the same class.

One of the more serious possible out-comes is the development of serotoninsyndrome – a potentially life threateningcondition caused by the accumulation ofserotonin in the central nervous system(1–4). Serotonin syndrome is a potentialadverse effect of all antidepressants andit can occur when treatment is not inter-rupted as well as during switching,particularly in the elderly (1,3,4).

The risk of serotonin syndrome increasesif there is simultaneous exposure to morethan one drug that can cause this syn-drome. The Therapeutic Goods Adminis-tration (TGA) has received severalreports describing this situation, some ofwhich include life-threatening outcomes.

To avoid the possibility of an interaction,an appropriate washout period is requiredto substantially clear the first antidepres-sant from the body before the second isintroduced. Unfortunately, no simpleadvice on the appropriate washout periodcan be given. In general, a drug is notcompletely cleared until a period equiva-lent to 4–5 half lives has elapsed after a

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drug is ceased. The half life of antide-pressants varies substantially from abouttwo hours for citalopram and moclobe-mide and up to six days or more forfluoxetine, while the effect of irreversibleMAOIs such as phenelzine can persist forseveral weeks after the drug has beenceased.

There are no set guidelines on switchingamongst antidepressants and factors thatshould be considered will vary dependingon the properties of the antidepressantsand the patient’s situation including theduration of time the patient has been onthe first antidepressant, patient age, othermedications and other health issues(5,6).

Useful information on antidepressant-freeintervals when changing from one antide-pressant to another is available in theTherapeutic Guidelines — PsychotropicMedicines and in the Australian Medi-cines Handbook (5,6).

Extracted from the Australian AdverseDrug Reactions Bulletin, Volume 28,Number 5, October 2009.

References

1. ADRAC. Serotonin syndrome. Aust AdvDrug Reactions Bull 2004; 23(1).

2. ADRAC. Tramadol and serotonin syndrome.Aust Adv Drug Reactions Bull 2001; 20(4).

3. ADRAC. Serotonin syndrome withduloxetine. Aust Adv Drug Reactions Bull2009; 28(4).

4. Isbister G, Buckley N, Whyte I. Serotonintoxicity: A practical approach to diagnosis andtreatment. MJA 2007;187: 361-365.

5. Changing Antidepressants. AustralianMedicines Handbook 2007, p 714.

6. Therapeutic Guidelines. Psychotropic.Version 6, 2008, pp 112-113.


Zanamivir inhalation powdermust not be nebulizedSingapore — Healthcare professionalshave been informed of the death of apatient with influenza who receivedzanamivir (Relenza®) inhalation powderwhich was solubilized and administeredby mechanical ventilation. The death wasattributed to obstruction of the ventilatorwhich could have been due to lactose inthe formulation causing stickiness whenthe powder is mixed with the nebulizingsolution.

The manufacturer wishes to highlight tohealthcare professionals that Relenza®Inhalation Powder is not intended forreconstitution in any liquid formulationand is not recommended for use in anynebulizer or mechanical ventilator. Zan-amivir for nebulization has not beenapproved by any regulatory authority andthe safety, effectiveness and stability ofzanamivir use by nebulization have notbeen established.

Reference: Health Sciences Authority (HSA).14 October 2009. http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/safety_information/DHCPL.html

Pandemrix®: risk of feverEuropean Union — The EuropeanMedicines Agency (EMEA) is warning thatyoung children may experience feverafter their second dose of the pandemicinfluenza vaccine Pandemrix.®. Prescrib-ers and parents should monitor thetemperature of the vaccinated child and, ifnecessary, take measures to lower thefever (e.g., giving an antipyretic such asparacetamol). However, the Agency notedthat the second dose increases theimmune response against pandemicinfluenza.

The Agency has recommended that thisinformation be included in the prescribing

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information, and be taken into considera-tion when deciding whether to give asecond dose to children.

Reference: EMEA Press Release, Doc. Ref.EMEA/784404/2009 4 December 2009 athttp://www.emea.europa.eu/

Weekly pandemicpharmacovigilance updatesEuropean Union — The EuropeanMedicines Agency (EMEA) has publishedthe first in a series of weekly pandemicpharmacovigilance updates.

These weekly bulletins will provideinformation on adverse reactions reportedafter the use of centrally authorizedpandemic influenza vaccines and


antivirals in the European Union andcomplement the information the Agencyhas been publishing regularly on thedevelopment and approval of medicinesfor use during the pandemic.

This information will support Europeaninstitutions and Member States in theircommunications, and provide an addi-tional resource when recommending theuse of vaccines and antiviral treatments.

The information on adverse reactions inthe update comes from EudraVigilance,the central European database on ad-verse reactions, managed by the Agency.

Reference: EMEA Press Release, Doc. Ref.EMEA/775140/2009 3 December 2009 athttp://www.emea.europa.eu/

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International biologicalstandards: 2009 updateInnovation in biological medicines isoccurring in more countries than everbefore. In addition, the supply chain forbiological medicines is increasinglycomplex and international in nature.Despite technological advances, control-ling the quality, safety and efficacy ofbiologicals remains difficult and highlyspecialized. Therefore, strengtheningbiological standardization and its imple-mentation, in particular in emergingeconomies, remains a fundamentalfunction for WHO. The aim is to providetools that will translate into appropriateoversight of new biologicals of potentialpublic health benefit or oversight ofbiological components in the supplychain. Developing standards for quality,and associated reference materialsthrough its Expert Committees and ExpertAdvisory Panels is a key priority for WHO.

The Expert Committee on BiologicalStandardization advises WHO on inter-national biological standardization andkey developments affecting the quality,safety and efficacy of vaccines, biologicaltherapeutics, blood products and biologi-cal diagnostics. The Expert Committeemet in Geneva from 19–23 October 2009to enable WHO to fulfil one of its constitu-tional responsibilities to “Develop, estab-lish and promote international standardsfor biological products”.

During its meeting, the Expert Committeeestablished new WHO guidelines on theregulatory evaluation of “similar biothera-peutic medicines”. These products have asuccessful record in treating many life-threatening and chronic diseases. How-ever, patients — particularly in developing

countries — have limited access to suchmedicines. The expiration of patents and/or data protection for the first major groupof innovative biotherapeutics is usheringin an era of products “similar” to theoriginals, with the potential to significantlyenhance accessibility. The guidancedeveloped by WHO on appropriateregulation of this new class of products isin response to requests from manydeveloping countries.

Revised WHO recommendations for theproduction and control of live attenuatedinfluenza vaccine were established by theExpert Committee. The purpose of theserecommendations is to provide vaccinemanufacturers and national regulatoryauthorities with guidance that can beapplied in developing specific processesfor the production and control of human,live attenuated influenza vaccines. Theserecommendations are also intended toprovide guidance on the nonclinical andclinical evaluation of influenza vaccinesand apply to the production and control ofinfluenza vaccines using embryonatedhen’s eggs as substrates. The futurepossibility to produce human, live attenu-ated influenza vaccines using cell cul-tures as substrates is anticipated and,therefore, guidance is also provided forthis eventuality. The recommendationswith possible modifications apply tohuman, live attenuated influenza vaccinesproduced with seasonal vaccine strainsfor use during the interpandemic periodas well as vaccines produced with strainsfor use during pandemics.

Infections caused by Streptococcuspneumoniae are responsible for substan-tial morbidity and mortality, particularly inthe very young and elderly. Pneumococciare grouped into many serotypes (~ 91)

Biomedicines and Vaccines

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on the basis of their chemically andserologically distinct capsular poly-saccharides. Certain serotypes are muchmore likely than others to be associatedwith clinically apparent infections, tocause severe invasive infections and toacquire resistance to one or more classesof antibacterial agents. The developmentof pneumococcal conjugate vaccines inwhich each of the selected bacterialcapsular polysaccharides is coupled witha protein carrier molecule has been amajor advance in the prevention ofinvasive pneumococcal disease (IPD).

Since 2006, WHO has recommended thatall countries should incorporate pneumo-coccal conjugate vaccines in routineimmunization schedules for children lessthan 2 years of age with prioritization oftheir introduction in countries with highchild mortality rates and/or high rates ofHIV infection. A 7-valent pneumococcalconjugate vaccine (7vPnC) that employsCRM197 as the carrier protein for allseven serotypes was the first to bedeveloped. This vaccine was licensed inthe USA in 2000 and subsequently hasbecome available in approximately 90countries worldwide. Pneumococcalconjugate vaccines that contain three orsix serotypes in addition to those in the7vPnC vaccine have recently becomeavailable in some countries. The 10-valent vaccine includes tetanus toxoid,diphtheria toxoid or a novel proteinderived from nontypable Haemophilusinfluenzae (protein D) as the carrierproteins while the 13-valent vaccine usesonly CRM197 as the carrier protein.

WHO recommendations for pneumo-coccal conjugate vaccine production andcontrol were first established in 2003 (1).Since the 7vPnC vaccine was alreadyapproved in many countries, it wasconsidered unethical to assess theprotective efficacy of future pneumococ-cal conjugate vaccines in infants andtoddlers in comparison to an unvacci-

nated control group. The recommenda-tions discussed the design of immuno-genicity studies to support licensure ofnew pneumococcal conjugate vaccines(including those containing conjugatedcapsular polysaccharides of serotypesadditional to those in the 7vPnC vaccine)intended to prevent IPD and for adminis-tration to children aged less than 2 years.It was considered essential that theimmunogenicity studies with a newpneumococcal conjugate vaccine shouldprovide a link back to the vaccine efficacyagainst IPD that was demonstrated forthe 7vPnC vaccine.

Therefore, it was recommended thatimmune responses to each serotype inthe 7vPnC vaccine that is also included ina new pneumococcal conjugate vaccineshould be directly compared in random-ized clinical studies and that the primarycomparison of immune responses shouldbe based on serotype-specific IgGantibody concentrations measured byenzyme-linked immuno-sorbant assay(ELISA). In order to facilitate thesecomparisons a WHO reference ELISAassay was established that includes pre-adsorption of sera with pneumococcal Cpolysaccharide (C-PS) and serotype 22Fpolysaccharide.

Prompted by issues raised during thedevelopment of newer pneumococcalconjugate vaccines since the publicationof the WHO 2003 recommendations (1),WHO held a consultation in 2008 toconsider new scientific evidence and todiscuss the need to provide revisedguidance for manufacturers and licensingauthorities. The Expert Committee onBiological Standardization has estab-lished a revised document that has beendeveloped to take into account the mostrecent developments (2).

The Expert Committee also reviewedproposals to establish 24 new or replace-ment reference preparations as WHO

Biomedicines and vaccines

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International Standards. Internationalstandards and biological referencepreparations for use in the quality andsafety control of biological products andin vitro diagnostic devices are submittedto the Expert Committee following valida-tion of candidate preparations in global,coordinated studies.

Among the proposals, a reference panelcovering the most prevalent hepatitis Bgenotypes worldwide was adopted tofacilitate improvement of the quality ofhepatitis B diagnostic devices and thetraceability of test results between coun-tries. Other reference materials for thecontrol of the potency of blood productsand the diagnosis of genetic diseases

were also adopted this year. Thesepreparations are expected to be widelyused by regulators, manufacturers andblood establishments worldwide and willsupport international regulations for bloodproducts and the safety of blood products(2).

References

1. World Health Organization. Expert Commit-tee on Biological Standardization. TechnicalReport Series, No. 927, annex 2 (2003).

2. Expert Committee on Biological Standardi-zation: written standards and referencepreparations; interim report. http://www.who.int/biologicals.

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International Harmonization

ICH Implementation:Quality Working GroupsIn Brussels 2003, a new quality visionwas agreed by parties of the InternationalConference on Harmonization (ICH) (1).This emphasized a risk and science-based approach to pharmaceuticals in anadequately implemented quality system.As a consequence, the guidelines onPharmaceutical Development (Q8),Quality Risk Management (Q9) andPharmaceutical Quality System (Q10)were drafted.

These concepts and principles departfrom the traditional approaches to qualityguidance, mainly based on end-producttesting. Since it is important that properimplementation is strenghtened byclarifying, explaining and removingambiguities and uncertainties, an ICHImplementation Working Group (IWG) onICH Q8, Q9 and Q10 has been formedand met during the recent ICH meetingheld in Yokohama in June 2009. The IWGis drawn from the six member parties ofthe ICH: industry and medicines regula-tory authorities of the European Union,Japan and United States of America (upto three experts per party). Observers tothe ICH are allowed one expert andInterested Parties one expert each. TheIWGs focus on the following issues:

Technical issues and relateddocumentation

• Common understanding of terminology.

• Interrelationship between Q8, Q9 andQ10.

• Applicability to both review and inspec-tion.

• Final status after partial implementationis established (level of details in thedossier).

Additional implementation issues

• Influence on existing ICH guidelines.

Communication and training

• Questions and Answers, ICH briefingpacks.

• External collaboration.

• Workshops.

The aim of the ICH Quality Implementa-tion Working Group (Q-IWG) is to provideenhanced harmonized implementationtraining to industry and regulators in thethree ICH regions. In addition, the groupcan offer opportunities to train colleaguesin non-ICH regions. The newly designedstandards workshop is planned to beconducted by those ICH experts whodeveloped the ICH Q8, Q9 and Q10guidelines and members of the ICH.These are intended to be the only work-shops reviewed and referenced by the Q-IWG and will be conducted by the samefaculty in all three ICH regions.

Training will cover the integrated use ofICH Q8, Q9 and Q10 guidelines and Q&A(question and answers) across theproduct life-cycle, from development tomanufacturing and commercialization.Unlike other conferences and workshopson these topics, training will present acase study throughout the entire life-cyclefrom development to manufacturing andcommercialization. Regulatory assess-ment and GMP inspection implementationaspects will be discussed. Furthermore,

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learning opportunities will be provided forparticipants to practise in small groupsthe necessary skills for implementation ofthe guidelines.

Workshop deliverables will includematerials to support understanding ofintegrated use of the concepts describedin ICH Q8, Q9 and Q10 guidelines. Thesematerials will be used by both regulatorsand industry to implement the threeguidelines in their organizations.If the ICH Global Cooperation Group(GCG) is organizing workshops outsidean ICH region the Q-IWG will providestructure and content of the workshops. IfWHO is organizing workshops, the Q-IWG can provide support.

The IWG is also looking into the availabil-ity of illustrative examples and casestudies relevant to harmonized andconsistent implementation. The initial goalwas to reference existing material anddevelop examples and position papers.

A survey of conferences, publications andpresentations has been carried out overthe past six months. As a result, a list ofrelevant topics and activities was identi-fied together with an analysis of specificneeds for additional work. The review

demonstrated that there is a large amountof publications and workshops availablecovering ICH Q 8, Q9 and Q 10. The finalconsensus was that the Q-IWG shouldinitiate, encourage and collaborate in thedevelopment of articles consistent withQ8, Q9, Q10 guidelines and the recentlydeveloped Questions and Answers.

Reference: ICH information available athttp://www.ich.org

ICH PharmacopoeialDiscussion GroupThe Pharmacopoeial Discussion Group(PDG) [European Pharmacopoeia(PhEur), Japanese Pharmacopoeia (JP)and United States Pharmacopeia (USP)]met in association with the Expert Work-ing Groups of the International Confer-ence on Harmonization (ICH), 8–12 June2009 in Yokohama, Japan. The WorldHealth Organization attended in its officialcapacity as observer.

Discussion focused on Q4B Evaluationand Recommendation of PharmacopoeialTexts for Use in the ICH Regions.The ICH Q4B guideline was finalized(Step 4) on 1 November 2007.


initial adopted open

General clarification 0 1 1

Quality by Design (QbD) topics 1• Design Space 6 2• Real Time Release Testing 8 3 3• Control Strategy 3 1 1

Pharmaceutical Quality System 6 2 3

GMP Inspection practice 2 3Knowledge Management 4 1Software solution 1

Total 41 10 11

Status of additional ICH questions & answers (Supplementary table)

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This document describes a process forthe evaluation and recommendation bythe Q4B Expert Working Group (EWG) ofselected pharmacopoeial texts to facilitatetheir recognition by regulatory authoritiesfor use as interchangeable texts in theICH regions. Following favourable evalua-tions, ICH will issue topic-specific an-nexes with information about these textsand their implementation (the Q4BOutcomes). Implementation of the Q4Bannexes is intended to avoid redundanttesting by industry.

Harmonization has been achieved by thePDG on nine of the ten General Chaptersidentified by the ICH Q6A Guideline.From those, eight have been evaluated inaddition to two newly harmonized texts bythe ICH Q4B Working Group as follows:

• Residue on Ignition/Sulphated AshGeneral Chapter (ICH Q4B Annex 1)

• Test for Extractable Volume ofParenteral Preparations General Chap-ter (ICH Q4B Annex 2)

• Test for Particulate Contamination: Sub-Visible Particles General Chapter (ICHQ4B Annex 3, includes English JP text)

• Microbial Enumeration Tests GeneralChapter (ICH Q4B Annex 4A)

• Tests for Specified Micro-organismsGeneral Chapter (ICH Q4B Annex 4B)

• Acceptance Criteria for PharmaceuticalPreparations and Substances forPharmaceutical Use General Chapter(ICH Q4B Annex 4C)

• Disintegration Test (ICH Q4B Annex 5,includes English JP text)

• Uniformity of Dosage Units GeneralChapter (ICH Q4B Annex 6)

• Dissolution Test General Chapter (ICHQ4B Annex 7)

• Sterility Test General Chapter (ICH Q4BAnnex 8, includes English JP text)

• Tablet Friability General Chapter (ICHQ4B Annex 9)

• Polyacrylamide Gel ElectrophoresisGeneral Chapter (ICH Q4B Annex 10).

ICH Q4B Annexes 1–5 and 8 have beensigned off as ICH step 4 documents.Annexes 6 and 7 are pending feedbackfrom PDG. Annex 9 and 10 are at theStep 2 stage.

PDG is working on the following generalchapters within the harmonization proc-ess and they will be submitted for ICHQ4B evaluation upon final PDG sign offas being harmonized:

• Bulk and Tapped Density of Powders

• Analytical Sieving

• Capillary Electrophoresis

• Bacterial Endotoxin Test

• Colour Test (new method being re-viewed).

Moreover, 26 of the 34 General Chaptersand 40 of the 63 excipient monographshave been harmonized by PDG. In thecourse of indicating the harmonizationstatement in the three ICHpharmacopoeias, PDG has reviewedseven excipient monograph texts andidentified typical discrepancies. A path toresolution has also been agreed that willfacilitate further harmonization projects.

The possible implementation of theseharmonized texts within the revisionprocess of The International Pharmaco-poeia will be reviewed by the forthcomingForty-fourth WHO Expert Committee onSpecifications for Pharmaceutical Prepa-rations.


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Background: The InternationalPharmacopoeiaThe International Pharmacopoeia com-prises a collection of quality specificationsfor pharmaceutical substances (activeingredients and excipients) and dosageforms together with supporting generalmethods of analysis intended to serve assource material for reference or adapta-tion by any WHO Member State wishingto establish pharmaceutical requirements.The International Pharmacopoeia, or anypart of it, may have legal status whenevera national or regional authority expresslyintroduces it into appropriate legislation.

Activities related to The InternationalPharmacopoeia are an essential elementin the overall quality control and assur-ance of pharmaceuticals contributing tothe safety and efficacy of medicines. Theselection of monographs for inclusion inThe International Pharmacopoeia recog-nizes the needs of specific disease

programmes and the essential medicinesnominated under these programmes; it isbased primarily on those substancesincluded in the current WHO Model List ofEssential Medicines.

Work on The International Pharmaco-poeia is carried out in collaboration withmembers of the WHO Expert AdvisoryPanel on the International Pharmaco-poeia and Pharmaceutical Preparationsand with other specialists. The processinvolves consultation of and input fromWHO Member States and drug regulatoryauthorities, WHO Collaborating Centresand national drug quality control laborato-ries in all six WHO regions, standard-setting organizations and parties, includ-ing regional and national pharmaco-poeias and with manufacturers aroundthe world. Clearly defined steps arefollowed in the development of newmonographs.


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Prequalification of MedicinesProgrammePrequalification of qualitycontrol laboratoriesIncreased availability and supply of goodquality essential medicines for countriesis an important component of the UnitedNations Millennium Development Goals.Unfortunately, several internationalfunders and suppliers of essential medi-cines have faced difficulty in monitoringthe quality of supplies in countries be-cause of a lack of fully operational medi-cines quality control laboratories.

Given this situation, international donorsand suppliers often preferred to havelocal medicine samples sent for analysisin quality control laboratories situated inEurope or North America. Such practicesdo not support sustainable developmentgoals and are counter productive inbuilding national capacity.

In collaboration with UNAIDS, UNICEF,UNFPA, the Global Fund, UNITAID, withsupport from the World Bank, WHO hasset up a process to prequalify qualitycontrol laboratories that meet recom-mended international norms and stand-ards for the analysis of medicines pre-qualified or being considered for prequali-fication by WHO.

As a first step, WHO has invited qualitycontrol laboratories in Africa to take partin the process. Laboratories were chosenbased on their commitment to providetesting of pharmaceutical products forHIV/AIDS, tuberculosis and malaria (1). InSeptember 2007, the scope of the proce-dure was extended and currently invita-tions are open to quality control laborato-ries in any region worldwide. WHOmanages the assessment process and

identifies which quality control laborato-ries should be given priority based onneed.

Participation in the prequalificationprocess is described in Procedures forassessing the acceptability, in principle, ofquality control laboratories for use byUnited Nations agencies (2). For the timebeing, applying for and participation in theprequalification procedure is free ofcharge. However, the procedure alsoenables WHO to charge for the assess-ment of laboratories on a cost-recoverybasis if the prequalification process is nolonger funded by donors.

WHO assesses quality control laborato-ries through evaluation of preliminaryinformation submitted by a laboratory andon-site inspection to assess compliancewith the WHO guidelines on Good Prac-tices for National Pharmaceutical ControlLaboratories (3) and Good ManufacturingPractices (4). These and other relatedguidelines are published on the Prequali-fication Programme’s web site (5). Inter-national Standard Organization (ISO)certification (ISO/IEC 17025) is alsoencouraged. If assessment demonstratesthat a laboratory meets WHO recom-mended standards, it is included in theofficial List of WHO Prequalified QualityControl Laboratories that is consideredacceptable for use by United Nationsagencies or other interested parties (6).

Once a laboratory is included in the WHOList of Prequalified Quality Control Labo-ratories, ongoing monitoring of its activi-ties is performed. This includes re-inspection at regular intervals, evaluationof results from participation in an appro-priate proficiency testing scheme, andmonitoring and investigation of any

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complaints concerning results of analysisor other service provided by the listedlaboratories. To facilitate monitoring, eachprequalified laboratory is requested tosubmit a brief annual report on its activi-ties. An outline of the expected content ofan annual report is available on the WHOweb site (7).

A laboratory will be removed from the listif it is found that it no longer complies withthe specified standards.

Update on progressAs of October 2009, eleven laboratorieshave been prequalified by WHO. Fiveprequalified laboratories are located inthe WHO Africa Region, three in theWestern Pacific Region and one in eachof the three regions: Eastern Mediterra-nean Region, Europe Region and South-east Asia Region. Apart from theseeleven prequalified laboratories, there aretwenty-four quality control laboratoriesparticipating in the procedure (See Table

Prequalification of Medicines Programme

Table 1. Prequalification of quality control laboratories

Country Region Number ofprequalified laboratories

Algeria Africa 1France Europe 1India South-East Asia 1Kenya Africa 2Morocco Eastern Mediterranean 1Singapore Western Pacific 2South Africa Africa 2Vietnam Western Pacific 1

QCLs Prequalified QCLs Participating

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1). The majority of participating laborato-ries (26 of 35) are national quality controllaboratories.

As part of the capacity building compo-nent of the WHO Prequalification ofMedicines Programme, national qualitycontrol laboratories participating in theprequalification procedure are provided, ifneeded, with t

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