WHO Drug Information Vol. 23, No. 4, 2009 World Health Organization
WHO Drug Information
Contents International Nonproprietary Prequalification of Medicines Names Programme INN identifiers for biological products 273 Prequalification of quality control laboratories 300 Safety and Efficacy Issues Rituximab: multifocal leuko- Pharmacovigilance Focus encephalopathy 282 A/H1N1 vaccination safety: PaniFlow¨ Darbepoetin alfa: risk of stroke 282 surveillance tool 305 Vigabatrin and movement disorders 283 Alendronate: risk of low-energy femoral Regulatory Action and News shaft fracture 283 Influenza vaccines for 2010 southern Ceftriaxone and calcium containing hemisphere winter 306 solutions 284 Romidepsin: approved for cutaneous Etravirine: severe skin and hyper- T-cell lymphoma 306 sensitivity reactions 285 Orciprenaline sulphate: withdrawal 306 Oseltamivir phosphate: dosing risk 285 Artemisinin antimalarials: not for Safety signal: hyponatraemia 286 use as monotherapy 307 Clopidogrel and omeprazole: reduced Vitespen: withdrawal of marketing effectiveness 286 authorization application 307 Bisphosphonates: osteonecrosis of Aripiprazole: withdrawal of application the jaw 287 for extension of indication 307 Intravenous promethazine: serious Substandard and counterfeit medicines: tissue injuries 287 USAIDÐUSP Agreement 308 Cyproterone: risk of meningiomas 288 Vandetinib: withdrawal of marketing Gadolinium-containing contrast agents 289 authorization application 308 Cesium chloride: cardiac risks 290 Washout or taper when switching antidepressants 290 Consultation Document Zanamivir inhalation powder must International Pharmacopoeia not be nebulized 291 Artesunate 309 Pandemrix¨: risk of fever 291 Artesunate tablets 313 Weekly pandemic pharmacovigilance updates 292 Recent Publications, Information and Events Biomedicines and Vaccines Illegal weight-loss medicines and International biological standards: dietary supplements 318 2009 update 292 Southern Med Review 318 International Harmonization Proposed International ICH Implementation: Quality Working Nonproprietary Names Groups 295 List 102 319 ICH Pharmacopoeial Discussion Group 296
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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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INN identifiers for cal substances of well-defined structure although other groups of non-homo- biological products genous established products, including from natural sources, were also consid- The International Nonproprietary Names ered. When substances which had (INN) Programme was created by WHO already been named by the INN Pro- in the 1950s with the intention of provid- gramme became available through new ing convenient common names for biotechnological processes, earlier pharmaceutical substances. At the time of decisions on naming non-homogenous its origin, as well as during its later products had an influence on defining development, the INN Programme was and naming novel products. Practices inherently linked to progress in drug recognized in naming and defining two research and its success was reliant on specific product groups: low molecular the ability to deal appropriately with each weight heparins and insulins strongly new group of medicinal products that influenced this approach. (A discussion entered into therapeutic use. In the of these practices is found on page 274 1980s, the development of biotechnology and 275.) products based on recombinant tech- niques led to highly novel therapeutic Specific approaches are needed when agents, thus creating a new need for formulating definitions and, in particular, adaptation of the INN system. The for creating suitable INN for biotechno- present article describes the ways that logical products. These approaches have the INN Programme has responded to the been under active consideration by the challenges that arose in connection with INN Programme since the 1980s and this evolution. were finally formulated in a 1994 INN guideline (1). Until now, 45 INN with Basic rules for the INN system set the Greek letter identifiers have been se- limits within which all INN can be con- lected for glycosylated biological prod- structed. They include the need to prop- ucts. erly define the substance or product that is named, to indicate in the name the Application of the guidelines in naming of pharmacological or therapeutic class to individual groups of biological products which the substance or product belongs containing carbohydrate residues in their by use of the INN stem system and, structure is described on pages 275Ð277. finally, to shape the name in a manner Difficulties that relate to the use of Greek which facilitates its use by prescribers. letter identifiers in naming of interferons (These issues are summarized on page are presented on page 279. The naming 274.) of monoclonal antibodies (mAbs), an important group of glycoproteins obtained In its initial phase, the INN Programme by biotechnology, is not considered in this was designed to cover only single chemi- document as issues related to mAb names have been discussed separately * Professor Witold Wieniawski,Counsellor, at recent INN meetings and are also Polish Pharmaceutical Society, Poland and reviewed in two issues of WHO Drug Member, WHO INN Expert Group. Information (2). Related documents of
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interest are also available on the INN is selected for an active moiety, while a website including a document on INN for salt or an ester are employed in practice, biological and biotechnology substances an INNM system is used to create suit- (3), documents relating to biologicals and able two-word names. mAbs (4) and an INN document on biosimilars (5). However, creating INN for products obtained by biotechnology is a more com- Creating INN plex process. While the selection of basic stems (-ase, -mab, -micin, -mycin, In the selection of INN, two separate -poetin, etc.) can be carried out according issues are considered which influence the to the normal INN system, the naming of final shape of the name: (i) the way in individual components of each series which the substance is identified, and (ii) requires specific decisions on the extent the structure of the name. of supplementary information to be included in the name. Those issues may In the case of individual chemical sub- vary for individual groups, but the follow- stances, the identification process is ing remarks apply to all situations. based on chemical names established by the International Union of Pure and General rules for the construction of INN Applied Chemistry (IUPAC). The chemical offer only a few options for introducing designation is further supported by a elements of additional information. In graphic formula. one-word names this can be done by insertion of specific infixes (or prefixes). In the case of products obtained by bio- Otherwise, inclusion of a second or even technology, the identification process is third word is necessary as in the case of more complicated because such products INNM names. This approach is also used usually form a mixture (the word “com- when describing complexes with metals plex” is sometimes used) of several (or or radioactive elements. The second- more) individual substances of similar word approach is used frequently for structure and activity. The use of these biological products when the second word products occurs without separation into consists of a spelled out Greek letter. individual active components. Definition of such products is complicated and is Other identifiers widely used in scientific made individually for each product group. texts like numerals (Arabic or Roman), Formulation of definitions has progressed single letters (Latin alphabet), or single in line with analytical methods that Greek letters in the original script, are increasingly allow a highly precise de- precluded in INN. The reason for this rule scription of the structure of individual is that such elements of names could components. Examples of such changes lead to confusion and mistakes when occurring for individual groups are pre- used on a medical prescription, as sented later. numerals are used also to describe the dose (or concentration) or the number of Creation of INN for single chemical dosage units. Single letters may also be substances involves selection of an confused, especially in handwriting. appropriate stem indicating the expected activity (or the decision to select an INN The rules indicated above are also outside the stem system) followed by applied when selecting names for biologi- additional elements (usually the prefix) to cal products with a glycoprotein structure. create a distinctive name. When an INN This can sometimes create additional difficulties, and is described later.
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Selecting INN for natural and followed (or preceded) by another word semisynthetic products (or words) which is indicative of changes in the structure of the parent compound. INN for LMW heparins Low molecular weight (LMW) heparins Insulin as such was never listed as an are products obtained from natural INN, being considered a well-established heparin by chemical reaction leading to name. Between 1956 and 1958, INN depolymerization and various changes in were given to 6 insulin preparations: structure. Natural heparin is a sulfated insulin zinc suspension (crystalline) and polysaccharide (polyuronic acid), which is (amorphous), protamine zinc insulin a mixture of components differing in chain injection, etc. The definition for each length. LMW heparins also form mixtures product described its preparation. of individual components that may differ in chain length and other structural The first insulin obtained in 1982 by features because they are produced from recombinant technology was given the a natural heterogenous material by INN insulin human, defined as “a protein processes that do not warrant full homo- having the normal structure of the natural geneity of the final product. antidiabetic principle produced by the human pancreas”. In this case the second In 1983, when the first INN request for a word in the name served a dual purpose, LMW heparin was made, the INN Expert to link the actual structure of the product Group held prolonged discussions on with that of a natural product, following whether this type of biological product the pattern established in the case of should be included in INN system. It was beef insulin and pork insulin. concluded finally that selecting INN for such products would serve a useful The two-word approach was maintained purpose, and the stem -parin was se- for six further INN for modified insulins lected for the group. The first name in the produced by biotechnology: insulin series was enoxaparin published in 1984. argine, insulin lispro, etc. containing (The name was later modified to enoxa- modifications in the amino-acid parin sodium.) The next group of requests sequences, but in these cases the sec- for LMW heparins was given the INN ond word serves to indicate a structural nadroparin calcium, parnaparin sodium, change. The substances are defined by reviparin sodium and tinzaparin sodium. describing their chemical structure. Since then, a further eight INN containing the -parin stem have been selected. INN for erythropoietins The first request for erythropoietin pro- As can be seen, individual members of duced by biotechnology was made in the group are distinguished by using INN 1988 by a US manufacturer. The request containing a common stem (-parin) and indicated that the substance was pro- different prefixes. Individual products are duced by “human clone λHEPOFL13 defined in a rather complicated manner protein moiety”. The manufacturer’s by description of manufacturing process, proposal to select erythropoietin as an information on the structure of compo- INN was modified to eripoetin and this nents and indication of molecular mass. name was considered to be suitable provided that the product corresponded INN for insulins to the natural endogenous substance. It Insulin serves as an example of the was also agreed that -poetin would be approach for naming a group of related considered in the future as a stem for all peptides by using a parent name (insulin) erythropoietin type blood factors. Later in
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1988 a second request for an INN for Definitions for all epoetins include infor- erythropoietin produced by biotechnology mation that the product is a 1-165- was received from another manufacturer. erythropoietin and contains a glycoform identifier expressed as α, β and γ, etc. However, during evaluation, the main In addition, definitions of epoetin alfa, problem that emerged concerning the epoetin beta, epoetin gamma, epoetin recombinant form was that erythropoietin epsilon and epoetin omega also indicate is a glycoprotein and that the activity of the designation “human clone the substance depends strongly on the λHEPOFL13 protein moiety” describing degree of glycosylation, as erythropoietin the gene coding of the amino acid without the carbohydrate moiety is not sequence for human erythropoietin active in vivo. Additionally, the recom- (HEPOFL being an abbreviation for binant forms differ in the type and degree Human Erythropoietin Fetal Liver source). of glycosylation and neither one is identi- cal to the endogenous substance. Litera- Definitions for three other epoetins ture published on the subject confirmed include gene codes which are not in line that N-glycosylation is cell specific and with symbols used in regular gene no- site specific creating different glycoforms menclature and are seemingly sugges- depending on the cell line used in the tions from manufacturers. The definition manufacturing process. It was also known of epoetin delta contains the expression that erythropoietin has three N-glycosyla- “human HMR4396” where the designation tion sites at Asn24, Asn38 and Asn83 and HMR4396 is the manufacturer’s code. A one O-glycosylation site at Ser126. It was similar situation occurred in the case of also known that carbohydrate moieties at epoetin kappa. In the case of epoetin N-terminals are quite complex (antennary zeta, the definition contains the expres- structure). sion “human clone B03XA01” where the designation B03XA01 is an ATC code for On the basis of these arguments, the INN anti-anaemic preparations. It may be Group decided in 1989 to consider each appropriate to later delete these designa- request as representing a different tions from the definitions. product and to give an individual INN (6). Subsequently, the INN guideline adopted INN for enzymes in 1994 (1) states that the Greek letter INN for enzymes obtained from natural would serve to differentiate between sources were usually selected to corre- compounds of the same amino acid spond to enzyme names established by sequence as human erythropoietin, the Nomenclature Committee of the which vary in the glycosylation pattern. International Union of Biochemistry and INN for products with different amino acid Molecular Biology. In those cases their sequence would be named using the structure was not further defined, but in -poetin stem and a random prefix (see the majority of cases the origin of the darbepoetin alfa). product was indicated. Recently, EC numbers have been added to the defini- Between 1992 and 2007, six other INN tions. were selected for erythropoietins pro- duced by biotechnology: epoetin gamma, The following examples show approaches epoetin delta, epoetin epsilon, epoetin that were used in this group of products. zeta (in Spanish dseta), epoetin theta (in INN urokinase (published in 1966) was Spanish zeta), epoetin kappa, and defined originally as “plasminogen activa- epoetin omega. In 2001, darbepoetin alfa tor isolated from human urine”, but the was selected for an erythropoietin with a definition was changed in 1982 to “plas- modified amino acid chain.
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minogen activator isolated from human binant plasminogen activator followed, for sources” to take account of the fact that which saruplase was selected in 1987. the product started to be produced by During the period 1985Ð1987 discussions human kidney cell culture in vitro. Peni- were centred on the suitability of treating cillinase was defined as an enzyme these products as enzymes by using the obtained by fermentation from cultures of -ase suffix, and the issue of glycosylation Bacillus cereus. Kallidinogenase was was not considered. Finally, two stems for defined as an enzyme isolated from the plasminogen activators: -teplase (for pancreas or urine of mammals. Sfericase tissue-type) and -uplase (for urokinase- was defined as alkaline Bacillus spheri- type) were established in 1987 (8). cus proteinase. As this decision was made before the In the 1990s, the situation progressed system of glycoform identifiers was further when some specific enzymes that introduced, subsequent INN containing are glycoproteins started to be produced -plase stems were selected without this by biotechnology. The INN Group consid- identifier, as in the majority of cases the ered it necessary to indicate the glyco- INN were given for products with modifi- form by using the Greek letter system and cations in the amino acid chain. In some a few examples are given here. INN definitions the notion that the product is a glycoprotein was included in the defini- dornase alfa, selected in 1993, was 2 defined as “deoxyribonuclease (human tion. Silteplase was defined as “N-[N - clone 18-1 protein moiety)”. Algluco- (N-glycyl-N-alanyl)-L-arginyl)plas- sidase alfa was defined as “human minogen activator (human tissue-type lysosomal prepro-α-glucosidase-(57- protein moiety reduced), glycoform”. A 952)-peptide 199-arginine-223-histidine similar remark was made in the definition variant”. Bucelipase alfa was defined as for nateplase where “glycoform β” is “human bile-salt-activated lipase (choles- mentioned. terol esterase, EC 3.1.1.13), glycoform However, the absence of a glycosylation alfa (recombinant hBSSL)”. identifier later created a specific difficulty in the group of urokinase-type plasmino- The use of Greek letters as identifiers gen activators. Nasaruplase was defined was useful in the case of INN for as “prourokinase (enzyme-activating) α-galactosidase. Agalsidase alfa was (human clone pA3/pD2/pF1) protein selected for a product isolated from moiety)”. This definition was later modi- recombinant human cell line and INN fied by adding “glycosylated”. At the same agalsidase beta for a product obtained time saruplase — defined originally as from a Chinese Hamster Ovary (CHO) “prourokinase (enzyme-activating) (hu- cell line. The same approach was used man clone pUK4/pUK18 protein moiety for conestat alfa which was selected in reduced) — had to be changed by addi- 2007 for a specific C1 esterase inhibitor tion of “non-glycosylated”. In 2001, when (serine protease inhibitor). another request was made for recom- binant prourokinase produced by another A rather different situation occurred in the cell line, nasaruplase beta was selected, group of plasminogen activators. Initial defined as “prourokinase (enzyme- discussion on these products was held in activating) human (clone pUK4/pUK18 April 1985 (7). The first request for a protein moiety), glycosylated (murine cell tissue plasminogen activator was made in line SP2/0)”. The use of a Greek letter 1985 for a recombinant product for which identifier permitted a better separation of alteplase was finally selected in 1988. products differing in glycosylation pat- Another one, for urokinase-type recom- terns.
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INN for other glycosylated defined as “(1-724)-(1637–1648)-blood biologicals coagulation factor VIII (human reduced) Production of biological products identical with 1649-2332- blood coagulation factor or analogous to natural proteins or glyco- VIII (human reduced)”. Octocog alfa was proteins by recombinant technology was defined as “blood coagulation factor VIII also applied to other types of products. (human), glycoform α”. Other INN in the The naming system used for creating INN blood coagulation factor group include for these products is similar to that beroctocog alfa, eptacog alfa pegol already discussed. (activated), nonacog alfa, and vatrepta- cog alfa (activated). Blood coagulation factors and related products INN were also selected for two blood coagulation cascade inhibitors: drotre- In the group of blood coagulation factors cogin alfa (activated) and taneptacogin (substances that are glycoproteins), the alfa, and for five further products related first INN requests for products obtained to blood coagulation processes: thrombin by biotechnology were made in 1993 for alfa. antithrombin alfa, troplasminogen three products: blood coagulation factor alfa, thrombomodulin alfa, and so- VIIA, blood coagulation factor VIII and for thrombomodulin alfa. blood coagulation factor VIII with a modified (truncated) amino acid structure. Interleukins The first INN in this group, teceleukin, The main issue centred on whether to retain the established descriptive names was selected in 1985 for N-L-methionyl- for products obtained by biotechnology or interleukin-2 obtained by biotechnology. Subsequently, aldesleukin was selected switch to the INN approach of one-word names composed of a suitable stem and in 1990 and celmoleukin in 1991 for a random prefix. The option that was interleukin-2 derivatives with modifica- tions in the amino acid chain. Although finally accepted is reflected in the follow- ing policy statements: natural interleukin-2 is a glycoprotein, the issue of glycosylation was not discussed at that time. ¥ New names will only be given to prod- ucts produced by recombinant biotech- nology, but not to plasma derived In 1994, the situation changed when a request was received for a derivative of products. interleukin-6. For this product, atexakin ¥ Suitable stems will be created, glyco- alfa was selected and defined as “1- sylation pattern may be reflected by (1-L-alanyl-l-proline)interleukin-6 (human addition of a Greek letter (spelled out). clone HGF-15 protein moiety reduced), cyclic (54->50), (73->83)-bis(disulfide)”. ¥ The distinction between natural and modified amino acid sequence will be The formal decision to publish INN for indicated by using different prefixes. glycosylated interleukins with a Greek letter in accordance with the general This system was referred to as the policy of naming glycosylated proteins “epoetin approach” (1). was later confirmed in 1995 (10).
INN eptacog alfa (activated) was selected Following this decision, edodekin alfa was in 1994 and defined as “blood coagula- selected in 1998 for interleukin-12 and tion factor VII (human clone λHVII2463 adargileukin alfa in 2003 for partially protein moiety). Moroctocog alfa was glycosylated modified interleukin-2.
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Tadekinig alfa was selected in 2004 for fusion protein composed of FSH and 118- interleukin-18 binding protein. 145-chorionic gonadotropin (human β subunit). Recently, varfollitropin alfa was Pituitary and placental selected as FSH with amino acid modifi- glycoprotein hormones cations in both subunits. Preparations produced from human post- menopausal urine containing a mixture of Other INN selected in this group for follicle-stimulating pituitary hormone glycoprotein hormones obtained by (FSH) and luteinizing hormone (LH) have biotechnology are thyrotropin alfa (thyro- been manufactured since the 1960s and tropin releasing hormone) and chorio- pINN menotrophin and follotrophin gonadotropin alfa (human chorionic (human) were selected in 1963 and 1965. gonadotropin). These INN were later withdrawn, as their definitions were considered not suitable. Other glycoproteins However, the issue was revisited in 1987 The Greek letter system was also em- when urofollitropin was selected for a ployed for several other glycoproteins product defined as “a preparation of obtained by recombinant technology: menopausal gonadotrophin extracted dibotermin alfa and eptotermin alfa were from human urine but possessing neglig- selected for bone morphogenic proteins, ible LH activity”. ismomultin alfa was selected for cartilage glycoprotein 39, and talactoferrin alfa was In 1991, a request was received for selected for human lactoferrin. human FSH produced by recombinant technology followed by a request for INN for interferons: difficulties with human LH also produced by biotechnol- Greek letter identifiers ogy. After discussion, follitropin alfa and When discussing the use of Greek letter lutropin alfa were suggested as INN, with identifiers to indicate possible differences Greek letters indicating glycosylation. in the glycosylation pattern of glycopro- This proposal was however contested, teins it is necessary to mention also the because natural pituitary hormones case of INN interferon nomenclature, contain two amino acid chains in their since, in the naming system used for this structure that were designated by bio- group of products, the Greek letters have chemists as α and β subunits and these a different meaning. A short review of this designations were widely used in the peculiar situation is thus necessary. scientific literature. Although members of the INN Expert Group considered that the The INN interferon was selected in 1962 use of Greek letters in INN may lead to and defined as “a protein formed by the confusion, they conceded that such risk interaction of animal cells with viruses was minor (9). capable of conferring on animal cells resistance to virus infection”. The defini- The arguments against this selection may tion corresponded to the level of scientific be of some relevance for scientists, but knowledge at that time. Later develop- INN are intended primarily for use by ments have shown that this designation health professionals such as physicians also covered substances produced by and pharmacists and not for scientists different types of cells. Three types of specialized in this area. As a result, interferons were established: leukocyte follitropin alfa and lutropin alfa were interferon, fibroblast interferon and selected as well as follitropin beta. immune interferon, each type corres- Corifollitropin alfa was selected as a ponding to a group of substances.
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In 1982, the first INN request for leuko- Research (ISICR)]. In the 1980s, cyte interferon produced by recombinant interferons were considered to be a highly technology was received, followed in important field of therapeutic progress, 1983 by a request for a fibroblast inter- and the INN Programme considered that feron. During discussions concerning it was preferable to follow biochemical interferon nomenclature, several options interferon nomenclature extensively used were considered. One was to create a at that time, and thereby ignoring diver- stem -feron, but this was rejected due to gence with established rules for creating conflicts with established trademarks for INN. interferon preparations. Another approach was to follow designations currently used Conclusion in biochemical literature: INF-a (for As shown, the INN Programme has leukocyte interferons), INF-b (for fibro- skilfully responded to the demand for blast interferons) and INF-l (for immune selection and naming of new groups of interferons). The latter approach was therapeutic products and, in particular, provisionally agreed in April 1982 (10) those manufactured by recombinant together with the decision to spell out the technology. The INN system has found Greek letter. This approach to interferon ways for naming these products either nomenclature was finally approved in by linkage to customary names for older 1984 (11) when interferon alfa, interferon biological products and/or creating beta and interferon gamma were selected appropriate names for newer members with appropriate definitions. of each series.
The general definition for interferon alfa The INN Programme has also been introduced the possibility of indicating challenged with developing appropriate protein variants in the name by hyphen- ways for defining products composed of ated addition of an Arabic number. In the mixtures of closely related components case of interferon alfa-2 further possibility and to gradually upgrade the definitions of distinguishing substances that differ in in response to the enormous progress in amino acid composition at specific elucidation of the structure of biological positions of the amino acid chain could substances. be made by the addition of a small case Latin letter. The system was published in This daunting task has required the use INN list PL52. Using this system inter- of individual approaches while taking into feron alfacon-1 was selected in 1997, account the specificity of each group. To peginterferon alfa-2a and peginterferon the extent possible, a common style of alfa-2b in 2000 and albinterferon alfa-2b coining INN nomenclature has evolved, in 2008. especially for products with the glycopro- tein structure, where the use of Greek In interferon nomenclature, the Greek letter identifiers is now firmly established letter acquired a separate meaning, as it and is confirmed by the use of these now identified the type of substance. The identifiers in 45 INN to date. nomenclature also uses single letters and numbers, which is against normal INN References practice. These differences are due to a decision by the INN Programme to follow 1. Report of the Twenty-fourth INN Consulta- the system established by the Interferon tion held in 1994. (See also reference 3: items Nomenclature Committee [later renamed 3.4 and 4.8.) Nomenclature Committee of the Interna- 2. World Health Organization. WHO Drug tional Society for Interferon and Cytokine Information, 22(2) (2008) and 23(3) (2009).
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3. World Health Organization. http:// 7. Report of the Fifteenth INN Consultation www.who.int/medicines/services/inn/ held in April 1985. CompleteBioRevDoc%2008-11-07_2_.pdf 8. Report of the Seventeenth INN Consultation 4. World Health Organization. http:// held in 1987. www.who.int/medicines/services/inn/publica- tion/en/index.html 9. Report of the Twenty-fifth INN Consultation held in April 1995. 5. World Health Organization. http:// www.who.int/medicines/services/inn/ 10. Report of the Twelfth INN Consultation BiosimilarsINN_Report.pdf held in April 1982.
6. Report of the Twentieth INN Consultation 11. Report of the Fourteenth INN Consultation held in April 1990. held in 1984.
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Safety and Efficacy Issues
Rituximab: multifocal factors leading to activation of the latent leuko-encephalopathy infection are not fully understood. PML has been reported in HIV-positive pa- Canada — Healthcare professionals tients, immunosuppressed cancer pa- have been informed of important new tients, transplantation patients and safety information regarding the use of patients with auto-immune diseases, rituximab (Rituxan¨) and progressive including RA. There are no known inter- multifocal leuko-encephalopathy (PML). ventions that can reliably prevent or adequately treat PML. Rituximab is authorized for the treatment of B-cell non-Hodgkin lymphoma (NHL), Reference: Communication dated 21 October previously untreated B-cell chronic 2009 from Hoffmann-La Roche Limited at lymphocytic leukaemia (B-CLL), stage B http://hc-sc.gc.ca/dhp-mps/medeff/advisories- or C, and rheumatoid arthritis in combina- avis/prof/_2009/rituxan_5_hpc-cps-eng.php tion with methotrexate to reduce signs and symptoms in adult patients with Darbepoetin alfa: moderate to severe rheumatoid arthritis risk of stroke who have had an inadequate response or intolerance to one or more tumour necro- United States of America — A study has sis factor (TNF) inhibitor therapies. been published in the New England Journal of Medicine raising safety con- This is the first case of PML in a patient cerns about darbepoetin alfa and the risk with rheumatoid arthritis who has not of stroke. Additionally, among patients been previously treated with other potent with a history of cancer, 60 of 188 pa- biologic immunomodulating therapies. tients taking darbepoetin alfa died com- Previously, two fatal cases of confirmed pared to 37 of 160 on placebo. PML were reported in patients with rheumatoid arthritis treated with rituxi- Anaemia is associated with an increased mab. risk of cardiovascular and renal events among patients with type 2 diabetes and
Physicians should consider PML in any chronic kidney disease. Although patient being treated with rituximab who darbepoetin alfa can effectively increase presents with new onset neurologic haemoglobin levels, its effect on clinical manifestations (i.e., cognitive impairment, outcomes in these patients has been motor deficit, speech and vision impair- inadequately tested. ment) and should be immediately referred for neurological consultation. The study involved 4038 patients with diabetes, chronic kidney disease, and PML is a rare, progressive, demyelinating anaemia. Primary end points were the disease of the central nervous system composite outcomes of death or a cardio- that usually leads to death or severe vascular event (nonfatal myocardial disability. PML is caused by activation of infarction, congestive heart failure, stroke, the JC virus. JC virus resides in latent or hospitalization for myocardial ischemia) form in 40Ð80% of healthy adults. The and of death or end-stage renal disease.
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During the study, death or a cardiovas- on MRI (interpreted as cytotoxic oedema) cular event occurred in 632 patients associated with the use of vigabatrin, assigned to darbepoetin alfa and 602 after they received reports of these patients assigned to placebo. Death or adverse drug reactions from a Finnish end-stage renal disease occurred in 652 healthcare professional. patients assigned to darbepoetin alfa and 618 patients assigned to placebo. Fatal A Europe-wide review completed in July or nonfatal stroke occurred in 101 patients 2009 involving experts in paediatric assigned to darbepoetin alfa and 53 neurology from the UK assessed the patients assigned to placebo. There was evidence available on this issue, including only a modest improvement in patient- preclinical data, clinical data, reported reported fatigue in the darbepoetin alfa cases of adverse drug reactions, and group as compared with the placebo relevant published literature. group. Clinical trial data (1) for vigabatrin in Furthermore, the use of darbepoetin alfa infantile spasms provide evidence of in patients with diabetes, chronic kidney brain MRI abnormalities at all doses, but disease and moderate anaemia who were in particular in young infants treated with not undergoing dialysis did not reduce the high doses (≥125 mg/kg/day). These MRI risk of either of the two primary composite abnormalities were transient, seemed to outcomes (either death or a cardiovascu- be dose dependent, and in most patients lar event or death or a renal event) and resolved even if treatment with vigabatrin was associated with an increased risk of continued. stroke. For many persons involved in clinical decision making, this risk will The review concluded that it is not possi- outweigh the potential benefits. ble to correlate the MRI findings with the movement disorders based on the current Reference: TREAT Investigators. A Trial of data. Therefore, the two events of move- Darbepoetin Alfa in Type 2 Diabetes and ment disorders and brain MRI abnormali- Chronic Kidney Disease. New England ties will be independently described in the Journal of Medicine 2009; 361:2019Ð2032 updated product information for vigabatrin to reflect these new data. If new move- Vigabatrin and movement ment disorders occur during treatment disorders with vigabatrin, consideration should be given to dose reduction or a gradual United Kingdom — Vigabatrin (Sabril¨) discontinuation of treatment in consulta- is an anti-epileptic indicated, in combina- tion with specialist advice. tion with other anti-epileptics, for the treatment of patients with resistant partial Reference: Medicines and Healthcare epilepsy (with or without secondary Products Regulatory Agency. Drug Safety generalization) who have not responded Update, Volume 3, Issue 4 November 2009. to or who are intolerant of all other appropriate drug combinations. Vigabatrin Alendronate: risk of low- is also indicated as monotherapy in the energy femoral shaft fracture treatment of infantile spasms (West syndrome). New Zealand — A number of published case reports have described atypical low Researchers in Finland first raised energy stress fractures of the sub- concerns about a risk of movement trochanteric and proximal femoral shaft disorders (including dystonia, dyskinesia, in patients taking alendronate long-term and hypertonia) and brain abnormalities (1Ð3). In some cases, the patient experi-
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enced prodromal pain in the affected area 4. Prescriber Update 2009;30(4):25 November weeks to months before a complete 2009 at http://www.medsafe.nz fracture occurred. Ceftriaxone and calcium Prescribers should consider the risk of containing solutions atypical stress fractures in alendronate- treated patients reporting pain of the Canada — Healthcare professionals subtrochanteric or proximal femoral shaft. have been informed of updated prescrib- It is important to note that the reported ing information for ceftriaxone when used alendronate-associated fractures were with calcium-containing solutions via the frequently bilateral; therefore the contra- intravenous (IV) route. This new safety lateral femur should be examined if a information is based on the results of two fracture is suspected. recent in vitro studies that showed an increased risk of ceftriaxone-calcium Factors which may increase the risk of precipitates in neonatal plasma. fractures include: vitamin D deficiency, malabsorption, glucocorticoid use, previ- The following are new recommendations: ous stress fracture, lower extremity arthritis or fracture, extreme or increased ¥ Ceftriaxone is contraindicated in neo- exercise, diabetes mellitus, and chronic nates if they require (or are expected to alcohol abuse. require) treatment with calcium-contain- ing intravenous solutions, including It is important to note that atypical stress continuous calcium-containing infusions fractures have also been reported in such as parenteral nutrition, because of patients not taking bisphosphonates. In the risk of precipitation of ceftriaxone- addition, it is possible that other bisphos- calcium. phonates may be associated with an increased risk of atypical stress fractures. ¥ In patients other than neonates, ceftriax- Medsafe advises that the interruption of one and calcium-containing solutions bisphosphonate therapy in patients with may be administered sequentially to atypical stress fractures should only be one another if the infusion lines are considered following an individual risk- thoroughly flushed between infusions benefit assessment. with a compatible fluid.
References ¥ Diluents containing calcium, such as Ringer solution or Hartmann solution, 1. Kwek EB, Goh K, Koh JSB, Png MA et al. are not to be used to reconstitute An emerging pattern of subtrochanteric stress ceftriaxone vials or to further dilute a fractures: A long-term complication of alendro- reconstituted vial for intravenous admin- nate therapy. Injury 2008;39: 224Ð231. istration because a precipitate can form. 2. Lenart BA, Lorich DG, Lane JM. Atypical Ceftriaxone must not be administered fractures of the femoral diaphysis in post- simultaneously with calcium-containing menopausal women taking alendronate. New intravenous solutions, including continu- England Journal of Medicine 2008;358(12): ous calcium-containing infusions such 1304Ð6. as parenteral nutrition via a Y-site, because precipitation of ceftriaxone- 3. Neviaser AS, Lane JM, Lenart BA et al. Low calcium can occur. energy femoral shaft fractures associated with alendronate use. Journal of Orthopaedic Ceftriaxone is a long-acting broad spec- Trauma 2008;22:346Ð50. trum cephalosporin antibiotic for paren-
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teral use. Ceftriaxone is indicated for the initiated. Delay in stopping etravirine treatment of lower respiratory tract treatment after the onset of severe rash infections, urinary tract infections, bac- may result in a life-threatening reaction. terial septicaemia, skin and skin structure infections, bone and joint infections, intra- Cases within clinical and postmarketing abdominal infections, and meningitis experience illustrate the importance of when caused by susceptible organisms. vigilance and familiarity with the signs Ceftriaxone is also indicated for uncompli- and symptoms of severe skin rash and cated gonorrhoea and for prophylaxis of hypersensitivity reactions. In Phase III patients undergoing certain surgical clinical trials, Grade 3 and 4 rashes were procedures. reported in 1.3 % of subjects receiving etravirine compared to 0.2 % of placebo Reference: Health Advisory dated 15 October subjects. A total of 2 % of HIV-1-infected 2009 at http://hc-sc.gc.ca/dhp-mps/medeff/ patients receiving etravirine discontinued advisories-avis/prof/_2009/rituxan_5_hpc-cps- from Phase III trials due to rash. Rash eng.php occurred most commonly during the first six weeks of therapy. Etravirine: severe skin and Reference: Communication dated 15 October hypersensitivity reactions 2009 from Janssen-Ortho Inc. at http://hc- Canada — Healthcare professionals sc.gc.ca/dhp-mps/medeff/advisories-avis/ prof/_2009/rituxan_5_hpc-cps-eng.php have been informed of important safety information regarding severe skin reac- tions in patients receiving combination Oseltamivir phosphate: therapy including etravirine (Intelence¨) dosing risk tablets. Specifically, there have been postmarketing reports of severe hyper- Canada — The manufacturer of oselta- sensitivity reactions sometimes accompa- mivir (Tamiflu¨) has informed healthcare nied by hepatic failure, and a fatality due professionals of important dosing and to toxic epidermal necrolysis. administration information regarding powder for oral suspension. Severe, potentially life-threatening and Oseltamivir is a viral neuraminidase fatal skin reactions have been reported. inhibitor authorized for use in the treat- These include cases of Stevens-Johnson ment and prevention of uncomplicated syndrome, toxic epidermal necrolysis and acute illness due to influenza infection in erythema multiforme. Hypersensitivity adults and children above one year of reactions were characterized by rash, age who have been symptomatic for no constitutional findings, and sometimes more than two days or have come in organ dysfunction, including hepatic close contact with an infected individual. failure. Health Canada has also issued an Interim Order in July 2009 expanding use of Discontinue etravirine immediately if Tamiflu¨ as a treatment or prophylaxis for signs or symptoms of severe skin reac- children less than one year of age for tions or hypersensitivity reactions develop infection caused by the pandemic H1N1 (including severe rash or rash accompa- 2009 virus. nied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral When dispensing commercially manufac- lesions, conjunctivitis, facial oedema, tured oseltamivir powder for oral suspen- hepatitis, eosinophilia). Clinical status sion (12 mg/mL), pharmacists should including liver transaminases should be ensure that the units of measure on the monitored and appropriate therapy prescription instructions match the dosing
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device provided (e.g., a device graduated development of clinical conditions that in mg for a prescription in mg). can decrease plasma sodium may lead to a more profound and symptomatic Reference: Communication from the manu- reaction. facturer dated 13 October 2009 at http://hc- sc.gc.ca/dhp-mps/medeff/advisories-avis/prof Reference: Prescriber Update 2009;30(4):23 November 2009 at http://www.medsafe.nz Safety signal: hyponatraemia Clopidogrel and omeprazole: New Zealand — The Centre for Adverse Reactions Monitoring (CARM) has reduced effectiveness examined recent reports of hyponatrae- United States of America — The Food mia in its database. and Drug Administration (FDA) is alerting Hyponatraemia, defined as plasma healthcare professionals to new safety sodium < 135 mmol/L, is caused by a information concerning an interaction range of medicines and clinical condi- between clopidogrel (Plavix¨), an anti- tions. Medicine-related hyponatraemia clotting medication, and omeprazole occurs most often in the elderly early in (Prilosec/Prilosec OTC¨), a proton pump the course of treatment. The mechanism inhibitor (PPI). New data show that when is most often a syndrome of inappropriate clopidogrel and omeprazole are taken antidiuretic hormone secretion or renal together, the effectiveness of clopidogrel loss. is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to Medicines most often implicated in recent prevent blood clots will not get the full reports to CARM are selective serotonin effect of this medicine if they are also or noradrenaline reuptake inhibitors taking omeprazole. (SSRIs/SNRIs) and thiazide diuretics. Other medicines reported more than once Omeprazole inhibits the drug metaboliz- in 2007 and 2008 were anticancer ing enzyme CYP2C19 which is responsi- agents, proton pump inhibitors, sodium ble for the conversion of clopidogrel into valproate and ACE inhibitor/diuretic its active metabolite. New studies com- combinations. Carbamazepine has also pared the active metabolite and its effect been frequently implicated in the data- on platelets in clopidogrel plus ome- base. prazole versus clopidogrel alone. The effect of clopidogrel on platelets was Serious hyponatraemia (plasma sodium reduced by as much as 47% in people < 120 mmol/L) can lead to confusion, receiving clopidogrel and omeprazole convulsions and serious neurological together. damage. Examination of serious sympto- matic reports to CARM revealed that in Other drugs that are potent inhibitors of most cases more than one hyponatrae- the CYP2C19 enzyme would be expected mic medicine was implicated. The reports to have a similar effect and should be that CARM has received support current avoided in combination with clopidogrel. advice that plasma sodium should be These include: cimetidine, fluconazole, measured shortly after starting potentially ketoconazole, voriconazole, etravirine, hyponatraemic medicines, especially felbamate, fluoxetine, fluvoxamine, and SSRIs or diuretics. Measurements should ticlopidine. Since the level of inhibition be repeated both before and after adding among other PPIs varies, it is unknown to another hyponatraemic medicine. If there what extent other PPIs may interfere with is mild persistent hyponatraemia the clopidogrel. However, esomeprazole, a addition of further medicines or the PPI that is a component of omeprazole,
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inhibits CYP2C19 and should also be provided by Marketing Authorization avoided in combination with clopidogrel. Holders (experimental and preclinical studies, clinical trials, and postmarketing Separating the dose of clopidogrel and reports) and guidelines. The review also omeprazole in time will not reduce drug incorporated advice from a group of interaction. Other drugs to avoid in experts representing all areas of medicine combination with clopidogrel because where bisphosphonates are used, den- they may have a similar interaction tistry and bone surgery, and representa- include: esomeprazole, cimetidine, tives of patient organizations. fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvox- The European Medicines Agency’s amine, and ticlopidine. Committee for Medicinal Products for Human Use (CHMP) reached conclusions Reference: Food and Drug Administration, on four main areas: definition and diagno- Medwatch, 17 November 2009 at http:// sis of ONJ related to bisphosphonates, www.fda.gov/Drugs/Drug Safety possible underlying pathophysiological mechanism(s), risk stratification, and risk Bisphosphonates: minimization. osteonecrosis of the jaw A patient may be considered to have United Kingdom — The risk of osteo- ONJ related to bisphosphonates if all necrosis of the jaw is greater for patients of the following three characteristics receiving intravenous bisphosphonates are present: for cancer than for patients receiving oral bisphosphonates for osteoporosis or ¥ Exposed or necrotic bone in the maxillo- Paget disease. All patients with cancer facial region that has persisted for more should have a dental check-up before than 8 weeks. bisphosphonate treatment. During treat- ment, patients should be encouraged to ¥ No history of irradiation of the jaw. maintain good oral hygiene, receive routine dental check-ups, and report any ¥ Current or previous treatment with a oral symptoms such as dental mobility, bisphosphonate. pain, or swelling Reference: Medicines and Healthcare Individual bisphosphonates with different Products Regulatory Agency. Drug Safety indications can be used for: Update, Volume 3, Issue 4 November 2009 at http://www.mhra.gov.uk ¥ Prophylaxis and treatment of osteo- porosis. Intravenous promethazine: serious tissue injuries ¥ Treatment of Paget disease. New Zealand — Promethazine injection ¥ As a component of some cancer regi- is highly caustic to the intima of blood mens, particularly for metastatic bone vessels and surrounding tissues (1). cancer and multiple myeloma. Reports from the United States describe serious tissue reactions including throm- A Europe-wide review has been com- bosis, nerve damage, tissue necrosis and pleted on the risk of osteonecrosis of the gangrene in patients who have received jaw (ONJ) in association with the use of intravenous promethazine. In rare cases, bisphosphonates. The review included surgical intervention such as skin graft, data from the published literature, data fasciectomy or amputation has been
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required (1, 2). In New Zealand, prometh- ¥ Patients should be advised to seek azine injection is approved for the treat- medical assistance if pain, a burning ment of vomiting, allergic reactions sensation, swelling or blistering occurs (including anaphylaxis) and to induce at any time after the administration of sedation. intravenous promethazine.
After reviewing the published literature, The New Zealand data sheet for prometh- assessing New Zealand case reports, azine is currently being updated in line and consulting with healthcare profes- with this advice (4). sionals, Medsafe has concluded that there remains a clinical need for intrave- References nous promethazine in New Zealand. 1. Grissiner M. Preventing serious tissue injury However, Medsafe recommends that with intravenous promethazine (Phenergan¨). intravenous promethazine should only be P&T 2009;34(4):175-176. used if the benefits clearly outweigh the risks in each patient. This may include 2. FDA. Information for Health Professionals Ð emergency situations (such as treatment Intravenous Promethazine and Severe Tissue of anaphylaxis) or situations where Injury, Including Gangrene. 16 September intramuscular or oral administration is 2009 at http://www.fda.gov/Drugs. contraindicated. 3. Prescriber Update 2009;30(4):23 November To maximize safe use, Medsafe has 2009 at http://www.medsasfe.nz offered the following advice: 4. Data sheet at http://www.medsafe. co.nz/ profs/Datasheet/dsform.asp ¥ Deep intramuscular injection is the preferred route of administration of Cyproterone: risk promethazine injection. of meningiomas ¥ Promethazine must not be administered United Kingdom — Cyproterone acetate subcutaneously or intra-arterially. is a derivative of progesterone, and has progestagenic, antiandrogenic, and ¥ An alternative medicine should be antigonadotrophic effects. High-dose considered if intravenous administration preparations available in the UK include is required. Cyprostat-50¨ and Cyprostat-100¨, which are indicated for use in the treat- ¥ Promethazine should be administered ment of prostate cancer. Cyproterone through large patent veins. Veins in the acetate is also available as Androcur- hand and wrist should be avoided if 50¨, which is indicated for the control of possible (1). libido in men with severe hypersexuality or sexual deviation (or both). In some EU ¥ If intravenous administration is required, countries, Androcur-50¨ is used for the the maximum recommended concentra- treatment of androgenization in women. tion is 25 mg/mL and the maximum recommended rate of administration is Lower-dose cyproterone acetate is 25 mg/minute. Further dilution and available for use in women as co- administration over 10Ð15 minutes may cyprindiol (Dianette¨) in combination with reduce the risks even further (1). 35 micrograms ethinylestradiol for the treatment of severe acne that is refractory ¥ The injection should be stopped immedi- to prolonged antibiotic therapy, and for ately if pain or a burning sensation moderately severe hirsutism. occurs.
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Meningiomas are the most common 2. Froelich S et al. Endocrine Abstracts. intracranial tumours, with an annual Proceedings of the 10th European incidence of six per 100 000 in the Congress of Endocrinology; Berlin, general population. Multiple meningiomas Germany. 2008; 16:158. http://www. endocrineabstracts.org account for approximately 1Ð10 % of all cases. Though histologically benign, they 3. Drug Safety Update. Volume 3 Issue 3, can have serious consequences. The October 2009 at http://www.mhra.gov.uk/ potential role of sex hormones in the Publications/Safetyguidance/DrugSafety development of meningiomas has been Update/CON059804 postulated: approximately 70% of menin- giomas express progesterone receptors Gadolinium-containing and about 30% express oestrogen contrast agents receptors (1). The occurrence of (multi- ple) meningiomas has been reported in Euroean Union — The European Medi- association with longer-term use (years) cines Agency (EMEA) has adopted a set of cyproterone acetate at doses of 25 mg/ of recommendations aimed at minimizing day or higher. the risk of nephrogenic systemic fibrosis (NSF) with gadolinium-containing contrast Up to September 2009, 36 cases of agents in patients at risk of developing meningioma, of which 19 described the condition. multiple meningioma, have been reported worldwide in association with high-dose Gadolinium-containing contrast agents cyproterone acetate. Nine cases were are used in patients undergoing magnetic discussed in a published case series, (2) resonance imaging (MRI) or magnetic and 27 cases are unpublished case resonance angiography (MRA) scans. reports. Duration of treatment with cypro- The Agency’s Committee for Medicinal terone acetate ranged from 4 to 27 years Products for Human Use (CHMP) re- and in all but one case it was prescribed viewed these agents because of the at doses higher than 25 mg per day. association between the use of gado- Thirty-one of the cases were from France linium-containing contrast agents and (which compared with other countries has NSF, a rare, serious and sometimes life- extensive use of high-dose cyproterone threatening condition that is characterized acetate). None of the reported cases had by formation of connective tissues in the a fatal outcome. skin, joints, muscles and internal organs, in patients with severe kidney problems. Advice for healthcare professionals: Based on currently available data, and ¥ Patients with existing meningioma or a with risk minimization measures in place, history of meningioma must not be the CHMP considers that the balance of prescribed cyproterone acetate at doses benefits and risks of these agents is of 25 mg per day or higher. acceptable. ¥ This advice does not apply to medicines References that contain low-dose cyproterone acetate such as co-cyprindiol 1. European Medicines Agency makes (Dianette¨). recommendations to minimise risk of nephro- genic systemic fibrosis with gadolinium- References containing contrast agents. Press Release, 1. Blitshteyn S et al. J Clin Oncol 2008; 26: Doc. Ref. EMEA/CHMP/739818/2009, 20 279Ð82. November 2009 at www.emea.europa.eu
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2. Question-and-answer document
290 WHO Drug Information Vol. 23, No. 4, 2009 Safety and Efficacy Issues drug is ceased. The half life of antide- Zanamivir inhalation powder pressants varies substantially from about must not be nebulized two hours for citalopram and moclobe- mide and up to six days or more for Singapore — Healthcare professionals fluoxetine, while the effect of irreversible have been informed of the death of a MAOIs such as phenelzine can persist for patient with influenza who received several weeks after the drug has been zanamivir (Relenza¨) inhalation powder ceased. which was solubilized and administered by mechanical ventilation. The death was There are no set guidelines on switching attributed to obstruction of the ventilator amongst antidepressants and factors that which could have been due to lactose in should be considered will vary depending the formulation causing stickiness when on the properties of the antidepressants the powder is mixed with the nebulizing and the patient’s situation including the solution. duration of time the patient has been on the first antidepressant, patient age, other The manufacturer wishes to highlight to medications and other health issues healthcare professionals that Relenza¨ (5,6). Inhalation Powder is not intended for reconstitution in any liquid formulation Useful information on antidepressant-free and is not recommended for use in any intervals when changing from one antide- nebulizer or mechanical ventilator. Zan- pressant to another is available in the amivir for nebulization has not been Therapeutic Guidelines — Psychotropic approved by any regulatory authority and Medicines and in the Australian Medi- the safety, effectiveness and stability of cines Handbook (5,6). zanamivir use by nebulization have not been established. Extracted from the Australian Adverse Drug Reactions Bulletin, Volume 28, Reference: Health Sciences Authority (HSA). Number 5, October 2009. 14 October 2009. http://www.hsa.gov.sg/ publish/hsaportal/en/health_products_ References regulation/safety_information/DHCPL.html 1. ADRAC. Serotonin syndrome. Aust Adv Pandemrix®: risk of fever Drug Reactions Bull 2004; 23(1). European Union — The European 2. ADRAC. Tramadol and serotonin syndrome. Medicines Agency (EMEA) is warning that Aust Adv Drug Reactions Bull 2001; 20(4). young children may experience fever after their second dose of the pandemic 3. ADRAC. Serotonin syndrome with influenza vaccine Pandemrix.¨. Prescrib- duloxetine. Aust Adv Drug Reactions Bull 2009; 28(4). ers and parents should monitor the temperature of the vaccinated child and, if 4. Isbister G, Buckley N, Whyte I. Serotonin necessary, take measures to lower the toxicity: A practical approach to diagnosis and fever (e.g., giving an antipyretic such as treatment. MJA 2007;187: 361-365. paracetamol). However, the Agency noted that the second dose increases the 5. Changing Antidepressants. Australian immune response against pandemic Medicines Handbook 2007, p 714. influenza.
6. Therapeutic Guidelines. Psychotropic. The Agency has recommended that this Version 6, 2008, pp 112-113. information be included in the prescribing
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information, and be taken into considera- antivirals in the European Union and tion when deciding whether to give a complement the information the Agency second dose to children. has been publishing regularly on the development and approval of medicines Reference: EMEA Press Release, Doc. Ref. for use during the pandemic. EMEA/784404/2009 4 December 2009 at http://www.emea.europa.eu/ This information will support European institutions and Member States in their Weekly pandemic communications, and provide an addi- pharmacovigilance updates tional resource when recommending the use of vaccines and antiviral treatments. European Union — The European Medicines Agency (EMEA) has published The information on adverse reactions in the first in a series of weekly pandemic the update comes from EudraVigilance, pharmacovigilance updates. the central European database on ad- verse reactions, managed by the Agency. These weekly bulletins will provide information on adverse reactions reported Reference: EMEA Press Release, Doc. Ref. after the use of centrally authorized EMEA/775140/2009 3 December 2009 at pandemic influenza vaccines and http://www.emea.europa.eu/
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Biomedicines and Vaccines
International biological countries — have limited access to such standards: 2009 update medicines. The expiration of patents and/ or data protection for the first major group Innovation in biological medicines is of innovative biotherapeutics is ushering occurring in more countries than ever in an era of products “similar” to the before. In addition, the supply chain for originals, with the potential to significantly biological medicines is increasingly enhance accessibility. The guidance complex and international in nature. developed by WHO on appropriate Despite technological advances, control- regulation of this new class of products is ling the quality, safety and efficacy of in response to requests from many biologicals remains difficult and highly developing countries. specialized. Therefore, strengthening biological standardization and its imple- Revised WHO recommendations for the mentation, in particular in emerging production and control of live attenuated economies, remains a fundamental influenza vaccine were established by the function for WHO. The aim is to provide Expert Committee. The purpose of these tools that will translate into appropriate recommendations is to provide vaccine oversight of new biologicals of potential manufacturers and national regulatory public health benefit or oversight of authorities with guidance that can be biological components in the supply applied in developing specific processes chain. Developing standards for quality, for the production and control of human, and associated reference materials live attenuated influenza vaccines. These through its Expert Committees and Expert recommendations are also intended to Advisory Panels is a key priority for WHO. provide guidance on the nonclinical and clinical evaluation of influenza vaccines The Expert Committee on Biological and apply to the production and control of Standardization advises WHO on inter- influenza vaccines using embryonated national biological standardization and hen’s eggs as substrates. The future key developments affecting the quality, possibility to produce human, live attenu- safety and efficacy of vaccines, biological ated influenza vaccines using cell cul- therapeutics, blood products and biologi- tures as substrates is anticipated and, cal diagnostics. The Expert Committee therefore, guidance is also provided for met in Geneva from 19Ð23 October 2009 this eventuality. The recommendations to enable WHO to fulfil one of its constitu- with possible modifications apply to tional responsibilities to “Develop, estab- human, live attenuated influenza vaccines lish and promote international standards produced with seasonal vaccine strains for biological products”. for use during the interpandemic period as well as vaccines produced with strains During its meeting, the Expert Committee for use during pandemics. established new WHO guidelines on the regulatory evaluation of “similar biothera- Infections caused by Streptococcus peutic medicines”. These products have a pneumoniae are responsible for substan- successful record in treating many life- tial morbidity and mortality, particularly in threatening and chronic diseases. How- the very young and elderly. Pneumococci ever, patients — particularly in developing are grouped into many serotypes (~ 91)
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on the basis of their chemically and nated control group. The recommenda- serologically distinct capsular poly- tions discussed the design of immuno- saccharides. Certain serotypes are much genicity studies to support licensure of more likely than others to be associated new pneumococcal conjugate vaccines with clinically apparent infections, to (including those containing conjugated cause severe invasive infections and to capsular polysaccharides of serotypes acquire resistance to one or more classes additional to those in the 7vPnC vaccine) of antibacterial agents. The development intended to prevent IPD and for adminis- of pneumococcal conjugate vaccines in tration to children aged less than 2 years. which each of the selected bacterial It was considered essential that the capsular polysaccharides is coupled with immunogenicity studies with a new a protein carrier molecule has been a pneumococcal conjugate vaccine should major advance in the prevention of provide a link back to the vaccine efficacy invasive pneumococcal disease (IPD). against IPD that was demonstrated for the 7vPnC vaccine. Since 2006, WHO has recommended that all countries should incorporate pneumo- Therefore, it was recommended that coccal conjugate vaccines in routine immune responses to each serotype in immunization schedules for children less the 7vPnC vaccine that is also included in than 2 years of age with prioritization of a new pneumococcal conjugate vaccine their introduction in countries with high should be directly compared in random- child mortality rates and/or high rates of ized clinical studies and that the primary HIV infection. A 7-valent pneumococcal comparison of immune responses should conjugate vaccine (7vPnC) that employs be based on serotype-specific IgG CRM197 as the carrier protein for all antibody concentrations measured by seven serotypes was the first to be enzyme-linked immuno-sorbant assay developed. This vaccine was licensed in (ELISA). In order to facilitate these the USA in 2000 and subsequently has comparisons a WHO reference ELISA become available in approximately 90 assay was established that includes pre- countries worldwide. Pneumococcal adsorption of sera with pneumococcal C conjugate vaccines that contain three or polysaccharide (C-PS) and serotype 22F six serotypes in addition to those in the polysaccharide. 7vPnC vaccine have recently become available in some countries. The 10- Prompted by issues raised during the valent vaccine includes tetanus toxoid, development of newer pneumococcal diphtheria toxoid or a novel protein conjugate vaccines since the publication derived from nontypable Haemophilus of the WHO 2003 recommendations (1), influenzae (protein D) as the carrier WHO held a consultation in 2008 to proteins while the 13-valent vaccine uses consider new scientific evidence and to only CRM197 as the carrier protein. discuss the need to provide revised guidance for manufacturers and licensing WHO recommendations for pneumo- authorities. The Expert Committee on coccal conjugate vaccine production and Biological Standardization has estab- control were first established in 2003 (1). lished a revised document that has been Since the 7vPnC vaccine was already developed to take into account the most approved in many countries, it was recent developments (2). considered unethical to assess the protective efficacy of future pneumococ- The Expert Committee also reviewed cal conjugate vaccines in infants and proposals to establish 24 new or replace- toddlers in comparison to an unvacci- ment reference preparations as WHO
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International Standards. International were also adopted this year. These standards and biological reference preparations are expected to be widely preparations for use in the quality and used by regulators, manufacturers and safety control of biological products and blood establishments worldwide and will in vitro diagnostic devices are submitted support international regulations for blood to the Expert Committee following valida- products and the safety of blood products tion of candidate preparations in global, (2). coordinated studies. References Among the proposals, a reference panel covering the most prevalent hepatitis B 1. World Health Organization. Expert Commit- genotypes worldwide was adopted to tee on Biological Standardization. Technical facilitate improvement of the quality of Report Series, No. 927, annex 2 (2003). hepatitis B diagnostic devices and the 2. Expert Committee on Biological Standardi- traceability of test results between coun- zation: written standards and reference tries. Other reference materials for the preparations; interim report. http://www. control of the potency of blood products who.int/biologicals. and the diagnosis of genetic diseases
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International Harmonization
ICH Implementation: ¥ Final status after partial implementation Quality Working Groups is established (level of details in the dossier). In Brussels 2003, a new quality vision was agreed by parties of the International Additional implementation issues Conference on Harmonization (ICH) (1). This emphasized a risk and science- ¥ Influence on existing ICH guidelines. based approach to pharmaceuticals in an adequately implemented quality system. Communication and training As a consequence, the guidelines on Pharmaceutical Development (Q8), ¥ Questions and Answers, ICH briefing Quality Risk Management (Q9) and packs. Pharmaceutical Quality System (Q10) were drafted. ¥ External collaboration. ¥ Workshops. These concepts and principles depart from the traditional approaches to quality The aim of the ICH Quality Implementa- guidance, mainly based on end-product tion Working Group (Q-IWG) is to provide testing. Since it is important that proper enhanced harmonized implementation implementation is strenghtened by training to industry and regulators in the clarifying, explaining and removing three ICH regions. In addition, the group ambiguities and uncertainties, an ICH can offer opportunities to train colleagues Implementation Working Group (IWG) on in non-ICH regions. The newly designed ICH Q8, Q9 and Q10 has been formed standards workshop is planned to be and met during the recent ICH meeting conducted by those ICH experts who held in Yokohama in June 2009. The IWG developed the ICH Q8, Q9 and Q10 is drawn from the six member parties of guidelines and members of the ICH. the ICH: industry and medicines regula- These are intended to be the only work- tory authorities of the European Union, shops reviewed and referenced by the Q- Japan and United States of America (up IWG and will be conducted by the same to three experts per party). Observers to faculty in all three ICH regions. the ICH are allowed one expert and Interested Parties one expert each. The Training will cover the integrated use of IWGs focus on the following issues: ICH Q8, Q9 and Q10 guidelines and Q&A (question and answers) across the Technical issues and related product life-cycle, from development to documentation manufacturing and commercialization. Unlike other conferences and workshops ¥ Common understanding of terminology. on these topics, training will present a ¥ Interrelationship between Q8, Q9 and case study throughout the entire life-cycle Q10. from development to manufacturing and commercialization. Regulatory assess- ¥ Applicability to both review and inspec- ment and GMP inspection implementation tion. aspects will be discussed. Furthermore,
296 WHO Drug Information Vol. 23, No. 4, 2009 International Harmonization
Status of additional ICH questions & answers (Supplementary table)
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 3 Knowledge Management 4 1 Software solution 1
Total 41 10 11 learning opportunities will be provided for demonstrated that there is a large amount participants to practise in small groups of publications and workshops available the necessary skills for implementation of covering ICH Q 8, Q9 and Q 10. The final the guidelines. consensus was that the Q-IWG should initiate, encourage and collaborate in the Workshop deliverables will include development of articles consistent with materials to support understanding of Q8, Q9, Q10 guidelines and the recently integrated use of the concepts described developed Questions and Answers. in ICH Q8, Q9 and Q10 guidelines. These materials will be used by both regulators Reference: ICH information available at and industry to implement the three http://www.ich.org guidelines in their organizations. If the ICH Global Cooperation Group ICH Pharmacopoeial (GCG) is organizing workshops outside an ICH region the Q-IWG will provide Discussion Group structure and content of the workshops. If The Pharmacopoeial Discussion Group WHO is organizing workshops, the Q- (PDG) [European Pharmacopoeia IWG can provide support. (PhEur), Japanese Pharmacopoeia (JP) and United States Pharmacopeia (USP)] The IWG is also looking into the availabil- met in association with the Expert Work- ity of illustrative examples and case ing Groups of the International Confer- studies relevant to harmonized and ence on Harmonization (ICH), 8Ð12 June consistent implementation. The initial goal 2009 in Yokohama, Japan. The World was to reference existing material and Health Organization attended in its official develop examples and position papers. capacity as observer. A survey of conferences, publications and Discussion focused on Q4B Evaluation presentations has been carried out over and Recommendation of Pharmacopoeial the past six months. As a result, a list of Texts for Use in the ICH Regions. relevant topics and activities was identi- The ICH Q4B guideline was finalized fied together with an analysis of specific (Step 4) on 1 November 2007. needs for additional work. The review
297 International Harmonization WHO Drug Information Vol. 23, No. 4, 2009
This document describes a process for ¥ Sterility Test General Chapter (ICH Q4B the evaluation and recommendation by Annex 8, includes English JP text) the Q4B Expert Working Group (EWG) of selected pharmacopoeial texts to facilitate ¥ Tablet Friability General Chapter (ICH their recognition by regulatory authorities Q4B Annex 9) for use as interchangeable texts in the ¥ Polyacrylamide Gel Electrophoresis ICH regions. Following favourable evalua- General Chapter (ICH Q4B Annex 10). tions, ICH will issue topic-specific an- nexes with information about these texts ICH Q4B Annexes 1Ð5 and 8 have been and their implementation (the Q4B signed off as ICH step 4 documents. Outcomes). Implementation of the Q4B Annexes 6 and 7 are pending feedback annexes is intended to avoid redundant from PDG. Annex 9 and 10 are at the testing by industry. Step 2 stage.
Harmonization has been achieved by the PDG is working on the following general PDG on nine of the ten General Chapters chapters within the harmonization proc- identified by the ICH Q6A Guideline. ess and they will be submitted for ICH From those, eight have been evaluated in Q4B evaluation upon final PDG sign off addition to two newly harmonized texts by as being harmonized: the ICH Q4B Working Group as follows: ¥ Bulk and Tapped Density of Powders ¥ Residue on Ignition/Sulphated Ash General Chapter (ICH Q4B Annex 1) ¥ Analytical Sieving ¥ Test for Extractable Volume of ¥ Capillary Electrophoresis Parenteral Preparations General Chap- ¥ Bacterial Endotoxin Test ter (ICH Q4B Annex 2) ¥ Colour Test (new method being re- ¥ Test for Particulate Contamination: Sub- viewed). Visible Particles General Chapter (ICH Q4B Annex 3, includes English JP text) Moreover, 26 of the 34 General Chapters ¥ Microbial Enumeration Tests General and 40 of the 63 excipient monographs Chapter (ICH Q4B Annex 4A) have been harmonized by PDG. In the course of indicating the harmonization ¥ Tests for Specified Micro-organisms statement in the three ICH General Chapter (ICH Q4B Annex 4B) pharmacopoeias, PDG has reviewed ¥ Acceptance Criteria for Pharmaceutical seven excipient monograph texts and Preparations and Substances for identified typical discrepancies. A path to Pharmaceutical Use General Chapter resolution has also been agreed that will (ICH Q4B Annex 4C) facilitate further harmonization projects. ¥ Disintegration Test (ICH Q4B Annex 5, The possible implementation of these includes English JP text) harmonized texts within the revision process of The International Pharmaco- ¥ Uniformity of Dosage Units General poeia will be reviewed by the forthcoming Chapter (ICH Q4B Annex 6) Forty-fourth WHO Expert Committee on ¥ Dissolution Test General Chapter (ICH Specifications for Pharmaceutical Prepa- Q4B Annex 7) rations.
298 WHO Drug Information Vol. 23, No. 4, 2009 International Harmonization
Background: The International programmes and the essential medicines Pharmacopoeia nominated under these programmes; it is The International Pharmacopoeia com- based primarily on those substances prises a collection of quality specifications included in the current WHO Model List of for pharmaceutical substances (active Essential Medicines. ingredients and excipients) and dosage forms together with supporting general Work on The International Pharmaco- methods of analysis intended to serve as poeia is carried out in collaboration with source material for reference or adapta- members of the WHO Expert Advisory tion by any WHO Member State wishing Panel on the International Pharmaco- to establish pharmaceutical requirements. poeia and Pharmaceutical Preparations The International Pharmacopoeia, or any and with other specialists. The process part of it, may have legal status whenever involves consultation of and input from a national or regional authority expressly WHO Member States and drug regulatory introduces it into appropriate legislation. authorities, WHO Collaborating Centres and national drug quality control laborato- Activities related to The International ries in all six WHO regions, standard- Pharmacopoeia are an essential element setting organizations and parties, includ- in the overall quality control and assur- ing regional and national pharmaco- ance of pharmaceuticals contributing to poeias and with manufacturers around the safety and efficacy of medicines. The the world. Clearly defined steps are selection of monographs for inclusion in followed in the development of new The International Pharmacopoeia recog- monographs. nizes the needs of specific disease
299 WHO Drug Information Vol. 23, No. 4, 2009
Prequalification of Medicines Programme
Prequalification of quality identifies which quality control laborato- ries should be given priority based on control laboratories need. Increased availability and supply of good Participation in the prequalification quality essential medicines for countries process is described in Procedures for is an important component of the United assessing the acceptability, in principle, of Nations Millennium Development Goals. quality control laboratories for use by Unfortunately, several international United Nations agencies (2). For the time funders and suppliers of essential medi- being, applying for and participation in the cines have faced difficulty in monitoring prequalification procedure is free of the quality of supplies in countries be- charge. However, the procedure also cause of a lack of fully operational medi- enables WHO to charge for the assess- cines quality control laboratories. ment of laboratories on a cost-recovery basis if the prequalification process is no Given this situation, international donors longer funded by donors. and suppliers often preferred to have local medicine samples sent for analysis WHO assesses quality control laborato- in quality control laboratories situated in ries through evaluation of preliminary Europe or North America. Such practices information submitted by a laboratory and do not support sustainable development on-site inspection to assess compliance goals and are counter productive in with the WHO guidelines on Good Prac- building national capacity. tices for National Pharmaceutical Control Laboratories (3) and Good Manufacturing In collaboration with UNAIDS, UNICEF, Practices (4). These and other related UNFPA, the Global Fund, UNITAID, with guidelines are published on the Prequali- support from the World Bank, WHO has fication Programme’s web site (5). Inter- set up a process to prequalify quality national Standard Organization (ISO) control laboratories that meet recom- certification (ISO/IEC 17025) is also mended international norms and stand- encouraged. If assessment demonstrates ards for the analysis of medicines pre- that a laboratory meets WHO recom- qualified or being considered for prequali- mended standards, it is included in the fication by WHO. official List of WHO Prequalified Quality Control Laboratories that is considered As a first step, WHO has invited quality acceptable for use by United Nations control laboratories in Africa to take part agencies or other interested parties (6). in the process. Laboratories were chosen based on their commitment to provide Once a laboratory is included in the WHO testing of pharmaceutical products for List of Prequalified Quality Control Labo- HIV/AIDS, tuberculosis and malaria (1). In ratories, ongoing monitoring of its activi- September 2007, the scope of the proce- ties is performed. This includes re- dure was extended and currently invita- inspection at regular intervals, evaluation tions are open to quality control laborato- of results from participation in an appro- ries in any region worldwide. WHO priate proficiency testing scheme, and manages the assessment process and monitoring and investigation of any
300 WHO Drug Information Vol. 23, No. 4, 2009 Prequalification of Medicines Programme
Country Region Number of prequalified laboratories
Algeria Africa 1 France Europe 1 India South-East Asia 1 Kenya Africa 2 Morocco Eastern Mediterranean 1 Singapore Western Pacific 2 South Africa Africa 2 Vietnam Western Pacific 1 complaints concerning results of analysis Update on progress or other service provided by the listed As of October 2009, eleven laboratories laboratories. To facilitate monitoring, each have been prequalified by WHO. Five prequalified laboratory is requested to prequalified laboratories are located in submit a brief annual report on its activi- the WHO Africa Region, three in the ties. An outline of the expected content of Western Pacific Region and one in each an annual report is available on the WHO of the three regions: Eastern Mediterra- web site (7). nean Region, Europe Region and South- east Asia Region. Apart from these A laboratory will be removed from the list eleven prequalified laboratories, there are if it is found that it no longer complies with twenty-four quality control laboratories the specified standards. participating in the procedure (See Table
Table 1. Prequalification of quality control laboratories
QCLs Prequalified QCLs Participating
301 Prequalification of Medicines Programme WHO Drug Information Vol. 23, No. 4, 2009
1). The majority of participating laborato- inspector appointed by WHO from a ries (26 of 35) are national quality control member inspectorate of the Pharmaceu- laboratories. tical Inspection Cooperation Scheme (PIC/S). An inspector (or inspectors) from As part of the capacity building compo- the national medicines regulatory author- nent of the WHO Prequalification of ity of the country in which the laboratory Medicines Programme, national quality is located is invited to participate as an control laboratories participating in the observer. Prequalified laboratories are re- prequalification procedure are provided, if inspected on a regular basis, usually needed, with technical assistance in the every two to three years. Fourteen quality form of a pre-audit or 1Ð3 week visit of an control laboratory inspections were expert to the laboratory. The Programme carried out between March 2004 and also organizes training for national quality September 2009. control laboratories and laboratories providing testing services to the govern- Over the years, the main observations of ment in the respective country. non-compliance during inspections include the following: Inspections An inspection team is composed of a 1. System of reference substances was WHO prequalification inspector and a co- insufficient in that:
Figure 1. Cumulative number of critical observations from 14 inspections
0123 4 Criteria*
1. Organization and management 2. Quality system 3. Control of documents 4. Records 5. Data processsing equipment 6. Personnel 7. Premises 8. Equiment, instruments and other devices 9. Specifications archiv 10. Reagents 11. Reference materials 12. Calibration, validation & verification of equipment, instruments & other devices 13. Traceability 14. Incoming samples 15. Analytical worksheet 16. Testing 17. Evaluation of test results 18. Retained samples 19. Safety
* Refers to sections of WHO Good Practices for National Pharmaceutical Control Laboratories
302 WHO Drug Information Vol. 23, No. 4, 2009 Prequalification of Medicines Programme
Figure 2. Cumulative number of major observations from 14 inspections
024681012141618 Criteria* 1. Organization and management 2. Quality system 3. Control of documents 4. Records 5. Data processsing equipment 6. Personnel 7. Premises 8. Equiment, instruments and other devices 9. Specifications archive 10. Reagents 11. Reference materials 12. Calibration, validation & verification of equipment, instruments & other devices 13. Traceability 14. Incoming samples 15. Analytical worksheet 16. Testing 17. Evaluation of test results 18. Retained samples 19. Safety
* Refers to sections of WHO Good Practices for National Pharmaceutical Control Laboratories
¥ Authorized written standard operating 2. Stocks of reagents and retention procedures for handling reference samples were not maintained under substances were not available, i.e., appropriate storage conditions.
- packing of working reference 3. The training system was insufficient in substances that:
- labelling of working reference ¥ Authorized written standard operating substances procedures for training were unavail- able. - acceptance criteria for working ¥ Training was not appropriately docu- substances mented and assessed.
¥ Inappropriate labelling of working 4. Authorized written standard operating standards procedures for internal audits were not available. ¥ Use of reference substances was not documented
303 Prequalification Programme WHO Drug Information Vol. 23, No. 4, 2009
5. Reagents were not managed properly References in that: 1. World Health Organization. Prequalification ¥ Labels of some reagents did not specify of Medicines Programme. http://www.who. int/ shelf-life. prequal/info_applicants/eoi/EOI- QCLabsV3.pdf
¥ Certificates of analysis were not avail- 2. World Health Organization. Expert Commit- able for all reagents. tee on Specifications for Pharmaceutical Preparations. Annex 5: Prequalification of ¥ Reagents were not properly labelled. quality control laboratories. Procedure for assessing the acceptability, in principle, of 6. Responsibilities, competencies and quality control laboratories for use by United functions were not clearly defined in Nations agencies. Technical Report Series, current job descriptions. No. 943 (2007) at http://www.who.int/prequal/ info_general/documents/TRS943/ 7. Computer software developed by the TRS943.pdf#page=111 users was not appropriately validated or 3. World Health Organization. Expert Commit- verified. Procedures were not established tee on Specifications for Pharmaceutical and implemented for protecting the Preparations. Annex 3: Good Practices for integrity of data. National Pharmaceutical Control Laborato- ries. Technical Report Series, No. 902 (2002). 8. Authorized written standard operating at http://www.who.int/prequal/info_general/ procedures for the calibration of critical documents/TRS902/WHO_TRS_ equipment were not available, i.e., HPLC, 902.pdf#page=37 GC, dissolution and disintegration instru- ments. Equipment calibration and mainte- 4. World Health Organization. Quality Assur- ance of pharmaceuticals. A compendium of nance schedules were not available. guidelines and related materials. Volume 2, Equipment not regularly qualified; IQ, OQ Second updated edition. Good manufacturing and prequalification protocols/reports were practices and inspection (2007). at http:// not available www.who.int/medicines/areas/quality_safety/ quality_assurance/production/en/index.html 9. Validation of microbiological laboratory autoclave was not conducted in accord- 5. World Health Organization. Prequalification ance with current guidelines. of Medicines Programme. http://www.who.int/ prequal/info_applicants/qclabs/ 10. Pharmacopoeial test methods were prequal_quality_control_labs.htm not verified. 6. World Health Organization. Prequalification of Medicines Programme. http://www.who.int/ 11. Out-of-specifications were not re- prequal/lists/PQ_QCLabsList.pdf corded and handled properly. 7. World Health Organization. Prequalification of Medicines Programme. http://www.who.int/ prequal/info_applicants/qclabs/Annual- Report_Labs.pdf
304 WHO Drug Information Vol. 23, No. 4, 2009
Pharmacovigilance Focus
A/H1N1 vaccination safety: In an emergency situation, where the PaniFlow® surveillance tool priority has been to secure supplies of vaccines and get them widely distributed, PaniFlow¨ is a new software tool for safety surveillance can sometimes take reporting adverse events following second place. As a result of multiple immunization which is now being offered variables and uncertainties only compre- free to a number of countries in a joint hensive monitoring on a global scale can Uppsala Monitoring Centre (UMC)/ World reveal the true, detailed picture of the Health Organization (WHO) initiative. impact of vaccination on individual patients and on public health. This is In response to A/H1N1 pandemic influ- important also in a situation where safety enza and plans for vaccination of large concerns have been publicly expressed populations, safety issues are a prime and/or the credibility of A/H1N1 vaccina- concern. Most developed countries tion challenged. already have well-established systems for monitoring the safety of vaccination PaniFlow¨ is based on VigiFlow¨, which programmes and detecting problems. is the programme used throughout the world by many members of the WHO PaniFlow¨ is a web-based data manage- Programme for International Drug Moni- ment software which allows vaccination toring for managing and reporting programme staff to record all adverse adverse drug reactions. It is based on the events as they occur from any location software originally developed jointly by with an Internet connection. This ensures the Swiss national drug regulatory author- continued reporting, even when infra- ity, Swissmedic, and UMC for use in structure, like regular mail, is disrupted. Switzerland. Both programmes are Cumulative data is immediately available uniquely designed to meet the needs of locally, nationally, and to the UMC where healthcare personnel and serve the international patterns of events can be interests of patient safety. While some analysed and shared. Data can also be training to use the programmes is incorporated into the international WHO needed, their user friendliness has been Global Individual Case Safety Report progressively improved and data entry database (VigiBase¨) managed by UMC. itself is a simple task. The software has search and analysis tools which permit issues and problems to The first countries being offered free use be examined in all relevant parameters. of PaniFlow¨ by UMC are: Croatia, Lithuania, Morocco, Serbia, Sierra Leone, Individual countries can quickly detect Togo and Turkey. All are countries with a potential safety problems in their own track-record of reporting adverse events populations and take remedial action if following immunization and are familiar causality is established. At UMC, the with using VigiFlow¨. global picture can be rapidly reviewed and the international community alerted Reference: Uppsala Monitoring Centre at when problems are suspected or con- http://www.who-umc.org firmed.
305 WHO Drug Information Vol. 23, No. 4, 2009
Regulatory Action and News
Influenza vaccines for 2010 lasted a median of 15 months in one southern hemisphere winter study and 11 months in the other study. Six per cent of those studied had com- World Health Organization — It is plete responses, indicating no apparent recommended that vaccines for use in the evidence of the tumour on physical, 2010 influenza season (southern hemi- laboratory, and X-ray examination. sphere winter) contain the following: Common side effects include nausea, ¥ an A/California/7/2009 (H1N1)-like virus fatigue, infections, vomiting, decreased appetite, decreased red blood cell count, ¥ an A/Perth/16/2009 (H3N2)-like virus decreased platelet count, and decreases in the components of white blood cells. ¥ a B/Brisbane/60/2008-like virus. Romidepsin may cause changes in an Reference: Weekly Epidemiological Record, electrocardiogram (ECG). Periodic blood No. 41, 2009, 84, 421Ð436 at http://www.who. int/wer tests should be carried out to monitor electrolytes, and periodic ECG monitoring should be considered in patients at risk Romidepsin: approved for for certain heart rhythm abnormalities. cutaneous T-cell lymphoma Romidepsin may harm the fetus and women should not become pregnant United States of America — The Food while taking the drug. and Drug Administration (FDA) has approved romidepsin (Istodax¨), an Reference: FDA News Release, 9 November injectable, for treatment of patients with 2009 at http://www.fda.gov cutaneous T-cell lymphoma (CTCL). Orciprenaline sulphate: Cutaneous T-cell lymphoma is a slow- withdrawal growing cancer of T-lymphocytes. Most cases start with dry skin, red rash, and United Kingdom — Orciprenaline severe itching. The skin may develop sulphate (Alupent¨) is to be withdrawn tumours that can become ulcerated, over the next year because a review has causing infection. In some cases, CTCL concluded that the benefit-risk profile is spreads to the blood, lymph nodes, or unfavourable. Patients who require a internal organs. Patients with localized liquid oral formulation of a β-agonist CTCL on the skin are treated with topical should be switched to a more-selective agents or phototherapy, but chemo- short-acting β2-agonist such as salbuta- therapy may be used if the cancer ad- mol or terbutaline vances. Romidepsin interferes with processes required for cell replication. Orciprenaline sulphate (Alupent¨) is a non-specific β-agonist indicated for Romidepsin evaluation was based on two reversible airways obstruction and sug- clinical studies involving 167 patients. gested for maintenance therapy. It is About 35% of patients in both of the trials currently available for oral administration experienced tumour responses which as a syrup.
306 WHO Drug Information Vol. 23, No. 4, 2009 Regulatory Action and News
An analysis of the available literature has Vitespen: withdrawal of demonstrated that orciprenaline sulphate marketing authorization is significantly less efficacious than salbutamol in terms of both the extent application and duration of bronchodilation. Reports European Union — The European and clinical trial data show a significantly Medicines Agency (EMEA) has been increased incidence of cardiac side formally notified by the manufacturer of its effects, mainly palpitations and tachycar- decision to withdraw an application for a dia because of its non-selectivity. Impor- centralized marketing authorization for tantly, clinical trial data show that the medicine vitespen (Oncophage¨), cardiac side effects occur before maxi- 20 µg solution for infusion. mum bronchodilation is achieved be- cause of its non-selectivity. Vitespen was expected to be used as an adjuvant treatment for localized renal cell Accordingly, the Commission on Human carcinoma patients but received a nega- Medicines (CHM) has advised that the tive opinion from the Committee for balance of benefit and risks for orcipren- Medicinal Products for Human Use aline sulphate is no longer favourable and (CHMP) on 19 November 2009. concluded that: Reference: EMEA Press Release, Doc. Ref. ¥ There should be a planned withdrawal EMEA/763056/2009, 26 October 2009. http:// of orciprenaline sulphate from the UK www.emea.europa.eu market. ¥ There are no patient groups for whom Aripiprazole: withdrawal of application for extension transfer to a more-selective β2-agonist would be inappropriate. of indication
Reference: Medicines and Healthcare European Union — The European Products Regulatory Agency. http:// Medicines Agency (EMEA) has been www.mhra.gov.uk/safety information/ notified by the manufacturer of its deci- sion to withdraw an application for an Artemisinin antimalarials: extension of indication for the centrally not for use as monotherapy authorized medicine aripiprazole (Abilify¨) tablets, orodispersible tablets Mozambique — The risks of therapeutic and oral solution. failure and cases of resistance to artem- isinin-derived antimalarials are elevated Aripiprazole was expected to be used in when used as monotherapy. In order to the treatment of major depressive epi- comply with World Health Organization sodes, as adjunctive therapy, in patients recommendations, the Ministry of Health who have had an inadequate response to has determined that circulation in the previous treatment with antidepressants. national market of all artemisinin derived antimalarial medicines for use as mono- The company stated in its official letter therapy in oral administration is no longer that the withdrawal was based on the permitted. CHMP’s consideration that the long-term data provided in support of the proposed Reference: Communication from Ministry of indication were insufficient, as long-term Health, Maputo, Mozambique. Presidential randomized controlled data are needed Decree no. 11/95. 4 November 2009 before this indication can be licensed.
307 Regulatory Action and News WHO Drug Information Vol. 23, No. 4, 2009
Reference: EMEA Press Release, Doc. Ref. Reference: USAID, 26 October 2009 at http:// EMEA/749487/2009 19 November 2009 at www.usaid.gov http://www.emea.europa.eu Vandetinib: withdrawal of Substandard and counterfeit marketing authorization medicines: USAID–USP application Agreement European Union — The European United States of America — With Medicines Agency (EMEA) has been substandard and counterfeit versions of formally notified of the manufacturer’s medicines intended to treat life-threaten- decision to withdraw its application for a ing diseases such as malaria, HIV/AIDS centralized marketing authorization for and tuberculosis posing a growing threat the medicine vandetinib (Zactima¨), throughout the developing world, the US 100 mg film-coated tablets. Agency for International Development (USAID) and the US Pharmacopeial Zactima was expected to be used in Convention (USP) have launched a new combination with chemotherapy for the five-year programme. Promoting the treatment of patients with locally ad- Quality of Medicines (PQM) Programme vanced or metastatic non-small cell lung will serve as a primary mechanism to help cancer (NSCLC) who have received prior assure the quality, safety and efficacy of anticancer therapy. medicines that are essential to USAID’s priority health programmes. This will be In its official letter, the company stated achieved by: that the withdrawal of the application was based on preliminary comments which ¥ Working with countries to strengthen indicate that at this point in time the their medicines regulatory bodies. Committee would be unlikely to conclude on a favourable benefit-risk balance for ¥ Increasing the supply of good-quality the product in the treatment of NSCLC in medicines. combination with chemotherapy. ¥ Combating the availability of counterfeit and substandard medicines through Reference: EMEA Press Release, Doc. Ref. testing programmes and other means. EMEA/698692/2009, 30 October 2009 at http://www.emea.europa.eu ¥ Conducting global advocacy to raise awareness of the dangers of substand- ard and counterfeit drugs.
308 WHO Drug Information Vol. 23, No. 4, 2009
Consultation Document
The International Pharmacopoeia
Artesunatum Artesunate
Draft proposal for the International Pharmocopoeia (September 2009). Please address any comments to Quality Assurance and Safety: Medi- cines, World Health Organization, 1211 Geneva 27, Switzerand. Fax +4122791 4730 or e-mail to [email protected]. A subscriber mailing list is now available to speed up consultation. For more information please contact [email protected].
[Note from Secretariat : The proposed revision deals primarily with the HPLC tests for related substances and assay.]
[Note from Secretariat: The structure shows the stereochemistry as corrected for the electronic version of the Ph.Int on the WHO medicines web site.]
C19H28O8 Relative molecular mass. 384.4
Chemical name. (3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-3,6,9-trimethyl- 3,12-epoxy-12H-pyrano[4,3-j ]-1,2-benzodioxepin-10-ol, hydrogen succinate; CAS Reg. No. 182824-33-5.
Description. A fine, white crystalline powder.
309 Consultation Document WHO Drug Information Vol. 23, No. 4, 2009
Solubility. Very slightly soluble in water; very soluble in dichloromethane R; freely soluble in ethanol (~750 g/l) TS and acetone R.
Category. Antimalarial.
Storage. Artesunate should be kept in a well-closed container and protected from light.
REQUIREMENTS
Artesunate contains not less than 96.0% and not more than the equivalent of 102.0% of artesunate (C19H28O8) using Assay method A, and not less than 99.0% and not more than the equivalent of 101.0% of artesunate (C19H28O8) using Assay method B, both calculated with reference to the anhydrous substance.
Identity tests
Either test A alone or tests B, C, and D may be applied.
A. Carry out the examination as described under 1.7 Spectrophotometry in the infra- red region. The infrared absorption spectrum is concordant with the spectrum obtained from artesunate RS or with the reference spectrum of artesunate.
B. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 5 volumes of ethyl acetate R and 95 volumes of toluene R as the mobile phase. Apply separately to the plate 2µl of the following 2 solutions in toluene R. For solution (A) use 0.10 mg of Artesunate per ml. For solution (B) use 0.10 mg of artesunate RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, spray with anisaldehyde/ methanol TS, and heat the plate to 120 ûC for 5 minutes. Examine the chromatogram in ultraviolet light (254 nm).
The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.
C. Dissolve 0.1 g of Artesunate in 40 ml of dehydrated ethanol R, shake, and filter. To half of the filtrate (keep the remaining filtrate for test D) add about 0.5 ml of hydroxy- lamine hydrochloride TS2 and 0.25 ml of sodium hydroxide (~80 g/l) TS. Heat the mixture in a water-bath to boiling, cool, add 2 drops of hydrochloric acid (~70 g/l) TS and 2 drops of ferric chloride (50 g/l) TS; a light red-violet colour is produced.
D. Evaporate the remaining filtrate from test C on a water-bath to a volume of about 5 ml. Place a few drops of the mixture on a white porcelain dish, add 1 drop of vanillin/ sulfuric acid TS1; a reddish-brown colour is produced.
[Note from the Secretariat: melting range test has been deleted.]
Specific optical rotation. Use a 10 mg/ml solution in dichloromethane R and calcu- late with reference to the anhydrous substance;
310 WHO Drug Information Vol. 23, No. 4, 2009 Consultation Document
Heavy metals. Use 1.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals content according to Method A; not more than 20 µg/g.
Sulfated ash. Not more than 1.0 mg/g.
Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using 2 g of Artesunate; the water content is not more than 5 mg/g. pH value. pH of an aqueous suspension containing 10 mg/g, 3.5 - 4.5.
Related substances
[Note from the Secretariat : ¥ the TLC method has been deleted
¥ HPLC chromatographic system has been changed to allow separation of the β-artenimol peak
¥ limits for related substances have been modified (3 related substances are now specified, and a separate limit for the unknowns is now given)]
Carry out the test as described under 1.14.4 High-performance liquid chromatography, using the conditions given below under Assay method A.
Use solutions (1) and (3) as described under Assay method A. For solution (4) dilute 1 ml of solution (1) to 100 ml with acetonitrile R.
Operate with a flow rate of 1.0 ml per minute. Maintain the column temperature at 30 ûC and use as detector an ultraviolet spectrophotometer set at a wavelength of about 216 nm.
Inject separately 20 µl each of solutions (1), (3) and (4). Record the chromatograms for about 4 times the retention time of artesunate. In the chromatogram obtained with solution (3), the following peaks are eluted at the following relative retention with reference to artesunate (retention time about 9 minutes): α-artenimol about 0.58, β- artenimol about 0.91 and impurity B (artemisinin) about 1.30. The assay is not valid unless the resolution factor between the peaks due to β-artenimol and artesunate is at least 1. The chromatogram obtained with solution (1) may show a peak due to impurity C eluting at a relative retention of about 2.7 with reference to artesunate.
In the chromatogram obtained with solution (1)
¥ the combined areas of any peaks corresponding to α-artenimol and β-artenimol (impurity A) are not greater than the area of the principal peak obtained with solution (4) (1.0%);
¥ the area of any peak corresponding to impurity B (artemisinin) is not greater than 0.5 times the area of the principal peak obtained with solution (4) (0.5%);
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¥ the area of any peak corresponding to impurity C, when multiplied by a correction factor of 0.07, is not greater than 0.2 times the area of the principal peak obtained with solution (4) (0.2%);
¥ the area of any other peak, other than the principal peak, is not greater than 0.2 times the area of the principal peak in the chromatogram obtained with solution (4) (0.2%);
¥ The sum of the corrected area of any peak corresponding to impurity C and the areas of all other peaks, other than the principal peak, is not greater than twice the area of the principal peak obtained with solution (4) (2.0%). Disregard any peak with an area less than 0.05 times the area of the principal peak in the chromatogram obtained with solution (4) (0.05%).
Assay
Either method A or method B may be applied.
A. Carry out the test as described under 1.14.4 High-performance liquid chromatogra- phy, using a stainless steel column (10 cm x 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (3 µm) (Luna¨ has been found suitable). As the mobile phase, use a mixture of 44 volumes of acetonitrile R and 56 volumes of buffer pH 3.0.
Prepare the buffer pH 3.0 by dissolving 1.36 g of potassium dihydrogen phosphate R in 900 ml of water R, adjust the pH to 3.0 with phosphoric acid (~1440 g/l) TS and dilute to 1000 ml with water R.
Prepare the following solutions in acetonitrile R. For solution (1) dissolve 40 mg of the test substance, accurately weighed, and dilute to 10 ml. For solution (2) dissolve 40 mg of artesunate RS, accurately weighed, and dilute to 10 ml. For solution (3) dissolve about 1 mg of artenimol RS, about 1 mg of artemisinin RS and about 10 mg of artesu- nate RS in 10 ml.
Operate with a flow rate of 1.0 ml per minute. Maintain the column temperature at 30 ûC and use as detector an ultraviolet spectrophotometer set at a wavelength of about 216 nm.
Inject separately 20 µl each of solutions (1), (2) and (3). Record the chromatograms for about 4 times the retention time of artesunate. In the chromatogram obtained with solution (3), the following peaks are eluted at the following relative retention with reference to artesunate (retention time about 9 minutes): α-artenimol about 0.58, β- artenimol about 0.91 and impurity B (artemisinin) about 1.30. The assay is not valid unless the resolution factor between the peaks due to β-artenimol and artesunate is at least 1. The chromatogram obtained with solution (1) may show a peak due to impu- rity C eluting at a relative retention of about 2.7 with reference to artesunate. Measure the areas of the peak responses obtained in the chromatograms from solu- tions (1) and (2), and calculate the percentage content of artesunate (C19H28O8) with reference to the anhydrous substance.
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B. Dissolve about 0.25 g of Artesunate, accurately weighed, in 25 ml of neutralized ethanol TS and titrate with sodium hydroxide (0.05 mol/l) VS, using 2 drops of phenol- phthalein/ethanol TS as indicator.
Each ml of sodium hydroxide (0.05 mol/l) VS is equivalent to 19.22 mg of C19H28O8. Impurities
The following list of known and potential impurities that have been shown to be con- trolled by the tests in this monograph is given for information.
A. Artenimol B. Artemisinin C.
(3R,5aS,6R,8aS, 12R,12aR)-Octahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j ]- 1,2-benzodioxepine; 9,10-Didehydro-10-deoxyartemisinin (Glycan).
[Note from Secretariat : Systematic name of impurity C to be confirmed.]
Artesunati compressi Artesunate tablets
Draft proposal for the International Pharmocopoeia (September 2009). Please address any comments to Quality Assurance and Safety: Medi- cines, World Health Organization, 1211 Geneva 27, Switzerand. Fax +4122791 4730 or e-mail to [email protected]. A subscriber mailing list is now available to speed up consultation. For more information please contact [email protected].
[Note from Secretariat : The proposed revision deals mainly with the HPLC tests for related substances and assay.]
Category. Antimalarial. Storage. Artesunate tablets should be kept in a well-closed container.
Additional information. Strength in the current WHO Model List of Essential Medi- cines: 50 mg. Strength in the current WHO Model List of Essential Medicines for children: 50 mg.
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REQUIREMENTS Comply with the monograph for “Tablets”. Artesunate tablets contain not less than 90.0% and not more than 110.0% of the amount of artesunate (C19H28O8) stated on the label. Identity tests Either test A alone or tests B, C, and D may be applied. A. To a quantity of the powdered tablets containing 0.050 g of Artesunate add 25 ml of acetone R, shake and filter. Evaporate the filtrate at low temperature and dry overnight over desiccant silica gel R. Carry out the examination with the residue as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from artesunate RS or with the reference spectrum of artesunate. B. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 5 volumes of ethyl acetate R and 95 volumes of toluene R as the mobile phase. Apply separately to the plate 2 µl of the following 2 solutions in toluene R. For solution (A) shake a quantity of the pow- dered tablets containing about 0.5 mg of Artesunate with 5 ml, filter and use the clear filtrate. For solution (B) use 0.10 mg of artesunate RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, spray with anisaldehyde/ methanol TS, and heat the plate to 120 ûC for 5 minutes. Examine the chromatogram in ultraviolet light (254 nm).
The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.
C. To a quantity of the powdered tablets containing 0.1 g of Artesunate add 40 ml of dehydrated ethanol R, shake for a few minutes, and filter. To half of the filtrate (keep the remaining filtrate for test D) add about 0.5 ml of hydroxylamine hydrochloride TS2 and 0.25 ml of sodium hydroxide (~80 g/l) TS. Heat the mixture in a water-bath to boiling, cool, add 2 drops of hydrochloric acid (~70 g/l) TS and 2 drops of ferric chlo- ride (50 g/l) TS; a light red-violet colour is produced.
D. Evaporate the remaining filtrate from test C on a water-bath to a volume of about 5 ml. Place a few drops of the mixture on a white porcelain dish, add 1 drop of vanillin/ sulfuric acid TS1, a reddish-brown colour is produced.
Related substances
[Note from the Secretariat :
¥ the TLC method has been deleted ¥ HPLC chromatographic system has been changed to allow separation of the β-artenimol peak ¥ limits for related substances have been modified (3 related substances are now specified, and a separate limit for the unknowns is now given).]
314 WHO Drug Information Vol. 23, No. 4, 2009 Consultation Document
Carry out the test as described under 1.14.4 High-performance liquid chromatography, using the conditions given below under Assay method A.
Use solutions (1) and (3) as described below under Assay method A. For solution (4) dilute 1 ml of solution (1) to 100 ml with acetonitrile R. For solution (5) shake or soni- cate a mixture of suitable amounts of each of the excipients stated on the label for 15 minutes with 10 ml acetonitrile, filter through a 0.45-µm filter and use the filtrate. Operate with a flow rate of 1.0 ml per minute. Maintain the column temperature at 30 ûC and use as detector an ultraviolet spectrophotometer set at a wavelength of about 216 nm.
Inject separately 20 µl each of solutions (1), (3), (4) and (5). Record the chromato- grams for about 4 times the retention time of artesunate. In the chromatogram ob- tained with solution (3), the following peaks are eluted at the following relative reten- tion with reference to artesunate (retention time about 9 minutes): α-artenimol about 0.58, β-artenimol about 0.91 and impurity B (artemisinin) about 1.30. The assay is not valid unless the resolution factor between the peaks due to β-artenimol and artesunate is at least 1. The chromatogram obtained with solution (1) may show a peak due to impurity C eluting at a relative retention of about 2.7 with reference to artesunate.
In the chromatogram obtained with solution (1)
¥ the combined areas of any peaks corresponding to α-artenimol and β-artenimol (impurity A) are not greater than 3 times the area of the principal peak obtained with solution (4) (3.0%);
¥ the area of any peak corresponding to impurity B (artemisinin) is not greater than 0.5 times the area of the principal peak obtained with solution (4) (0.5%);
¥ the area of any peak corresponding to impurity C, when multiplied by a correction factor of 0.07, is not greater than 0.3 times the area of the principal peak obtained with solution (4) (0.3%);
¥ the area of any other peak, other than the principal peak, is not greater than 0.3 times the area of the principal peak in the chromatogram obtained with solution (4) (0.3%);
¥ the sum of the corrected area of any peak corresponding to impurity C and the areas of all other peaks, other than the principal peak, is not greater than 4 times the area of the principal peak obtained with solution (4) (4.0%). Disregard any peak with an area less than 0.1 times the area of the principal peak in the chromatogram obtained with solution (4) (0.1%), and any peak eluting before acetonitrile, and, if information concerning the excipients used in manufacturing of the tablets is available, disregard any peak with the same retention time as that of any of the peaks in the chromato- gram obtained with solution (5).
Assay
Either method A or method B may be applied.
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A. Carry out the test as described under 1.14.4 High-performance liquid chromatogra- phy, using a stainless steel column (10 cm x 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (3 µm) (Luna¨ is suitable). As the mobile phase, use a mixture of 44 volumes of acetonitrile R and 56 volumes of buffer pH 3.0.
Prepare the buffer pH 3.0 by dissolving 1.36 g of potassium dihydrogen phosphate R in 900 ml of water R, adjust the pH to 3.0 with phosphoric acid (~1440 g/l) TS and dilute to 1000 ml with water R.
Prepare the following solutions in acetonitrile R. For solution (1) weigh and powder 20 tablets. Shake or sonicate a quantity of the powder containing about 40 mg of Artesu- nate, accurately weighed, for 15 minutes with 10 ml of acetonitrile R. Filter the result- ing solution through a 0.45-µm filter, discarding the first few ml of the filtrate. For solution (2) dissolve 40 mg of artesunate RS, accurately weighed, and dilute to 10 ml. For solution (3) dissolve about 1 mg of artenimol RS, about 1 mg of artemisinin RS and about 10 mg of artesunate RS in 10 ml.
Operate with a flow rate of 1.0 ml per minute. Maintain the column temperature at 30 ûC and use as detector an ultraviolet spectrophotometer set at a wavelength of about 216 nm.
Inject separately 20 µl each of solutions (1), (2) and (3). Record the chromatograms for about 4 times the retention time of artesunate. In the chromatogram obtained with solution (3), the following peaks are eluted at the following relative retention with reference to artesunate (retention time about 9 minutes): α-artenimol about 0.58, β-artenimol about 0.91 and impurity B (artemisinin) about 1.30. The assay is not valid unless the resolution factor between the peaks due to β-artenimol and artesunate is at least 1. The chromatogram obtained with solution (1) may show a peak due to impurity C eluting at a relative retention of about 2.7 with reference to artesunate.
Measure the areas of the peak responses obtained in the chromatograms from solu- tions (1) and (2), and calculate the content of artesunate (C19H28O8). B. Weigh and powder 20 tablets. To a quantity of the powder containing about 0.5 g of Artesunate, accurately weighed, add 50 ml of neutralized ethanol TS, shake thor- oughly, filter, and discard about 10 ml of the initial filtrate. Titrate 25 ml of the filtrate with sodium hydroxide (0.05 mol/l) VS, using 2 drops of phenolphthalein/ethanol TS as indicator.
Each ml of sodium hydroxide (0.05 mol/l) VS is equivalent to 19.22 mg of C19H28O8. Dissolution. Analyse the dissolution samples without delay.
Carry out the test as described under 5.5 Dissolution test for solid oral dosage forms, using as the dissolution medium, 900 ml of dissolution buffer, pH 6.8, TS and rotating the paddle at 75 revolutions per minute. At 45 minutes withdraw a sample of 10 ml of the medium through an inline filter. Allow the filtered sample to cool to room tempera- ture [solution (1)].
316 WHO Drug Information Vol. 23, No. 4, 2009 Consultation Document
Determine the concentration in solution (1) by carrying out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25 cm x 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5 µm) (Luna¨ has been found suitable). As the mobile phase, use a mixture of equal volumes of acetonitrile R and buffer pH 3.0 (prepare the buffer as described under Assay method A).
For solution (2) dissolve 25 mg of artesunate RS, accurately weighed, in acetonitrile R and dilute to 20 ml with the same solvent. Dilute 2 ml of the resulting solution to 50 ml with acetonitrile R.
Operate with a flow rate of 1.5 ml per minute. Maintain the column temperature at 30 ûC and use as detector an ultraviolet spectrophotometer set at a wavelength of about 210 nm.
Inject alternately 100 µl each of solutions (1) and (2).
For each of the six tablets tested, calculate the total amount of artesunate (C19H28O8) in the medium from the results obtained. The amount in solution for each tablet is not less than 80% of the amount stated on the label. If the amount obtained for one of the six tablets is less than 80%, repeat the test using a further six tablets; the average amount for all 12 tablets tested is not less than 75% and the amount obtained for no tablet is less than 60%.
Impurities. The impurities limited by the requirements of this monograph include those listed in the monograph for Artesunate.
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Recent Publications, Information and Events
Illegal weight-loss medicines medicines and dietary supplements has and dietary supplements led to many cases of serious health conditions and occasionally even to Netherlands — A survey on the health death. risk of drug substances detected in illegal weight-loss medicines and dietary supple- Reference: Venhuis BJ, Zwaagstra ME, van ments has recently been published by the den Berg JDJ. Trends in drug substances National Institute for Public Health and detected in illegal weight-loss medicines and the Environment (RIVM). dietary supplements. A 2002-2007 survey and health risk analysis. RIVM Report, No. Between 2002 and 2007, analyses 37003000212009 available at http:// showed increasing numbers of counterfeit www.rivm.com medicines and dietary supplements adulterated with drug substances. Use of Southern Med Review these products may lead to psychosis, cardiovascular problems and even death. The Southern Med Review (SMR) is a This is shown by a trend analysis on 256 growing independent, open access; peer suspect samples gathered by four na- reviewed journal which is currently tional laboratories in the Netherlands, published from Auckland, New Zealand. including the RIVM. The journal is focusing on pharmaceutical policy and the aim of the journal is to Adulterated dietary supplements pose the disseminate commentary and empirical highest health risks. Because the sub- research findings, with a view to improve stances used in the product are not the rational use of and access to essen- mentioned on the label, consumers are tial medicines. not aware of the risks and assume they are taking a natural product. In the event All issues of the journal are freely acces- of an adverse reaction, an adulterated sible from the web site and the Editor dietary supplement is difficult to identify welcomes submissions for its upcoming and correct medical treatment may be issues. Instruction for authors can be delayed. downloaded from http://www.fmhs. auckland.ac.nz/sop/smr/_docs/instruction Health risks are also high for counterfeit toauthors.pdf medicines because the composition and quality of ingredients are unknown. Inter- Reference: University of Auckland at http:// nationally, use of illegal weight-loss www.fmhs.auckland. ac.nz/sop/smr
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