WHO Drug Information Vol 17, No. 2, 2003 World Health

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WHO Drug Information Vol 17, No. 2, 2003

WHO Drug Information

Contents

World Health Organization

Good Manufacturing PracticesImplementation of good manufacturing

practices 81

Personal PerspectivesPharmacogenetics and existing therapies 84

Safety IssuesFluticasone and adrenal crisis 92Thiazolidinediones experience 92Cefepime, ceftazidime and neurotoxicity 93Interstitial nephritis and proton pump

inhibitors 94Interactions with grapefruit juice 95

Current TopicsNew network for guideline development 96Fake artesunate tablets circulating again 96European Union enlargement: observers

to EMEA 97Clinical cancer research review 97New foundation will develop tests for

infectious diseases 98TDR research training in 2004 99Managing drug supply for primary

health care 100Latin American pharmacotherapy course 100

Regulatory and Safety ActionGefitinib approved for lung cancer 102New breath test for monitoring asthma 103Risperidone: prescribing information update 103Pan Pharmaceuticals product recalls 103

Telithromycine and myasthenia gravis 104Astemizole: marketing suspension 105Somatropin: negative opinion 105Repaglinide and gemfibrozil: hazardous

interaction 105Adhesion prevention solution global

withdrawal 105Counterfeit Lipitor® 106Paroxetine: avoid in children

and adolescents 106Aprepitant for nausea and vomiting during

chemotherapy 107Agalsidase beta approved 107Imatinib mesylate approved for paediatric

leukaemia 108Drug-eluting stent for clogged heart arteries 108Pegvisomant for acromegaly 109

Aspects of Quality AssuranceFixed-combination medicines: an Australian

perspective 110

Recent Publications and Sources of InformationInternational travel and health 113Affordability of medicines 113Drugs and money 113ABPI launches online clinical trials register 114Report of Expert Committee on Drug

Dependance 114Biomedical research in human subjects 114

Recommended InternationalNonproprietary Names: List 49 115

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WHO Drug Informationis now available at:

http://www.who.int/druginformation

World Health Organization

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Good Manufacturing Practices

Implementation of goodmanufacturing practicesMedicines are important tools in improving andmaintaining health. Whilst standards for ensuringthe quality of medicines at international level arebecoming increasingly rigorous, quality assurancewithin many countries still remains a major publichealth concern. In recent years, there have beennumerous reports highlighting problems surround-ing poor quality drugs including contamination bytoxic substances, increase in counterfeiting, andpresence of substandard medicines on themarket. Very often, these cases can be avoidedby strict application of good manufacturingpractices (GMP) which has an essential role toplay in the quality assurance of medicines.

The need for inspection is intimately linked to thesuccess of quality assurance systems. Without acompetent inspectorate operating to high pro-fessional standards, neither GMP compliance norlicensing provisions can effectively be enforced.In addition, inspection of manufacturing facilitiesis pivotal to operation of the WHO CertificationScheme on the Quality of PharmaceuticalProducts Moving in International Commerce (1).

GMP Implementation ProjectIn 1998, the WHO Department of Essential Drugsand Medicines Policy received funding from theGovernment of Japan to operate a three-yearproject on Promotion of Implementation of GMP*.The aims of the project were:

• to improve the quality of locally manufacturedpharmaceutical products by identifying obsta-cles to implementing GMP; and

• to develop tools and methods to assist countriesimprove implementation of GMP.

A WHO Working Group was established to plan,

coordinate and evaluate project activities andoversee the development of training modules tobe produced as a CD-ROM and aimed to buildtraining courses on GMP and inspection (2).Material was focussed to the needs ofgovernment officials carrying out inspection ofmanufacturing facilities for either finishedproducts, medicines or pharmaceutical startingmaterials.

Criteria for country participation in the projectwere to:

• sustain existing collaboration with WHO;

• be a developing country;

• have a functioning drug regulatory authority;

• be able to serve as regional centres for GMPtraining in the future; and

• have significant levels of local pharmaceuticalproduction.

GMP training modulesGMP training material comprised 20 modules(see table on page 82), with slide presentations,tutorial notes, group session exercises, handouts,comprehension tests and answer sheets.Separate modules covered: Basic Principles ofGMP, GMP Inspection Processes, and trainers’notes for the setting up and running of the course.These were completed in November 1999 fortesting at the first WHO Pilot Training Workshopheld in Beijing in December 1999.

WHO pilot workshopsThe first workshop was organized in collaborationwith the State Drug Administration (SDA), China.Participants comprised government inspectorsand administrative officers with a good knowledgeof GMP inspection from eight countries in theWHO Western Pacific and South-east AsiaRegions.

The resulting material was tested at a secondWHO Pilot Training Workshop held in Pretoria,South Africa, in July 2000, along with a firstviewing of the GMP Implementation video.

*Responsible officer, Dr Kazushige Morimoto, SPMIProject, Essential Drugs and Medicines Policy, WorldHealth Organization, Geneva, [email protected]

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Two one-day courses were further held at the endof 2000 using finalized versions of two modules,and the GMP implementation video. Participantscame from a broader range of backgrounds, suchas government institutions, national and privatepharmaceutical facilities and universities.

GMP implementation videoThe 18-minute training video was developedduring the first half of 2000 as part of the GMPmodular package to serve as a stand-alonetraining tool. Film sequences and narrativeillustrated examples show GMP-compliant andnon-compliant situations in pharmaceuticalmanufacturing facilities and include scenes ofmanufacturing processes, premises and qualitycontrol procedures.

For the GMP-compliant footage, a facility wasselected where a full range of pharmaceuticalswas being produced. Illustrations of non-GMPcompliance were taken from black and white filmfootage originally prepared by the US Food andDrug Administration during the 1970s. Thepersons and company featured in the sceneswere fictional. However, the situations shownwere based on true events and demonstrated theconsequences of human error for product qualityand end-user well being. The “compliant” exam-

ple contained some “non-compliant” features foruse as a case study exercise during training. Thevideo was completed in June 2000.

GMP CD-ROMWork on the production of a CD-ROM began inMarch 2000. The CD contains modular trainingtexts, WHO published documents on goodmanufacturing practices and inspection (3), theGMP implementation video, and backgroundproject information. Copies have been distribuedto drug regulatory authorities, WHO country andregional offices and participants of GMPworkshops.

Project on Strengthening ofPharmaceutical ManufacturingInspectionUpon conclusion of the GMP ImplementationProject in December 2000, the Strengthening ofPharmaceutical Manufacturing Inspection (SPMI)Project was initiated to consolidate achievementsof the former project and focus on strengtheningpharmaceutical manufacturing inspectorates bypromoting the global use of the completed trainingmaterials. The SPMI Project ended in March2003.

WHO Basic Training Modules on GMP: a resource and study pack for trainers*

Basic principles of GMP

1 Introduction 8 Personnel2 Quality management 9 Premises3 Sanitation and hygiene 10 Equipment4 Validation 11 Materials5 Complaints and recalls 12 Documentation6 Contract production and analysis 13 Sterile production7 Self-inspection 14 Active pharmaceutical ingredients

GMP inspection process

15 Introduction 18 Types of GMP inspection16 The role of the inspector 19 The inspection17 Preparation for the inspection 20 Trainer’s notes

WHO Supplementary Training Modules on GMP*

1 Validation2 Water for pharmaceutical use3 Air handling systems

*CD-ROM available from: Essential Drugs and Medicines Policy,World Health Organization, 1211 Geneva 27, Switzerland. e-mail [email protected]

http://www.who.int/medicines


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Training workshops involving 134 participantsfrom 31 countries were organized utilizing theGMP Implementation Project modules. Wherepossible, a visit to a pharmaceutical factory site orlaboratory was included in the programme toenable participants to be exposed to practicalaspects of GMP training.

Results of SPMIInitial distribution of the CD-ROM in April 2001was followed by a questionnaire to national drugregulatory authorities and participants of theworkshops in June 2001. The questionnaireaimed to elicit feedback on the five components ofthe training package (slides, tutorial notes, groupsessions, handouts and the GMP implementationvideo) in terms of technical content and user’sopinion on the usefulness of the materials fordeveloping skills in GMP inspection and com-pliance. A total of 702 questionnaires weredistributed between June and November 2001.

Course evaluation and feedback from participantshas indicated a strong desire for further trainingfor inspectors and for longer courses to be set upencompassing all the modules. At the workshopsin Chong Qing, China, and New Delhi, India, therewas a particular focus on promoting GMP in themanufacture of antituberculosis drugs, andparticipants expressed a desire for further trainingto be specifically aimed at inspectors andmanufacturers of these products.

It is hoped that wide distribution of the CD-ROM ,together with availability of the materials throughthe WHO Internet (http://www.who.int/medicines),

will greatly enhance accessibility to trainingpossibilities supporting GMP. For some countries,however, the viability of future training will dependon the availability of computer equipment,software and translation of materials. Themodules have also been translated into Spanishand produced as a CD-ROM by the Pan AmericanSanitary Bureau (PAHO). Feedback to date hasindicated that further translations into otherlanguages are planned, including Chinese,German, Japanese, Portuguese, Russian andTurkish.

An article describing the two projects in moredetail has recently appeared in the journal QualityAssurance (4).

References

1. World Health Organization. WHO CertificationScheme on the Quality of Pharmaceutical ProductsMoving in International Commerce. HTP/EDM/QSM82.4 Rev 5 (1997).

2. World Health Organization. CD-ROM WHO BasicTraining Modules on GMP: A resource and study packfor trainers. Essential Drugs and Medicines Policy,World Health Organization, 1211 Geneva 27, Switzer-land . e-mail [email protected]

3. World Health Organization. Quality Assurance ofPharmaceuticals. A compendium of guidelines andrelated materials. Volume II. Good manufacturingpractices and inspection (1999).

4. Morimoto, K., Curry, J., Kopp, S. et al. PromotingGMP implementation: developing training materials forthe international audience. Quality Assurance, 10: 11–27 (2003).


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Personal Perspectives

Despite the notable successes achieved in drugdevelopment during the past five decades, notherapy can yet be considered either fully effec-tive or entirely safe. This contrasts starkly to theprevailing perception that taking drugs is invari-ably beneficial. In fact, it is probably true to saythat a significant proportion of patients treatedwith existing therapies* obtain only minimalbenefit. Depending on the therapy and endpointused, efficacy can range from a rare 90% down toonly a couple of percentage points. Historically,

drugs have been produced in a “one-size-fits-all”model in the hope that all patients respond in thesame way. More recently, however, scrutiny of theindications on new drug applications approved byregulatory authorities clearly shows a trendtowards indicating those patients most likely tobenefit.

Because existing therapies have been officiallyapproved for marketing, they are generallyassumed to be effective and safe. This has led to

*Within the frame of this article, the term “existing therapies” refers to those medicines currently available and ap-proved by competent authorities (i.e. drug regulatory authorities) for the prevention or treatment of disease in humans,whether under or off patent. The term thus covers both multisource (generic) pharmaceutical products and innovativeproducts which may or may not be covered by patent protection. In certain cases, it is also applicable to products thatmay have been withdrawn from one or all markets after initial approval.

Pharmacogenetics and existing therapiesThere is increasing evidence that pharmacogenetics will soon be playing a vital role in public health.Understanding genetic factors that determine the response to drugs, together with increased knowl-edge of drug action mechanisms and identification of drug targets is now leading to the design ofdrugs that are specifically targeted towards particular populations and that avoid genetic variabilityin therapeutic response. The ability to identify sensitive individuals before drug treatment usingpharmacogenetic methods would be an improvement on the current time-consuming practice ofattempting to match the most appropriate drug to each patient. It might also substantially reducethe need for hospitalization and avoid the costs associated with adverse drug reactions. Indeed,one day it may well be considered unethical not to carry out routine genetic testing to avoid expos-ing particular individuals to drugs that could be harmful and/or ineffective for them.

The development of pharmacogenetics provides at least one mechanism for taking prescriptionaway from its current empiricism and progressing towards more patient-tailored, individualizeddrug treatment. The extent of genetic polymorphism in the human population indicates that phar-macogenetic variability is an issue for many existing therapies and may also be an issue for mostnew drugs. Thus, pharmacogenetics could pre-empt potential treatment failures, leading to betterhealth outcomes for patients and reducing the waste associated with ineffective treatments. Nonethe less, although pharmacogenetics promise to provide a mechanism whereby DNA testing canbe applied to populations in general, we are still some way from having a pharmacogenetic DNAchip that general practitioners can use to identify those drugs which will individually benefit eachpatient.

Readers comments are invited on this article, which attempts to define the difficulties and opportu-nities facing manufacturers of both innovative and generic products, and the role of acadaemia andnational drug regulatory authorities in the application of this challenging new area. Please addressany comments to the author: Dr Lembit Rägo, Quality and Safety: Medicines, Essential Drugs andMedicines Policy, World health Organization, Geneva, Switzerland or e-mail: [email protected]

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the assumption that the net outcome of treatmentfor populations in general is positive. However,this does not mean that all individuals benefit fromtreatment. Some individuals may not benefit at allfrom existing therapies and others may well sufferserious adverse reactions.

It was not until the 1950s that modern scientistsdiscovered the presence of inherited enzymaticdeficiencies that can lead to unexpected and evenharmful effects from therapies. An importantlandmark was the publication of Motulsky’s paperentitled “Drug reactions, enzymes, and biochemi-cal genetics” (1) written upon invitation from theAmerican Medical Association.

The paper described haemolysis caused by theantimalarial drug primaquine in about 10% ofblack American servicemen during World War II.This adverse reaction was very rare among whiteservicemen. Haemolysis and resulting anaemiawere later shown to be due to an inborn fault ofred blood cells or, more precisely, variation of theenzyme glucose-6-phosphate dehydrogenase(G6PD) gene leading to a deficiency of thisenzyme (2) commonly found among people ofAfrican descent. Until now, however, this type ofknowledge has resulted in only limited practicaloutcomes.

Individual variation in response to drugs is asubstantial clinical problem. Variation in drugresponse ranges from response failure, adversedrug reactions, or drug-drug interactions whenseveral drugs are taken concomitantly. Theclinical consequences range from treatmentfailure and patient discomfort through to seriousclinical illness and the occasional fatality. A recentUS study estimated that 106 000 patients die and2.2 million are injured each year by adversereactions to prescribed drugs (3).

The role of pharmacogenetics*Pharmacogenetics could lead to the improvementof existing therapies and seriously reduce theguesswork in prescribing by ensuring that theright drug is given to the right person from the

very beginning. This will considerably reduce thetime and resources taken in finding the correcttreatment regimen. By avoiding prescribing to‘non-responders’ and by reducing the occurrenceof adverse drug reactions, better targeted or evenindividualized pharmacotherapy can be achieved.

Existing therapies:room for improvementTypically, the physician prescribes the recom-mended medicines in the recommended dosageto his or her patient. If the medicine does notwork, the doctor will usually try the best alterna-tive. Time and money is lost through unnecessaryvisits to the doctor and the cost of ineffectivemedicine(s) either used or remaining unused, andwhich usually cannot be resold. It is now clearthat much individuality in response to drugs isinherited and that not all patients can benefitequally, as demonstrated by the examples below.

Acetylsalicylic acidThe usefulness of low-dose acetylsalicylic acid(75–325 mg) in secondary prevention of throm-botic cardiovascular or cerebrovascular disease iswell known. In many countries it is also approvedfor primary prevention of vascular events relatedto coronary heart disease. However, it is prema-ture to suggest that all patients with the appropri-ate indications will benefit equally from the use oflow-dose aspirin where there may be increasedrisk of haemorrhage, including fatal haemorrhagicstroke. Neither do we have the scientific means todetermine whether acetylsalicylic acid is beinggiven to patients who can really benefit or whomay be at risk for serious side effects.

Angiotensin-converting-enzymeinhibitorsIt is estimated that currently 35–40 million peopleare treated worldwide (4) with angiotensin-converting-enzyme (ACE) inhibitors for cardiovas-cular conditions. Pharmacogenetics may help toreduce the risks associated with increasing use.Some ACE inhibitors are already out of patent in anumber of countries and others follow. There is nodoubt that this group of drugs has the potential to

* The European Union (EMEA/CMPM) definition for pharmacogenetics and pharmacogenomics [see: WHO DrugInformation, 17(1):17 (2003)] is:

“Pharmacogenetics is the study of interindividual variations in DNA sequence related to drug response.

Pharmacogenomics is the study of the variability of the expression of individual genes relevant to disease susceptibilityas well as drug response at cellular, tissue, individual or population level. The term is broadly applicable to drug design,discovery and clinical development.“


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save millions of lives worldwide if access to themcan be guaranteed. However, even in developedcountries only 21–36% of patients with chronicheart failure are treated with ACE inhibitors (4–6),and over 40% of them discontinue the drug within6 months of starting therapy (5). We need to knowmore precisely which individuals can benefit fromACE inhibitors with minimal or no risk of seriousside effects.

Angio-oedema is a well-known side-effect of ACEinhibitors, with a reported incidence of 0.1–0.2%.This is probably an underestimate (6). Blackpeople using ACE inhibitors are at a threefold riskof side effects and also for occurrence of fatalcases (7, 8). Learning more of the true incidenceof angio-oedema may require monitoring of allpatients, especially black patients, for this poten-tially serious side effect. If pharmacogenetics canoffer tests with high predictability, patients atincreased risk for angio-oedema could beswitched to an alternative class of medicines andthus avoid extra costs of monitoring and risk ofdeath. The benefits may well outweigh the costsof tests.

In the case of adverse drug reactions, we have atleast some estimates of the magnitude of theproblem, but in the case of treatment failure wehave no studies to demonstrate how effective orineffective many of the well established existingtherapies really are. For example, how manyyears and how many patients does one need totreat with statins to avoid one death from cardio-vascular disease? If it could be predicted withhigh probability in which individuals statins do ordo not work, we could save enormous amounts oftime and effort and avoid giving unjustified hopeto patients — while focusing resources on findingalternative solutions.

Polymorphism and drug responseWith recent advances in molecular genetics andgenome sequencing, pharmacogenetic researchhas gained attention from scientific communitiesand the public. The introduction of new technolo-gies has permitted rapid screening for specificpolymorphisms (differences in DNA sequenceamong individuals), as well as recently gainedknowledge of the genetic sequences (sequenceof nucleotides in a particular section of DNA) oftarget genes such as those coding for enzymes,ion channels, and other types of receptorsinvolved in drug response. As a result of thecompletion of the Human Genome Project andother public initiatives such as The SNP Consor-

tium (SNP=single nucleotide polymorphisms, seehttp://snp.cshl.org) comprehensive maps of thehuman genome have been established includinginformation identifying genetic variations associ-ated with disease susceptibility as well as phar-macokinetics.

What do pharmacogeneticshave to offer?Research in pharmacogenetics is developing intwo main directions:

• identifying specific genes and gene productsassociated with various diseases which may actas targets for new drugs and/or diagnostic tools;and

• identifying genes and allelic variants of genesthat affect the response to existing therapies.

Pharmacogenetics may offer feasible solutions forbetter targeting of patients and provide a cost-effective method with a consequential benefit forpublic health. Increasing numbers of researchprogrammes have sprung from the humangenome project, including genome-wide screen-ing to identify differences between individuals of asingle base pair in DNA or single nucleotidepolymorphisms. Single nucleotide polymorphismscan be used to map and identify specific genesassociated with various diseases such as cancer,diabetes, and arthritis.

Many of the proteins encoded by these genes areexpected to be new targets for drug therapy butmay also improve our diagnostic capacities byhelping to stratify diagnostic groups into moreprecise subgroups with different responses toexisting therapies. The fact that these genes wereidentified by polymorphism analysis indicates thatdrugs directed at such targets may have differenteffects in different patients. This leads to theconcept of drug stratification or individualizeddrug treatment, in which the choice of drug isinfluenced by a patient’s genetic status.

Genomic analysis has generated an enormousamount of information on human polymorphisms.There are over 4 million single nucleotide poly-morphisms in public databases and more willprobably be identified in the next few years.However, a greater challenge will be in determin-ing the function of each polymorphic gene or, tobe more exact, of the gene product and its variantforms. In particular, it will be necessary to deter-


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mine whether a gene product is of pharmacologi-cal or toxicological importance and whetherindividual allelic variants are of therapeuticimportance. Such expression profiling enablestesting of genotype-phenotype correlates and isextremely important for further advancement inpharmacogenomics.

The determination of the genetic variations thataffect the efficacy of current drugs is much closerto clinical application. Polymorphism in any one ofmany genes including those encoding drugreceptors, drug transporters, and cell signallingpathways can be important factors determiningclinical response. The most immediate utility islikely to be polymorphisms of the genes involvedin drug metabolism and disposition.

Functional polymorphisms in any one of thegenes involved in drug metabolism can lead toeither a lack of therapeutic effect or unexpectedclinical responses including:

• lack of pro-drug activation• metabolism by alternative deleterious path-

ways• extended pharmacological effect• adverse drug reactions• drug toxicity• modified drug-drug interactions.

Polymorphisms have now been identified in morethan 20 human drug metabolising enzymes —several with substantial ethnic differences in theirfrequencies — which promote drug effectsthrough affecting their metabolism.

In general, pharmacogenetics can be related to:

pharmacokinetics, which includes absorption,metabolism, generation of pharmacologicallyactive metabolites, activation of pro-drugs,distribution and elimination i.e. the fate of the drugas a chemical compound in the organism; and

pharmacodynamics, affecting receptors andreceptor-coupled mechanisms, modulation ofdrug effects via targeting physiologically-relevantsystems without affecting the primary cause of thedisease or symptom, i.e. anything that is relatedto the mechanism of action of the drug in theorganism.

Important examples of how pharmacogeneticsaffect pharmacokinetics are polymorphisms in thecytochrome P450 enzymes and in thiopurine S-methyltransferase. Clinical problems can arise

from the co-administration of drugs that inhibit orcompete for CYP2D6 (one of the more studiedcytochrome P450 iso-enzymes).

A drug may interact with and inhibit CYP2D6 tothe extent that it is no longer functionally active,resulting in a patient responding as a poormetaboliser even though he or she has an‘extensive metaboliser’ genotype. Thus, quinidine,a powerful CYP2D6 inhibitor, may exaggerate theeffects of other drugs that are prescribed con-comitantly or may prevent the metabolic activationof drugs such as codeine by CYP2D6.

Pharmacogenetics andchanges in pharmacokinetics

Cytochrome P450 iso-enzymesThe cytochrome P450s are a multigene family ofenzymes found predominantly in the liver (butalso present in other tissues such as the brain)and are responsible for the metabolic eliminationof most of the drugs currently used in medicine.Thus, genetically determined variability in thelevel of expression or function of these enzymeshas a profound effect on drug efficacy. In ‘poormetabolisers’ the genes encoding specific cyto-chrome P450s often contain inactivating muta-tions, which result in a complete lack of activeenzyme and a severely compromised ability tometabolise drugs.

Mutations in the gene encoding cytochrome P450iso-enzyme CYP2C9, which metabolises warfarin,affect patients’ response to the drug and theirdose requirements (9). Polymorphism not onlyaffects drug disposition but can also be importantin the conversion of prodrugs to their active form.For example, codeine is metabolised to the morepotent analgesic, morphine, by CYP2D6 and thedesired analgesic effect is not achieved inCYP2D6 poor metabolisers. CYP2D6 (also knownas debrisoquine hydroxylase) is highly polymor-phic and is inactive in about 6% of white people.Thus, worldwide, millions of people are at risk ofcompromised metabolism or adverse drugreactions when prescribed drugs that areCYP2D6 substrates. Many such drugs are usedfor treating diseases such as psychiatric, neuro-logical, and cardiovascular diseases having anarrow therapeutic window and common sideeffects (see table on page 88).

Another variant results from amplification of theentire CYP2D6 gene, with some individualsinheriting up to 13 copies of the gene, arranged intandem (10). This amplification polymorphism


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results in affected people metabolising drugs thatare CYP2D6 substrates so quickly that a thera-peutic effect cannot be obtained at conventionaldoses. For example, it has been estimated that,while a daily dose of 10–20 mg nortriptyline wouldbe sufficient for a patient who is a CYP2D6 poormetaboliser, an ‘ultra-rapid metaboliser’ inheritingmultiple copies of the gene could require as muchas 500 mg a day (11).

Thiopurine methyltransferaseAnother clinically important polymorphism occursin the enzyme thiopurine S-methyltransferase(TPMT), (12) which is responsible for the metabo-lism of the antitumour agents 6-mercaptopurineand 6-thioguanine. Genetic polymorphism at thisgene locus is associated with difficulty in achiev-ing an effective dose of these drugs in childrenwith childhood acute lymphoblastic leukaemia(13). Children with inherited TPMT deficiencyexhibit severe haematopoietic toxicity whenexposed to drugs such as 6-mercaptopurine,whereas those with a high activity form of theenzyme require high doses of the drug to achieveany clinical benefit. The TPMT polymorphism isrelatively rare, with only about 1% of the whitepopulation being homozygous for it, but, sincethese individuals show exaggerated toxic re-sponses to normal doses of thiopurine, TPMTphenotype may be an important factor in thesuccessful treatment of childhood leukaemia.Some centres already provide a diagnosticphenotyping service to guide the clinical use of6-mercaptopurine. Other major polymorphicmetabolizing enzymes, including members of thecytochrome P450 family and II phase enzymes(including G6PD, glutathione S-transferase, etc.)have recently been reviewed (14).

Pharmacogenetics and changes inpharmacodynamicsPharmacodynamic changes that are caused bypharmacogenetic reasons have been less

explored than pharmacokinetic changes. Thisprobably reflects the relative complexity ofmechanisms of action (receptor, ion channels,biology) and environmental influences that affectthem.

Ethnic variations in the response to psychotropicdrugs which are not connected to pharmacokinet-ics are well known (15). Genetic variation ofadrenergic, dopamine and serotonin receptors aswell as serotonin transporters and histamine havebeen examined and linked to therapeutic re-sponse in both schizophrenia and depression.Polymorphisms involved in the regulation of theserotonin transporter protein for instance havebeen described as influencing the therapeuticefficacy in depressive patients of selectiveserotonin reuptake inhibitors such as fluvoxamine(16) and paroxetine (17). Unfortunately, conflict-ing results have been reported in another ethnicgroup (18) without any explanation for thediscrepancies at present.

Clozapine, an atypical antipsychotic drug used forthe therapy of schizophrenia has potentiallysevere side effects and is efficacious in only 30 to60 percent of otherwise treatment-resistantpatients.

Predicting response would help clinicians tremen-dously and has been attempted with a number ofgene markers by different researchers. One of themost comprehensive studies to date of a phar-macogenetic screening strategy combining 6 outof 19 candidate gene markers defined responseto clozapine with a level of prediction of 76.9%(19). Unfortunately, another group applying thesame approach could not replicate the findingslater. Clearly more work has to be done in thisarea.

Other examples of polymorphisms of drug targetswhich could influence the therapeutic response,include beta-adrenergic receptors and response

Examples of drugs that are substrates of cytochrome P450 CYP2D6

Drugs for treating cardiovascular diseaseAlprenolol, amiodarane, flecainide, indoramin, mexiletine, nimodipine, oxprenolol, propranolol, timolol

Drugs for treating psychiatric and neurological diseaseAmitriptyline, clomipramine, clozapine, desipraminc, desmethylcitalopram, fluvoxamine, fluoxetine,haloperidol, imipramine, levomepromazine, maprotiline, mianserin, nortriptyline, olanzapine, par-oxetine, perphenazine, risperidone, thioridazine, tranylcypromine, venlafaxine, zuclopenthixol


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to beta-agonists in asthmatics (20). Currentresearch in asthma pharmacogenetics hashighlighted associations between single nucle-otide polymorphisms in the betadrenergic recep-tors and modified response to regular inhaledbeta-agonist treatments (e.g. albuterol). Variantswithin the 5-lipoxygenase gene have beensuggested to predict the response to antileuko-trienes in subjects with asthma (21). Confirmationof these findings, together with the current rapidcreation of new knowledge, may mark thebeginning of the clinical use of genotyping at anindividual level as an adjunct to pharmacotherapyfor asthma and many other disorders.

There seems to be one substantial differencewhen comparing known pharmacodynamic andpharmacokinetic examples. In the case of muta-tions that result in pharmacodynamic effectsthese often seem to be family-specific. Geno-typing may be useful in identifying carrier status(heterozygote) for instance, and as a researchinstrument to shed light on receptor control andstructure. However, genotyping may not currentlybe useful outside such defined family groups.Compared with pharmacokinetic changes, at thecurrent state of knowledge, pharmacodynamicchanges have not been reported to be as impor-tant on a population basis, owing to low incidenceand prevalence. It may well reflect current lack ofunderstanding and could rapidly change in thefuture.

Gene expression and existing therapiesIncreasing knowledge of gene expression repre-sents a new aspect of genetics, including pharma-cogenetics. Initiated by development of micro-array analysis new methodologies allow determi-nation of the amount of RNA or of protein pro-duced by the gene to measure gene ‘efficiency’.For decades it has been known that some drugscan increase their own rate of metabolism or thatof other drugs, mostly through enzyme induction.The inducing drug may stimulate expression ofthe gene responsible for the production of theenzyme.

The use of microassays to measure rifampicineffect on the pattern of mRNA expression of drug-metabolizing enzymes in hepatocytes demon-strated that it had no effect on CYP2C18,CYP2E1 or CYP2D6. However, it caused almosta 3.7-fold increase of CYP2C9, 6.5-fold increaseof CYP2C8 and 55.1-fold increase of CYP3A4(22). Naturally, gene expression can be altered

by many other factors including gene-geneinteractions, diseases, hormones, foods andchemicals in the environment.

However, drugs already currently in use canpotentially affect gene expression and we may notknow whether a pharmacological effect resultsfrom the drug acting on the gene itself or on itsprotein product. Recent studies suggest that drugaddiction may represent an alteration of genes bythe drug (23). More knowledge on the variation ofdrug response due to altered gene expressionmay lead to better targeted therapy. In the past,pharmacogenetics studied the effect of genes ondrug action but attention to the reverse, i.e. drugsaffecting gene function should also be consid-ered.

The current situationPharmacogenetic testing is currently used in arelatively limited number of teaching hospitals andspecialist academic centres and is probably mostadvanced in Scandinavian countries. The mostwidely accepted application of pharmacogenetictesting is the use of CYP2D6 genotyping to aidindividual dose selection for drugs used to treatpsychiatric illness.

Several independent testing laboratories havestarted to provide the pharmaceutical industry andmedical practice with high throughput DNA-basedtesting service for a range of pharmacogeneticpolymorphisms. It is, however, difficult to predictto what extent the pharmaceutical industry willroutinely incorporate pharmacogenetic testing intoprescribing schedules for drugs that are subject topolymorphic metabolism. This will depend tosome extent on the attitude taken by drug regula-tory authorities.

The clinical applicability of pharmacogenetictesting depends on the relative importance ofeach polymorphism in determining therapeuticoutcome. Doctors need to be aware of whether adrug they are prescribing is subject to pharmaco-genetic variability and know how to use thisknowledge. In addition, a reliable DNA-basedtesting service with affordable prices needs to bemade available. For certain pharmacogeneticpolymorphisms (such as CYP2D6) there isalready sufficient knowledge about the implica-tions of genetically-determined variation toinstigate population based pharmacogenetictesting. Details of more than 20 drugs that areknown to be CYP2D6 substrates are now pro-


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vided in both the ABPI Compendium of DataSheets in Britain and the Physicians DeskReference in the United States (24, 25).

This may allow the choice and doses of specificdrugs, particularly those for treating psychiatricdisorders, to be used more appropriately. Atpresent, adverse drug reactions occur in asubstantial proportion of patients. A recent USstudy showed that, in patients prescribed psychi-atric drugs that are CYP2D6 substrates, adversedrug reactions were observed in every patientwith inherited mutations inactivating the CYP2D6gene (21). Approximately 7% of people of Cauca-sian origin have genetically impaired activity ofCYP2D6.

The future

The following developments may be predictedwith some confidence:

• Changes in labelling and prescribing advice willstart to relate dose to genotype and will highlightthe possibility of drug interactions when multipledrugs are prescribed concomitantly.

• The step-by-step creation and implementation ofprescribing guidelines based on clinical studiesfor drugs that are subject to substantial polymor-phic metabolism will increase.

• The establishment and recording of individualpatient genotypes and phenotypes i.e. ‘personalpharmacogenetic expression profiles’ willbecome part of medical records.

• Implemention of pharmacogenetics testing willsubstantially reduce the need for hospitalizationcaused by adverse drug reactions.

• Chanelling of public funds for improved use ofexisting therapies which will unfreeze financesfor new therapies and lead to better overallhealth outcomes for the population.

The anticipated benefits of pharmacogeneticsand pharmacogenomics could be considered as:

1. Improving rational drug use by identifyingpeople who respond and avoiding use in thosewho are at risk of serious adverse reactions.

2. A review of failed drugs and drug candidatesand expansion of the indications for drugs on themarkets.

3. A stepwise elimination of “trial-and-error” and“one-size-fits-all” prescribing.

4. Saving resources by avoiding treatment ofpopulations who cannot benefit from the drug inquestion.

Limitations

1. Funding motivation for research related toexisting therapies may be low and have tocompete with investment in new and innovativetherapies.

2. Public acceptance of genetic profiling mayneed time.

3. Access to a personalized approach may be toocostly to attract funds.

4. Distinguishing environmental factors fromgenetic factors may be more difficult than ex-pected and cause failure to achieve bettertreatment outcomes with pharmacogeneticapproaches.

5. Complexities of interactions with drugs andother types of health products may complicate apharmacogenetic targeting approach.

6. Pharmacogenetic targeting may raise ethicalconsiderations which need to be identified anddebated openly.

With a view to promoting more effective and safepersonalized medicine, existing therapies need tobe reviewed in the light of new scientific technolo-gies and data. It may be that some existingtherapies can offer improved outcomes withrelatively little investment and cost. However,more open discussion on how pharmacogeneticscould improve existing therapies is vital if this is tobecome a reality in everyday clinical practice.

References

1. Motulsky, A.G. Drug reactions, enzymes, andbiochemical genetics. Journal of the American MedicalAssociation, 165: 835–837 (1957).

2. Beutler, E. The hemolytic effect of primaquine andrelated compounds: a review. Blood, 24:103–139(1959).

3. Lazarou, J., Pomeranz, B.H., Corey, P.N. Incidence ofadverse drug reactions in hospitalised patients: a meta-analysis of prospective studies. Journal of the AmericanMedical Association, 279: 1200–1205 (1998).


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4. Agostoni, A., Cicardi, M. Drug-induced angioedemawithout urticaria. Drug Safety, 24: 599–606 (2001).

5. Smith, N.L., Psaty, B.M., Pitt, B. et al. Temporalpatterns in the medical treatment of congestive heartfailure with angiotensin-converting enzyme inhibitors inolder adults, 1989 through 1995. Archives of InternalMedicine, 158: 1074–1080 (1998).

6. Vleeming, W., van Amsterdam, J.G., Stricker, B.H. etal. ACE inhibitor-induced angioedema: incidence,prevention and management. Drug Safety, 18: 171–188(1998).

7. Brown, N.J., Snowden, M., Griffin, M.R. Recurrentangiotensin-converting enzyme inhibitor-associatedangioedema. Journal of the American Medical Associa-tion, 278: 232–233 (1997).

8. Dean, D.E., Schultz, D.L., Powers, R.H. Asphyxia dueto angiotensin converting enzyme (ACE) inhibitormediated angioedema of the tongue during thetreatment of hypertensive heart diseases. Journal ofForensic Science, 46: 1239–1243 (2001).

9. Aithal, G.P., Day, C.P., Kesteven, P.J. et al. Associa-tion of polymorphisms in the cytochrome P450 CYP2C9with warfarin dose requirement and risk of bleedingcomplications. Lancet, 353: 717–719 (1999).

10. Johansson, I., Lundquist, E., Bertilsson, L. et al.Inherited amplification of an active gene in the cyto-chrome P450 CYP2D locus as a cause of ultrarapidmetabolism of debrisoquine. Proceedings of theNational Academy of Science, 90: 11825–11829 (1993).

11. Bertilsson, L., Dahl, ML, Sjöqvist F, Aberg-Wistedt A,Humble M, Johansson I, et al. Molecular basis forrational mega-prescribing in ultrarapid hydroxylators ofdebrisoquin. Lancet, 341: 363 (1993).

12. Krynetski, E.Y., Tai, H.L., Yates, C.R. et al. Geneticpolymorphism of thiopurine S-methyltransferase: clinicalimportance and molecular mechanisms. Pharmacoge-netics, 6: 279–290 (1996).

13. Lennard, L., Lilleyman, J.S., Van Loon, et al.Genetic variation in response to 6-mercaptopurine forchildhood acute lymphoblastic leukaemia. Lancet, 336:225–229 (1990).

14. Daly, A.K. Pharmacogenetics of the major polymor-phic metabolizing enzymes. Fundamental & ClinicalPharmacology, 17: 27–41 (2003).

15. Poolsup, N., Li Wan Po, A., Knight, T.L. Pharmaco-genetics and psychopharmacotherapy. Journal ofClinical Pharmacology and Therapeutics, 25(3): 197–220 (2000).

16. Smeraldi, E., Zanardi, R., Benedetti, F. et al.Polymorphism within the promoter of the serotonintransporter gene and antidepressant efficacy offluvoxamine. Molecular Psychiatry, 3(6): 508–511(1998).

17. Zanardi, R., Benedetti, F., Di Bella, D. et al. Efficacyof paroxetine in depression is influenced by a functionalpolymorphism within the promoter of the serotonintransporter gene. Journal of Clinical Psychopharmacol-ogy, 20(1): 105–107 (2000).

18. Kim, D.K., Lim, S.W., Lee, S. et al. Serotonintransporter gene polymorphism and antidepressantresponse. NeuroReport, 11(1): 215–219 (2000).

19. Arranz, M.J., Munro, J., Birkett, J. et al., Pharmaco-genetic prediction of clozapine response. Lancet, 355:1615–1616 (2000).

20. Lima, J.J., Mohamed, M.H., Self, T.H. et al. Impor-tance of beta(2)adrenergic receptor genotype, genderand race on albuterol-evoked bronchodilation inasthmatics. Pulmonary Pharmacology and Therapeu-tics, 13(3),127–134 (2000).

21. Palmer, L. J., Silverman, E.S., Weiss, S.T. et al.Pharmacogenetics of asthma. American Journal ofRespiratory and Critical Care Medicine, 165(7), 861–866 (2002).

22. Rae, J.M., Johnson, M.D., Lippman, M.E. et al.Rifampin is a selective, pleiotropic inducer of drugmetabolism genes in human hepatocytes: studies withcDNA and oligonucleotide expression arrays. Journal ofPharmacology and Experimental Therapy, 299: 849–857 (2001).

23. Shalev, U., Grimm, J.W., Shaham, Y. Neurobiologyof relapse to heroin and cocaine seeking: A review.Pharmacology Reviews, 54: 1–42 (2002).

24. Association of the British Pharmaceutical Industry.ABPI compendium of data sheets and summaries ofproduct characteristics 1999–2000. DatapharmPublications. London, 2000.

25. PDR Publications. 2003 Physicians Desk Refer-ence. 57th edition. USA.

26. Chou, W.H., Yan, F-X., de Leon, J. et al. Extensionof a pilot study: impact from the cytochrome P450 2D6(CYP2D6) polymorphism on outcome and costs insevere mental illness. Journal of Clinical Psychophar-macology, 20(2): 246–251 (2000).


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Safety Issues

Fluticasone and adrenal crisisThere have recently been several reports world-wide of adrenal insufficiency developing inchildren using inhaled corticosteroids. TheAustralian Adverse Reactions Advisory Commit-tee (ADRAC) has received 10 such reports fromAustralia. Eight involved the use of fluticasone,either alone (Flixotide®) or in combination withsalmeterol (Seretide®) (1).

In 8 cases, the ages ranged from 3 to 10 years,and the doses of fluticasone from 250 to 1500 µgdaily; the daily dose was over 500 µg in 6 of thereports. Six of the children had adrenal crisis,which was associated with hypoglycaemia in allcases, convulsions in two, and coma in one. Inthree of the reports the adrenal crisis had beenprecipitated by an episode of gastroenteritis.

Adrenal crisis associated with inhaled cortico-steroid use occurs because of the systemicabsorption of the corticosteroid and consequentsuppression of endogenous glucocorticoids,leaving insufficient adrenal reserve to respond tostress (for example, infection). It may also resultfrom abrupt discontinuation or non-compliancewith treatment, leading to acute steroid deficiency.It may present as hypoglycaemia, abdominalpain, tiredness or vomiting, with or withoutconvulsions or coma.

Although adrenal insufficiency can occur with anyinhaled corticosteroid, it may be more commonwith fluticasone because of its greater potencyand hence lower equivalent dose (half the dose ofbudesonide or beclomethasone) (2, 3).

The Australian approved dose of inhaled flutica-sone for children is 100–200 µg daily. At thisdose, adrenal suppression is unlikely (4). The useof higher doses, however, is common. TheThoracic Society of Australia and New Zealandrecommends a maximum dose of 250 µg daily inchildren up to 5 years, and 500 µg daily inchildren over 5 years, before referral to a respira-tory physician (5). The National Asthma Councilrecommends a maximum dose of 500 µg daily forall children, before referral to a respiratory

physician. Higher doses may not confer greaterefficacy; a meta-analysis of trials of fluticasone inadolescents (>12 years) and adults indicated thatin patients using regular, long-term inhaledcorticosteroids, maximal efficacy was achieved atdoses around 500 µg/day, but 90% of the benefitwas achieved at doses of 100–250 µg/day (2).

Prescribers are reminded that inhaled cortico-steroids should be given at the lowest effectivedose and reviewed regularly, and should not bediscontinued suddenly. Screening for adrenalinsufficiency in children receiving high doseinhaled corticosteroids is generally not useful.Instead, parents of these children should bewarned of the potential for adrenal suppression,and advised to seek medical attention if the childexperiences any of the symptoms describedabove, particularly in the setting of an intercurrentillness (6).

References

1. Fluticasone and adrenal crisis. Australian AdverseDrug Reactions Bulletin, 22: 2 (2003).

2. Todd, G.R.G. et al. Survey of adrenal crisis associ-ated with inhaled corticosteroids in the United Kingdom.Archives of Diseases in Children, 87: 457–461 (2002).

3. Holt, S. et al. Dose-response relation of inhaledfluticasone propionate in adolescents and adults withasthma: meta-analysis. British Medical Journal, 323:1–8 (2001).

4. Flixotide Australian approved product information.

5. van Asperen, P.P. et al. The role of corticosteroids inthe management of childhood asthma. Medical Journalof Australia, 176: 169–174 (2002).

6. Macdessi, J.S. et al. Adrenal crisis in children treatedwith high-dose inhaled corticosteroids for asthma.Medical Journal of Australia, 178: 214–216 (2003).

Thiazolidinediones experiencePioglitazone (Actos®) and rosiglitazone(Avandia®) are thiazolidinediones, a new class oforal antidiabetic drugs, which act on the peroxi-some proliferator activated gamma (PPARg)

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nuclear receptor to reduce tissue insulin resist-ance. These glitazones may be used alone or incombination with sulfonylureas or metformin.Pioglitazone is also approved for use with insulin.

The Australian Drug Reactions Advisory Commit-tee (ADRAC) has received 44 reports associatedwith rosiglitazone, and 28 reports with pioglita-zone. Twelve reports with rosiglitazone and 4 withpioglitazone were of hepatic reactions, includingelevated liver enzyme levels (13 reports; 1 withjaundice), abnormal liver function (1), hepatocellu-lar damage (1) and hepatitis (1). However, liverenzyme levels may be elevated with diabetes orobesity.

Twelve possible cardiac reactions were reportedwith rosiglitazone and 6 with pioglitazone. Theevents were myocardial infarction (4 reports),cardiac failure (4), prolonged QT-interval (2),ventricular fibrillation with cardiac arrest (1) anddependent oedema (7: all with rosiglitazone). In 3of the 4 cases of myocardial infarction or cardiacfailure with rosiglitazone the patient had a historyof ischaemic heart disease. The cardiac events inthese patients may be related to co-morbidities,including age, diabetes, hypertension andischaemic heart disease. However, the glitazoneshave been associated with cardiac failure (1).

The first glitazone, troglitazone (Rezulin®) wasbriefly marketed, but was withdrawn due tohepatotoxicity. The glitazones should not be usedin patients with liver disease (including increasedtransaminase levels > 2.5 times the upper limit ofnormal), or in patients whose cardiac failure limitstheir physical activity. Careful monitoring ofhepatic and cardiac function is required, includingliver function tests every two months for at leastone year, even in patients with normal baselineliver enzyme levels.

The glitazones can increase subcutaneous fat,and cause fluid retention, with oedema andhaemodilution. Clinical studies suggest thatweight gain may be associated with improvedglycaemic control, but treatment should be re-evaluated in patients with excessive weight gain.The effect of glitazones on mortality and their rolein long-term treatment of type 2 diabetes are notyet established (2).

References

1. Wooltorton E. Rosiglitazone (Avandia®) andpioglitazone (Actos®) and heart failure. CanadianMedical Association Journal, 166: 219 (2002).

2. The glitazones — Early experience. AustralianAdverse Drug Reactions Bulletin, 22: 2 (2003).

Cefepime, ceftazidimeand neurotoxicityA recent study appearing in Pharmacotherapy hasreviewed 42 cases of cefepime-induced neurotox-icity and 12 cases of ceftazidime-induced neuro-toxicity. Both the frequency of drug resistance andthe prescription of broad-spectrum antibioticssuch as cefepime and ceftazidime have increasedover the last decade. However, antibiotic-inducedneurotoxicity seems to have been overlooked ormisinterpreted despite extensive administration ofthese agents. Early recognition of neurologictoxicity and withdrawal of the offending antibioticscan avoid serious consequences.

Clinical characteristics and timing of diagnosiswere examined. Common findings were confusionwith temporospatial disorientation (96% ofpatients), myoclonus (33%), and seizures (13%).These neurologic disorders frequently are en-countered in uraemic and elderly patients, whoare often in a confused state when they visit theirphysician. The risk of delayed diagnosis wasgreater with cefepime than ceftazidime neuro-toxicity.

Cefepime has had a good safety profile in termsof neurological complications. The occurrence ofseizures attributed to cefepime and ceftazidimehas been 1/10 000 and 3/1000 patients, respec-tively. Possible reactions were confused state,dysarthria, somnolence, psychosis, myoclonus,seizures, and sometimes, coma. Resolution ofthese manifestations after withdrawal of theimplicated antibiotic was considered appropriatesupportive evidence.

Mean age of 54 patients in the review was 61years in the cefepime group and 65 years in theceftazidime group. Confusion was the chiefsymptom in 93% and 91% of patients withcefepime and ceftazidime neurotoxicity, respec-tively. Myoclonus was subsequently detected in29% of the cefepime group and 50% of theceftazidime group.

Electro-encephalographic results were availablefor most patients (41/42 cefepime- and 8/12ceftazidime-treated patients); three distinctiveelectroclinical patterns of antibiotic neurotoxicitywere described. Patients in the cefepime groupwere in an encephalopathic state; their EEGs

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showed loss of background activity, increasedslow rhythms in the theta and delta range, andtriphasic waves. Symptoms of neurotoxicityabated in these patients with discontinuation ofthe drug rather than because of any change indegree of uraemia.

In the ceftazidime group, EEGs demonstratedepileptic activity; that is, epileptiform dischargessuch as polyspike discharges, rhythmic slowwaves, or irregular spikes or sharps, which initiallymight be confined to one region and becomemore widespread, subsequently spreading to bothcerebral hemispheres. Spike and wave dis-charges were suppressed after intravenousadministration of benzodiazepines. Electro-encephalographic abnormalities in ceftazidime-treated patients were accompanied by either overtconvulsions or continuous subclinical seizures.The latter condition, nonconvulsive status epilepti-cus, occurred in 35% of the cefepime group and75% of the ceftazidime group. The condition ischaracterized by prolonged clouding of con-sciousness and confusion associated withpersistent epileptiform discharges seen on EEG inthe absence of motor convulsive activity. General-ized convulsive seizure was observed in sixpatients with cefepime neurotoxicity.

The median interval between symptom onset anddiagnosis of cefepime versus ceftazidime neuro-toxicity was 5 and 3 days, respectively (p=0.005).Delayed diagnosis of cefepime neurotoxicity maybe due to lack of awareness of the adverse effect.Data gathered since these two broad-spectrumantibiotics were first marketed underscore thepotential for neurologic adverse events secondaryto their administration. Thus, clinicians’ aware-ness must be increased so that the time betweensymptom onset and diagnosis can be reduced.

Reference: Kai Ming Chow, Cheuk Chun Szeto,Andrew Che Fai Hui, et al. Retrospective Review ofNeurotoxicity Induced by cefepime and ceftazidime.Pharmacotherapy, 23(3): 369–373 (203).

Interstitial nephritis andproton pump inhibitorsInterstitial nephritis is a well-recognized but rarehypersensitivity reaction to omeprazole (1).Patients present with non-specific symptoms ofillness. The classic triad for interstitial nephritis offever, rash and eosinophilia is uncommon (2).Laboratory investigation confirms the presence ofrenal dysfunction and urine examination, including

microscopy, may show haematuria and proteinu-ria but may be unremarkable (3). The diagnosiscan only be confirmed by renal biopsy. Manage-ment involves withdrawal of omeprazole andsupportive treatment. Cases are commonlytreated with glucocorticoids, but the efficacy ofthis therapy has not been demonstrated incontrolled trials (2).

The Australian Drug Reactions Advisory Commit-tee (ADRAC) has received 18 biopsy-confirmedreports of interstitial nephritis with omeprazole.The median age was 68 (range 47–86) years,with 5 males and 13 females affected. Themedian time to onset was 3 months (range 12days to 12 months). In 7 cases the associationwas not made immediately, and withdrawal ofomeprazole occurred 3 weeks to 6 months afterthe first symptoms of interstitial nephritis. Nine ofthe 18 patients had recovered at the time of thereporting, including two who showed rapidrecovery over 2 or 3 weeks (4).

Presenting symptoms included weight loss,malaise, fever and nausea. Polyuria and polydip-sia were present in one case. Elevation of plasmaurea and/or creatinine was documented in mostcases. Urine microscopy, in 3 cases, showed redcells, white cells and casts. In the 8 cases forwhich details of the results of renal biopsy wereprovided, mononuclear infiltrates of lymphocytes,plasma cells and eosinophils were usually presentand some also had histiocytes.

ADRAC has also received two reports of biopsy-proven interstitial nephritis with rabeprazole(Pariet®). No reports have been received inAustralia for the other proton pump inhibitors, butinterstitial nephritis is listed as an adverse effectin the product information for esomeprazole(Nexium®), lansoprazole (Zoton®) andpantoprazole (Somac®).

Interstitial nephritis has also been associated withthe ß-lactam and sulphonamide antibiotics,diuretics, NSAIDs, cimetidine, allopurinol andrifampicin. Patients taking a proton pump inhibitor,or any of the medicines listed above who becomeunwell without identified cause should have renalfunction assessed.

References

1. Australian Adverse Drug Reactions Advisory Commit-tee (ADRAC). Omeprazole and interstitial nephritis.Australian Adverse Drug Reactions Bulletin, 14: 15(1995).

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2. Myers, R.P., McLaughlin, K., Hollomby, D.J. Acuteinterstitial nephritis due to omeprazole. AmericanJournal of Gastroenterology, 96: 3428–3431 (2001).

3. Savage, R. Omeprazole-induced interstitial nephritis.Prescriber Update, No. 20, 2001, pp.11–13.

4. Interstitial nephritis with the proton pump inhibitors.Australian Adverse Drug Reactions Bulletin, 22: 2(2003).

Interactions withgrapefruit juiceFollowing comments received after publication ofits recent article (1), the Australian Adverse DrugReactions Advisory Committee (ADRAC) has re-evaluated the literature, and wishes to revise itsadvice. Although there are no case reports of

significant clinical problems occurring whengrapefruit juice and medication ingestion havebeen separated by more than a few hours,studies suggest there is a potential for grapefruitjuice to have an interacting effect for up to 3 daysafter ingestion, particularly with daily consump-tion. ADRAC now considers that the safest courseis to avoid grapefruit and its juice altogether whentaking medicines that interact (2).

References

1. Australian Adverse Drug Reactions Advisory Commit-tee (ADRAC). Interactions with grapefruit juice.Australian Adverse Drug Reactions Bulletin, 21: 14(2002).

2. Interactions with grapefruit juice — amendmentAustralian Adverse Drug Reactions Bulletin, 22: 2(2003).

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and unexpected adversedrug reactions. A signal is defined as "reported information on a possible causal relationship between an adverseevent and a drug, the relationship being unknown or incompletely documented previously. Usually, more than a singlereport is required to generate a signal, depending upon the seriousness of the event and the quality of the informa-tion". All signals must be validated before any regulatory decision can be made.

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Current Topics

New network for guidelinedevelopmentThe World Health Organization has become afounding member of the new Guidelines Interna-tional Network (GIN). This is a major new interna-tional collaboration involving organizations fromaround the world. GIN seeks to improve thequality of health care by promoting systematicdevelopment of clinical practice guidelines andtheir application into practice. GIN’s aims are:

• To facilitate information sharing, education andknowledge transfer, and collaborative workingbetween guideline programmes to promote bestpractice and avoid duplication of effort.

• To improve and harmonize methodologies forsystematic guideline development in existingand new guideline programmes.

• To improve methodologies for dissemination andimplementation of clinical practice guidelinesand evaluation of their effects.

• To identify priorities for and support researchrelating to guideline development, dissemina-tion, implementation, and evaluation; and tofacilitate the application of research findings intopractice.

• To build links between organizations to improvecoordination with other health care qualityinitiatives.

So far, about forty organizations dealing withguideline development and quality of care fromAustralia, Austria, Belgium, Canada, Denmark,Finland, France, Germany, Ireland, Italy, Nether-lands, New Zealand, Norway, Portugal, Slovenia,Spain, Sweden, Switzerland, United Kingdom andUSA have become founding members, at EUR2500 per year.

WHO has become a founding member with theaim of representing the global perspective, andespecially the developing country perspective.WHO has also negotiated a limited number of

subsidized GIN memberships for organizationsfrom developing countries.

Reference: Guidelines International Network, PO Box13163, Duns, TD11 3YT, UK. Tel: +44.1361.884012,Fax: +44.1361.884013 e-mail: [email protected]. http:/www. guidelines-international.net

Fake artesunate tabletscirculating againIn the late 1990s, counterfeits of artesunate, avital life-saving antimalarial drug, were dis-covered circulating in South-east Asia (1). Up to38% of ‘artesunate’ labelled as manufactured byGuilin Pharma, People’s Republic of China,bought in pharmacies and shops in mainlandSouth-east Asia contained no detectable artesu-nate. This has led to an unquantified but inevita-bly high mortality and morbidity amongst falci-parum malaria patients in the region. Fakesdescribed in 2001 were relatively easy to distin-guish from the genuine product by the appear-ance of the packaging and holograms (2). Asimple, inexpensive dye test allows one to reliablycheck the authenticity of artesunate tablets (3).

A team of researchers has now warned of twofurther sophisticated ‘generations’ of counterfeit‘artesunate’, again labelled as produced by GuilinPharma — bought in Laos and Cambodia — withnew, convincing and very well crafted but fakeholograms attached to the blister pack.

The first-generation fake hologram described in2000 is not a true hologram but a sticker and easyto distinguish from the genuine hologram. This isstill in circulation.

The second-generation hologram is a truehologram and only appears to differ from thegenuine hologram in the shape of the mountainoutline and the lack of the microscopic legend‘Guilin Pharma’ printed below the ‘waves’. Theprinting on the blister pack is not clear. Threeblisterpacks were recently bought in southernLaos and one in North-east Cambodia with thissecond-generation hologram. All have the same

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code, manufacture and expiry dates. It is likelyhowever that artesunate with this second -generation fake hologram has or will be madewith different dates and codes.

The third-generation hologram has a mountainoutline similar to the genuine Guilin product butlacks the microscopic legend ‘Guilin Pharma’printed below the ‘waves’. The printing on theblister pack is crisp and similar to that on thegenuine product. Two blister packs bearing thisnew hologram were recently bought in southernLaos.

All six artesunate blister packs with the second-and third-generation fake holograms werenegative for artesunate by the Fast Red dye testand contained no artesunate on HPLC analysis.Fake artesunate with the new sophisticatedsecond- and third-generation fake holograms arewidely distributed but because of their similarity tothe genuine product they are probably unrecog-nized by pharmacists, health staff and patients.

It is also possible that Guilin Pharma artesunate isnow being sold in some West African countries,such as Togo, and fakes may also be circulatingthere.

PDF files of documents warning of the recentdiscovery of sophisticated counterfeit artesunate,with photographs of the different holograms, anda description of the Fast-Red dye test, areavailable from [email protected] [email protected]. Pictures of thegenuine and fake holograms are also posted onthe Shoklo Malaria Research Unit website (http://www.shoklo-unit.com/fakes2.pdf).

Communication to WHO from Paul Newton, ArjenDondorp, Michael Green, Shunmay Yeung,Nicholas J. White on 19 June 2003.

References

1. Rozendaal, J. Fake antimalarials circulating inCambodia. Bulletin of Mekong Malaria Forum, 7: 62–68(2000).

2. Newton, P.N., Proux, S., Green, M. et al. Fakeartesunate in southeast Asia. Lancet, 357: 1948–1950(2001).

3. Green, M.D., Mount, D.L., Wirtz, R.A. Authenticationof artemether, artesunate and dihydro-artemisininantimalarial tablets using a simple colorimetric method.Tropical Medicine and International Health, 6: 980–982(2001).

European Union enlargement:observers to EMEAThe ten accession candidate countries expectedto join the European Union in May 2004 —Cyprus, Czeck Republic, Estonia, Hungary,Latvia, Lithuania, Malta, Poland, The SlovakRepublic and Slovenia — began work with theEuropean Agency for the Evaluation of MedicinalProducts (EMEA) on 1 April 2003 in a new phaseof cooperation and will join scientific committeesand working parties as observers. This builds onsuccessful PERF (Pan-European RegulatoryForum) (1) preparatory training and exchangeprogrammes.

As part of the ongoing preparations for accession,the EMEA has put in place a programme ofbenchmarking visits to national authorities of theaccession countries, including Bulgaria andRomania. The visits are intended to enhance theimplementation of an integrated quality manage-ment system to ensure good regulatory practicesin the EU and provide targeted audit training forparticipating quality professionals (2).

References

1. http://perf.eudra.org

2. Document EMEA/D/8004/03, 31 March 2003, http://europa.eu.int

Clinical cancer research reviewThe American Society of Clinical Oncology(ASCO) has released new recommendations toimprove the cancer clinical trial review system.The new policy is unique in its recommendationthat oversight and review of cancer clinical trialsbe centralized, reducing some of the burden onlocal institutional review boards (IRBs) caused byduplication in the system, improving patientsafety, and streamlining clinical cancer researchreview.

ASCO has also released a revised conflict ofinterest policy requiring clinical cancer research-ers seeking to publish or present trial outcomes todisclose virtually all financial ties to trial sponsors,and restricting the financial interests of principalinvestigators and other clinical trial leaders. Theadditional requirements apply to all those en-gaged in ASCO activities including presenters atthe Society’s Annual Meeting, authors who submitmanuscripts for publication in the Journal of

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Clinical Oncology, and anyone serving on ASCO’sBoard of Directors, committees, or task forces.The policies were developed by a special TaskForce on Oversight of Clinical Research, and willappear in the June 15 issue of ASCO’s Journal ofClinical Oncology. They are published online athttp://www.jco.org.

Oversight of Clinical TrialsThe Task Force examined the current structure,expertise and function of IRB’s, including theirinitial and ongoing review and oversight of trials.The ASCO Task Force calls for centralized trialreview, beginning with cancer trials conductedthrough the National Institutes of Health (NIH)cooperative group system. Under this system, acentralized review board (CRB) would be respon-sible for the initial ethical review of a trial, coordi-nate data gathering, monitor adverse events, andgive local IRBs an analysis and summation ofadverse events across the trial sites. The policystatement does not recommend changing thelocal IRB’s critical role in monitoring patient safetyonsite during a trial or ensuring proper staffingand adherence to protocol.

Recommendations:

• Education and Training: All IRB members,investigators, and members of the research staffshould receive comprehensive, ongoing educa-tion and training on the ethical conduct ofresearch to ensure the safety of researchparticipants and the scientific integrity ofresearch.

• Informed Consent: The IRB should focusattention on oversight of the informed consentprocess, not chiefly the informed consentdocument. Where possible, consent formsshould be simplified to ensure understanding bypotential trial participants.

• Oversight: The Department of Health andHuman Services’ Office of Human ResearchProtections (OHRP) and the Food and DrugAdministration (FDA) should provide clearregulatory support and uniform guidance to localIRBs and modify regulations to allow greateruse of centralized review.

• Resources Supporting Clinical ResearchInfrastructure: Institutions should devoteadequate funding and institutional support totheir research review system to ensure effectiveresearch oversight.

Conflict-of-InterestThe Task Force also updated ASCO’s conflict-of-interest policy, outlining new financial disclosurelevels, restricted activities for researchers inleadership roles, and general prohibitions for allclinical investigators.

The new guidelines also restrict individuals in atrial leadership role – including principal investiga-tors, members of the data safety monitoringboard, and members of the trial’s executivecommittee – from receiving or holding stock orequity interest in the trial sponsor royalties orlicensing fees, patents, position as officer, boardof directors’ member, or employee of the trialsponsor. Travel or trips paid by the trial sponsorResearch-related payments, honoraria or giftsfrom the trial sponsor. The new conflict-of-interestpolicy will take effect April 29, 2004.

Reference: http://www.jco.org/early_release/.

New foundation will developtests for infectious diseasesIn response to a critical need for new tools todetect infectious diseases, the UNDP/WorldBank/WHO Special Programme for Research andTraining in Tropical Diseases (TDR) and the Bill &Melinda Gates Foundation have announced anew initiative focused on developing newdiagnostic tests for the world’s most deadlydiseases. The Foundation for Innovative NewDiagnostics (FIND) will work in collaboration withWHO/TDR, the diagnostics industry and otherorganizations to apply the latest biotechnologyinnovations to develop and validate affordablediagnostic tests for diseases of the developingworld. The Gates Foundation has committed up to$30 million over the next five years to the initia-tive.

There is an urgent need for more accurate andcost-effective diagnostic technologies, particularlyfor diseases of the developing world. While thebiotech revolution has yielded important progressin the diagnosis and treatment of diseases thataffect affluent societies, these advances havenot been applied to diseases that kill millions eachyear in developing countries. As a result, manydiseases go undetected and untreated in thedeveloping world, accelerating their spread.

Building on the accomplishments of TDR’sTuberculosis Diagnostics Initiative, FIND will

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focus initially on TB, speeding up the develop-ment and evaluation of new tests to detect thedisease, including drug resistant forms. TB waschosen as the first target for FIND because of themagnitude of the problem — one-third of theworld’s population carries the TB pathogen— andthe ability of existing health systems to treatcases once they are detected.

Today’s standard TB detection method, examiningsputum under a microscope, was developed overa century ago. It is time-consuming and frequentlyinaccurate. While the success of the Global DrugFacility and other treatment programmes haveimproved the access of TB patients to effectivetherapy, diagnostics are now recognized as aprimary stumbling block in TB control and patientcare.

Research carried out over the past two years bythe TB Diagnostics Initiative show that althoughTB and other diseases of the poor have beenlargely neglected by the bigger diagnosticscompanies, there is considerable work going on insmaller biotechnology companies andacademic research groups. However, even whendiagnostics are developed for infectious diseases,they do not always reach the public sector. FINDwill also work with private industry, WHO, andother technical agencies to ensure that the toolsin development match public health needs.

TB kills one person every 15 seconds. The casefatality rate of TB is high, in large part because oflack of diagnosis and treatment. More sensitivediagnostics will open the possibility of treating theless contagious cases before they infect others.Faster, simpler diagnostics will make TB controlefforts more effective, especially in places wherepatients have difficulty reaching health care.

TB is responsible for 5% of all deaths worldwideand 9.6% of adult deaths in the 15–59 age group.TB kills more women worldwide than all causes ofmaternal mortality. The disease is concentrated inlow income countries. Some 80% of all TB casesare found in 22 countries, with more than half thecases occurring in five South East Asian coun-tries. Nine out of 10 countries with the highestincidence rates are in Africa, where prevalent HIVinfection has fuelled the epidemic and furthercomplicated diagnosis.

In addition to developing and evaluating tests,FIND will fund demonstration projects to deter-mine the potential impact of newly developed

products and improve their use in developingcountries. WHO/TDR will be a key player inthe interaction with researchers, in setting upclinical trials and carrying on the implementationresearch required during the introduction of thenew diagnostic tools by the health services ofdisease-endemic countries. FIND represents anexpansion of TDR’s ongoing efforts to discoverand develop diagnostics for neglected infectiousdiseases. In coordination with public healthofficials, the collaboration between WHO/TDRand FIND will ensure that appropriate technolo-gies reach appropriate settings. Findings willprovide input to the WHO on standard setting fordiagnostics and regulatory harmonization.

References: http://www.who.int/tdrhttp://www.gatesfoundation.orghttp://www.finddiagnostics.org

TDR research training in 2004The UNDP/World Bank/WHO Special Programmefor Research and Training in Tropical Diseases(TDR) invites applications for the award ofresearch training grants from individuals who arenationals of and employed in developing disease-endemic countries with lesser developed researchcapacities. Grants are awarded on a competitivebasis for studies leading to a postgraduate degreeor for acquiring specialized skills.

Studies must be on one or more of the TDR targetdiseases — malaria, leishmaniasis, schistosomia-sis, lymphatic filariasis and onchocerciasis,African trypanosomiasis and Chagas disease,leprosy, dengue and tuberculosis, in laboratory,clinical or applied field research disciplinesrelevant to TDR and/or national priorities. Trainingmay take place in the home country, in anotherdeveloping country, or in a developed country.TDR reserves the right to select the academicinstitution, research programme or TDR-fundedproject where it is felt the most suitable trainingcan be obtained.

Research capability strengthening is a cross-cutting area of TDR established to promote andfund research training and institution developmentto increase the participation of developingcountries in the development and use of new orimproved tools for the prevention and control ofcommunicable diseases. The long-term mission isto increase research self-reliance in endemiccountries for identifying needs and developingsolutions to public health problems caused by

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neglected infectious diseases. TDR contributes tothe attainment of these goals by strengtheningresearch institutions, generating new scientificknowledge in biomedical and social sciences andbuilding a critical mass of human resources torespond to research and public health needs.Partnerships, networking and promoting equalopportunities constitute the core of the strategyand the basis for promoting a gender and geo-graphically balanced generation of scientists.

The TDR web site is available on http://www.who.int/tdr/grants/workplans and containsResearch Capability Strengthening (RCS),Multilateral Initiative on Malaria /TDR (MIM)TaskForce and other specific calls for research trainingapplications and Career Development Fellow-ships. All applications must be received by 1November 2003 at the following address: Re-search Training, UNDP/World Bank/WHO SpecialProgramme for Research and Training in TropicalDiseases (TDR), 1211 Geneva 27 SwitzerlandFax (41 22) 791-4854 e-mail: [email protected]

Reference: http://www.who.int/tdr/grants/workplans

Managing drug supply forprimary health careWHO, in association with the InternationalDispensary Association (IDA), ManagementSciences for Health (MSH), and RéseauMédicaments et Développement (ReMeD), hasorganized a training course for pharmacists,physicians, senior health system managers andtechnical assistance professionals from non-governmental and governmental organizations.

The course, Managing drug supply for primaryhealth care, has the following objectives:

• Expose participants to modern managementtechniques of drug supply systems and to teachthem how to apply these in their own specificsituation;

• Provide practical tools for decision-makers toimprove performance of essential drugs pro-grammes;

• Exchange views and experiences betweensenior decision-makers.

The course will be held in Amsterdam, Nether-lands, from 15–26 September 2003 (in English)and from 20–31 October 2003 (in French).

This year will be the eighth year of organization ofthe course. Past experience has shown that it isparticularly effective in helping to close the gapbetween what is known about public healthproblems and what is done to solve them.

For additional information and registration form,contact: Julie Pasquier, IDA Solutions, Tel: +31 2040 33 051 Fax : +31 20 40 31 854 or e-mail:[email protected]

Reference. http://www.ida.nl

Latin Americanpharmacotherapy courseThe Fifth Latin American Course on Pharmaco-therapy will be held from 31 August –12 Septem-ber 2003, in La Plata, Argentina. It is beingorganized by the Universidad Nacional de LaPlata (Argentina) in collaboration with the WorldHealth Organization and the PanAmerican HealthOrganization, Argentina.

The course, conducted in Spanish, will beoperated for the benefit of two audiences: (i)trainers of trainers, who can replicate this course,and (ii) teachers of pharmacotherapy, clinicalmedicine, paediatrics, and gerontology working inundergraduate or postgraduate settings, medicalschools, or teaching hospitals.

The general objective of the course is to provideknowledge and practical experience on a prob-lem-based approach for pharmacotherapyteaching. At the end of the course, it is expectedthat the participants will have:

• Developed and identified methodologies tofacilitate criteria selection in the choice andapplication of drug therapy and/or appropriatetreatment to solve health problems.

• Obtained appropriate knowledge on problem-based methods of learning/teaching medicineand pharmacotherapy.

• Obtained the experience, knowledge andnecessary skills to train teachers to developabilities and be facilitators.

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• Obtained the knowledge and necessary skills toplan, develop, implement and assess a prob-lem-based pharmacotherapy course, in theirown medical school or educational institution.

• Acquired critical appraisal in the use of sourcesof information about drugs and treatments.

The course is based on methodology developedby the University of Groningen, Faculty of MedicalSciences, Department of Clinical Pharmacology,Netherlands. The principles of the model underlythose set out in the WHO Guide to Good Pre-scribing (1, 2). This course has been successfullyintroduced in Europe, Africa and Asia. Since1999, it has been developed in America.

The Course will be run by academic staff of thePharmacology Department, Faculty of Medical

Sciences, Universidad Nacional de La Plata, withcontributions from national and internationalguests. Representatives of the World HealthOrganization will also be present.

More information is available from: CentroUniversitario de Farmacologia (CUFAR), Facultadde Ciencias Medicas, Universidad Nacional de LaPlata, Calle 60 y 120- 3er piso, La Plata 1900,Argentina. Tel: 54 (221) 421-6932 Fax : 54 (221)423-6710 e-mail: [email protected] [email protected]

References

1. World Health organization. Guide to Good Prescrib-ing, WHO/DAP/94.11 (1994).

2. World Health organization.Teachers Guide to GoodPrescribing. WHO/EDM/PAR/2001.2 (2001).

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Regulatory and Safety Action

Gefitinib approvedfor lung cancerUnited States of America — The Food and DrugAdministration (FDA) has announced the approvalof gefitinib (Iressa®) tablets as a single agenttreatment for patients with advanced non small-cell lung cancer (NSCLC), the most common formof lung cancer in USA. Gefitinib is being approvedas a treatment for patients whose cancer hascontinued to progress despite treatment withplatinum-based and docetaxel chemotherapy, twodrugs that are currently the standard of care inthis disease.

Gefitinib was reviewed and approved under FDA’saccelerated approval programme, which isintended to allow patients suffering from seriousor life-threatening diseases earlier access topromising new drugs. As required by the acceler-ated approval regulations, additional studies willbe performed to verify the drug’s clinical benefit.

The mechanism by which gefitinib exerts itsclinical benefit is not fully understood. However,gefitinib was developed to block growth stimula-tory signals in cancer cells. These signals aremediated in part by enzymes called tyrosinekinases. Gefitinib blocks several of these tyrosinekinases, including the one associated withepidermal growth factor receptor (EGFR).

FDA based the approval on the results of a studyof 216 patients with NSCLC, including 142patients with refractory disease, i.e., tumoursresistant or unresponsive to two prior treatments.The response rate (defined as at least 50%tumour shrinkage lasting at least one month) wasabout 10%. There were more dramatic responsesin some patients and the median duration ofresponse was 7 months. On September 24, 2002,the Oncologic Drugs Advisory Committee (ODAC)recommended that in third-line treatment ofNSCLC, where there are no viable treatmentoptions, a 10% response rate was reasonablylikely to predict clinical benefit and recommendedthat gefitinib be approved.

Results from two large, controlled, randomizedtrials in initial treatment of NSCLC showed nobenefit from adding gefitinib to standard, plati-num-based chemotherapy. Therefore, gefitinib isnot indicated for use in this setting.

There appeared to be substantial differences inresponse rates in subsets of patients, with higherresponse rates for women (about 17%) andpatients with adenocarcinoma, and with lowerresponse rates seen in men (about 5%) andsmokers.

The sponsor has agreed to conduct furtherstudies after approval to measure its clinicalbenefit. One study will evaluate treatment inpatients with lung cancer resistant to two previouschemotherapy regimens and will determinewhether gefitinib prolongs survival compared tobest supportive care. A second study will comparetreatment with an approved chemotherapy drug(docetaxel) in patients with lung cancer resistantto one previous chemotherapy regimen. The thirdtrial will evaluate whether gefitinib will decreasecancer symptoms in patients with lung cancerresistant to all available chemotherapy.

Common side effects reported with gefitinib inclinical trials were nausea, vomiting, diarrhoea,rash, acne, and dry skin. Gefitinib may cause fetalharm when administered to pregnant women.A significant safety concern associated withgefitinib emerged just after the ODAC meeting.Reports from Japan described the occurrence ofserious and sometimes fatal interstitial lungdisease (ILD) in patients treated with gefitinib.The FDA extended its review by three months toreview these reports.

After careful review of information from allsources, including a comprehensive analysis ofupdated toxicity information from clinical trials andthe Iressa® Expanded Access Program, involvingapproximately 23 000 patients, FDA determinedthat the incidence of ILD was approximately 2% inthe Japanese experience and approximately 0.3%in the United States, with about one-third ofaffected patients dying from this toxicity. FDAbelieves that this rare but serious toxicity of

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gefitinib does not outweigh the benefits demon-strated in patients with advanced NCSLC.

Reference: FDA News, P03-36, May 5, 2003

New breath testfor monitoring asthmaUnited States of America — The Food and DrugAdministration (FDA) has cleared for marketing afirst-of-a-kind, non-invasive test system tomeasure the concentration of nitric oxide inexhaled human breath. The test system shouldmake it easier to monitor asthma.

Doctors can use the device in their office toevaluate their patient’s response to anti-inflamma-tory treatment. A decrease in exhaled nitric oxideconcentration suggests that the anti-inflammatorytreatment may be decreasing the lung inflamma-tion associated with asthma. Recent evidence hasshown that nitric oxide levels are increased in thebreath of people with asthma and that changes innitric oxide levels may indicate whether or nottreatment for asthma is working.

The test system, called the NIOX Nitric Oxide TestSystem®, combines equipment that detects nitricoxide and equipment that analyses exhaledbreath with a special computer system. To usethis new device, the patient places a mouthpiece,connected by a breathing tube to the computer,over his mouth. The nitric oxide concentration isdisplayed immediately on the computer screen.

FDA cleared the NIOX system based on clinicalstudies conducted by the manufacturer of 65patients, both adults and children aged four yearsand older, with confirmed diagnoses of asthma.The patients were tested with the NIOX systembefore they began drug treatment and again twoweeks later. The studies were conducted at ninemedical centres in the United States. The resultsshowed that most patients had a 30%–70%decrease of nitric oxide levels after two weeks oftreatment with inhaled steroids. In this study,elevated nitric oxide levels above 30 parts perbillion correlated with moderate to severe asthma.

Asthma is a highly variable disease affectingmillions of people worldwide. With asthma, thelungs become inflamed and constrict, limitingairflow and making breathing difficult. The inci-dence of asthma in the United States has in-creased in recent years and it now affects about15 million Americans, including almost five

million children. Every year, asthma causesroughly 2 million emergency room visits, approxi-mately 500 000 hospitalizations, and 4500deaths.

Reference: FDA Talk Paper, T03-33, 1 May 2003

Risperidone: prescribinginformation updateUnited States of America — The manufacturerof the antipsychotic, risperidone (Risperdal®), hasupdated the prescribing information to include awarning of cerebrovascular adverse events,including stroke, in elderly patients with dementia.Action is based on data from four placebo-controlled trials conducted in elderly patients withdementia.

Cerebrovascular adverse events (e.g., stroke,transient ischaemic attack), including fatalities,were reported in patients (mean age 85 years;range 73–97) in trials of risperidone in elderlypatients with dementia-related psychosis. Inplacebo-controlled trials, there was a significantlyhigher incidence of cerebrovascular adverseevents in patients treated with risperidonecompared to patients treated with placebo.risperidone has not been shown to be safe oreffective in the treatment of patients with demen-tia-related psychosis.

Like all other antipsychotics, risperidone is notindicated for the treatment of dementia.

Reference: Communication from JanssenPharmaceutica, 16 April 2003 accessed on http://www.fda.gov/medwatch.

Pan Pharmaceuticals productrecallsAustralia — The Therapeutic Goods Administra-tion (TGA), has suspended the licence held byPan Pharmaceuticals Limited, Sydney, to manu-facture medicines following a series of serioussafety and quality breaches by the company.These included substitution of ingredients,manipulation of test results and substandardmanufacturing processes. In addition, the TGAhas ordered an urgent recall of 219 productswhich Pan Pharmaceuticals manufactures andsupplies in Australia. Pan Pharmaceuticals isAustralia’s largest contract manufacturer ofcomplementary medicines such as herbal,

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vitamin, mineral and nutritional supplements.They also manufacture some over-the-counter(OTC) medicines including pain relievers(paracetamol & codeine) and cold and flu prepa-rations (antihistamine & pseudoephedrine).

Other companies also use Pan Pharmaceuticalsto manufacture their own brand products and theTGA will be working with these companies toidentify which other products should be subject torecall. The action by the TGA follows advicereceived from an expert advisory group that thequality and safety concerns posed by the manu-facturing breaches at Pan Pharmaceuticalsneeded to be urgently addressed. Acting on thatadvice the TGA has suspended the company’slicence with immediate effect.

This is not the first action taken against PanPharmaceuticals. In January 2003 an anti-travelsickness tablet, Travacalm® manufactured byPan Pharmaceuticals for another company, wasthe subject of a consumer recall. Faulty batchesof the tablets were responsible for 19 peoplebeing hospitalized and 68 others experiencingpotentially life-threatening adverse reactions tothis over-the-counter medicine. Subsequentlaboratory testing by the TGA of some of thetablets revealed that one of the active ingredients— hyoscine hydrobromide — varied in contentfrom 0–700% of the listed dose.

The TGA undertook further audits of the companywhich also revealed serious deficiencies in thecompany’s manufacturing and quality controlprocedures, including systematic and deliberatemanipulation of quality control test data.

Some examples identified by the audit included:

• On 13 March 2003 the status of 270 rawmaterials was changed in the company’scomputer from Quarantine to Pass. In a randomsample of these, none had been tested. It hasbeen clearly identified that some were used inmanufacture but not tested by the time of theaudit on 14 April 2003. For example, 7 of theseraw materials were used in the manufacture of34 batches of products.

• Four recent examples of manipulation of theassay results of finished products in order tocomply with specifications. These occurredbetween October 2002 and 22 January 2003and involved an “energy” product, a vitaminproduct and a cough and cold formula.

• Four recent examples of the fabrication offinished product assay results of a vitaminproduct for export in order to comply withspecifications. In two instances the product wasover-strength (March 2003); in the other two,under-strength.

• In the past two and a half years, several in-stances of the use of beef cartilage in place ofshark cartilage and one instance of use of sharkcartilage in place of beef cartilage.

• Five instances where products were releasedand dispatched in the period 24 March 2003 to31 March 2003 without completion of the testingof the raw materials used.

Reference : Therapeutic Goods Administration, on http://www.tga.health.gov.au

Telithromycine andmyasthenia gravisSpain — The Spanish Medicines Agency, in linewith other Agencies of the European Union, hasannounced the urgent modification to the datasheet information concerning administration oftelithromycine (Ketek®) in myasthenia gravispatients. Telithromycine is a semi-syntheticsubstance derived from erythromycin marketed inthe European Union since July 2001. Its use islimited to adults for treatment of communityacquired pneumonia, severe bronchitis or sinusi-tis. For patients over 12 years of age, it is alsoindicated in group A streptococcal pharyngitis andtonsillitis when beta lactam antibiotics are notconsidered appropriate.

Eight cases (one fatal) of exacerbation ofmyasthenia gravis have been reported in associa-tion with use of telithromycine. Symptoms re-ported were exacerbation of muscular weakness,dyspnoea, and acute pulmonary failure within afew hours of administration.

The mechanism of action causing worsening ofmyasthenia gravis is unknown, but cases havebeen reported in association with aminoglycoside,macrolide antibiotics, and certain fluoroquino-lones.

The following points are brought to the attentionof prescribers:

1. Given the severity of risk, telithromycine is notindicated in myasthenia gravis patients unlessalternative treatment is not available.

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2. Myasthenia gravis patients using telithromycineshould be closely monitored and should reportimmediately to their physician any worsening ofsymptoms. Treatment should be discontinuedin such cases.

Reference: No. 2003/05, 23 April 2003. http:/www.msc.es/agemed

Astemizole: marketingsuspensionSpain — The Spanish Medicines Agency hasdecided to suspend the marketing authorizationfor the non-sedating antihistamine, astemizole.Use has been associated with a risk of cardiacarrhythmia which has been demonstrated in areview of data. Consumption of astemizole inSpain and other European countries has de-creased considerably.

Given this situation, the Committee on Safety ofHuman medicines has concluded that the benefit/risk ratio is unfavourable since safer alternativesare available on the market.

Reference: No. 2003/04, 8 April 2003. http://www.msc.es/agemed

Somatropin: negative opinionEuropean Union — The Committee for Propri-etary Medicinal Products of the European Agencyfor the Evaluation of Medicinal Products (EMEA)has adopted a negative opinion on the requestfor marketing authorization for somatropin(Serostim®) for the following reasons:

• A target population could not be identified fortreatment.

• Doubts remain about the clinical relevance ofthe primary endpoints.

• Long-term efficacy data under controlledconditions are lacking.

• There is concern about the long-term safetyprofile.

Serostim® was designated an orphan medicinalproduct on 8 August 2000. The active substanceis somatropin, a recombinant human growthhormone with anabolic effects.

Reference: CPMP/5330/02,. 25 April 2003.

Repaglinide and gemfibrozil:hazardous interactionEuropean Union — The European Agency forthe Evaluation of Medicinal Products (EMEA) hasissued a public statement concerning an interac-tion between repaglinide (NovoNorm® andPrandin®), a medicine used to lower blood sugarin diabetic patients, and gemfibrozil, a lipid-lowering agent.

A recent study indicates that the blood glucose-lowering effect of repuglinide may be markedlyenhanced and prolonged when administeredtogether with gemfibrozil, with an increased risk ofhypoglycaemia. In addition, five reports of serioushypoglycaemic episodes in patients usingrepaglinide and gemfibrozil at the same time havebeen received.

Repaglinide is indicated in patients with Type 2diabetes (non insulin-dependent diabetesmellitus) whose hyperglycaemia can no longer becontrolled satisfactorily by diet, weight reductionand exercise. Repaglinide is also indicated incombination with metformin in Type 2 diabetespatients who are no satisfactorily controlled onmetformin alone.

In view of the documented interaction and risk ofhypoglycaemia, the concomitant use ofrepaglinide and gemfibrozil is contraindicated.Patients already receiving repaglinide withgemfibrozil should be reviewed and alternativecombination treatment considered under closemonitoring of diabetic status.

Reference: EMEA Public Statement. EMEA/11700/03(2003).

Adhesion prevention solutionglobal withdrawalUnited States of America — The Food and DrugAdministration (FDA) has received notification ofa voluntary withdrawal of Gynecare IntergelAdhesion Prevention Solution® from the market.The manufacturer is urging customers to immedi-ately stop using this device. This product hasbeen distributed in Austria, Canada, Egypt,England, France, Germany, Greece, Ireland,Israel, Italy, Japan, Kuwait, Netherlands, Portugal,Republic of Singapore, Saudi Arabia, Scotland,South Africa, Spain, Sweden, Switzerland, UnitedArab Emirates and the United States.

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This product is intended to be used in open,conservative gynecological surgery as an adjunctto good surgical technique to reduce post-surgicaladhesions. The manufacturer is conducting thisvoluntary withdrawal to complete an assessmentof information obtained during post-marketingexperience with the device, including adverseevents associated with off-label use inlaparoscopy and non-conservative surgicalprocedures such as hysterectomy. However, fromthe launch of this device in 1998 to February2003, the overall complaint rate worldwide is low.

Post-marketing reports include late-onset post-operative pain and repeat surgeries following theonset of pain, non-infectious foreign body reac-tions, and tissue adherence. In some patients aresidual material was observed during the repeatsurgery. Post-operative pain could be suggestiveof other serious complications and physiciansshould be aware of this in managing patients inthe post-operative period.

Reference: Communication to the FDA, 16 April 2003on http://www.fda.gov

Counterfeit Lipitor®United States of America — The Food and DrugAdministration (FDA) has announced that threelots of 90-count bottles of the cholesterol-loweringdrug Lipitor® have been voluntarily recalled and iswarning of a potentially significant risk to consum-ers.

• The product was repackaged by Med-Pro, Inc.,of Lexington, Neb., and the labels say“Repackaged by: MED-PRO, Inc. Lexington,Neb.” in the lower left-hand corner.

• The following lots are involved in this recall:20722V - 90-tablet bottles, Expiration 09-200404132V - 90-tablet bottles, Expiration 01-200416942V - 90-tablet bottles, Expiration 09-2004

FDA is urging healthcare providers and patientsalike to check the packaging very carefully beforeusing this product. Any of the product (labelled as“Repackaged by MED-PRO, Inc.”) with thesethree lot numbers should not be taken, butreturned to the pharmacy.

FDA’s investigation into this matter is continuing.

Reference: FDA Talk Paper, T03-38, 23 May 2003.

Paroxetine: avoid inchildren and adolescentsUnited Kingdom —The Chairman of the Commit-tee on Safety of Medicines (CSM) has informedprescribers of new evidence relating to theefficacy and safety of the selective serotonin re-uptake inhibitors (SSRI), paroxetine (Seroxat®) inchildren and adolescents under the age of 18years when used to treat depressive illness.Paroxetine is not licensed for paediatric use.

New data from clinical trials in children andadolescents were received by the Medicines andHealthcare products Regulatory Agency (MHRA)at the end of May 2003. These new data havebeen reviewed by an Expert Working Group onSSRIs and the Committee on Safety of Medi-cines. These data do not demonstrate efficacy indepressive illness in this age group and show anincrease in the risk of harmful outcomes includingepisodes of self-harm and potentially suicidalbehaviour in the paroxetine group compared toplacebo. Various analyses suggest that the risk ofthese outcomes is between 1.5 and 3.2 timesgreater with paroxetine compared to placebo.

On the basis of these data, the CSM has advisedthat the balance of risks and benefits of paroxet-ine is unfavourable when used to treat depressiveillness in this age group. The CSM has advisedthat paroxetine should not be used in children andadolescents under the age of 18 years to treatdepressive illness. The efficacy and safety ofparoxetine for children in other indications havenot been established.

Prescribing advice for children and adolescentswith depressive illness:

1. Paroxetine should not be prescribed as newtherapy for patients under 18 years of age withdepressive illness.

2. If a patient is being successfully treated withparoxetine, then the completion of the plannedtreatment course should be considered asan option in the management of the illness.

3. If a patient is not doing well on paroxetine,change of treatment should be considered.

When stopping treatment:

• Paroxetine should not be stopped suddenlybecause of the risk of withdrawal reactions.


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• The dose should be reduced very gradually,using half tablets, and then alternating days, ifnecessary.

• If the dose is not tapered, there is a greaterchance of experiencing side effects.

• For the majority of people, symptoms go awayon their own within 2 weeks.

• If side effects are intolerable on dose reductionor stopping, the dose should be increased andsubsequently reduced more gradually.

Adults: Paroxetine has been demonstrated to beeffective in adults with depressive illness and theCSM advises that the balance of risks andbenefits of paroxetine remains positive. Howeverthe implications of the new paediatric data on thesafety of paroxetine in the adult populationremains under close review by the CSM and itsExpert Working Group.

Reference: Medicines and Health Care ProductsRegulatory Agency, 10 June 2003 (MHRA). http://www.mca.gov.uik

Aprepitant for nausea andvomiting during chemotherapyUnited States of America — The Food and DrugAdministration (FDA) has announced the approvalof a new drug called aprepitant (Emend®), to beused in combination with other anti-nausea andanti-vomiting drugs for prevention of acute anddelayed nausea and vomiting associated withinitial and repeat courses of chemotherapy knownto cause these problems, including high-dosecisplatin.

Aprepitant is the first FDA approved treatmentthat prevents the delayed nausea and vomitingsymptoms that many patients experience greaterthan 24 hours after receiving chemotherapy.Chemotherapy is often very distressing for cancerpatients due to severe nausea and vomiting.These symptoms can be severely debilitating,often resulting in patients’ refusing further coursesof chemotherapy or in serious limitations on theirlifestyle.

In 2002, the American Cancer Society found thatover 1 284 900 new cases of cancer werediagnosed in the United States. Aprepitant canreduce nausea associated with chemotherapytreatments used to treat cancers such as lung

cancer, head and neck cancer, and some femalecancers. It is part of a three-drug therapy thatworks with other drugs to treat nausea andvomiting in a new way by blocking NK1 receptorsin the brain. Approval was based on the results oftwo well-controlled studies that included over1000 cancer patients receiving chemotherapy.

Aprepitant may interact with other drugs, includingsome chemotherapies, birth control pills, andblood thinners. It may reduce the effectiveness oforal contraceptives and women should use analternative form of birth control. Patients beingtreated with blood thinners such as warfarin andCoumadin® will need to have their blood testedafter the completion of their 3-day regimen witheach chemotherapy cycle to see if dosage needsto be changed.

Reference; FDA News , P02–23 (2003).

Agalsidase beta approvedUnited States of America — The Food and DrugAdministration (FDA) has approved the firsttreatment for patients with Fabry Disease, aserious metabolic genetic disorder affectingapproximately one in 40 000 males. While it isbelieved that fewer females suffer the mostserious consequences of the disease, they can besimilarly and seriously affected as well. Becauseof a deficiency in an enzyme, alpha-galactosidaseA, Fabry Disease causes certain fats to accumu-late in the blood vessels over many years, leadingto the involvement of various tissues and organsof the body, including the kidneys and the heart,which can then cause organ failure. As a result,patients with Fabry Disease often have to copewith significant pain and disability and typicallyhave a shortened life span.

The new product, agalsidase beta (Fabrazyme®),is a version of the human form of the naturalenzyme produced by recombinant DNA technol-ogy. It is given intravenously. This replacement ofthe missing enzyme reduces a particular type oflipid (fat) accumulation in many types of cells,including blood vessels in the kidney and otherorgans. It is believed likely that this reduction offat deposition will prevent the development of life-threatening organ damage and have a positivehealth effect on patients.

Agalsidase beta was approved under an acceler-ated or early approval mechanism. Biopsies of thecells lining the blood vessels within the kidney


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and other organs in patients with Fabry Diseasehave shown significant clearance of lipid depositsafter agalsidase beta treatment.

The manufacturer will continue to conduct anongoing randomized placebo-controlled trial toverify agalsidase beta ’s benefit to patients andassess the drug’s effects on the progression ofkidney and heart disease and the incidence ofstrokes. In addition, the availability of informationto determine long-term effects of treatment withagalsidase beta will be assured. A patient registryhas been established to follow the long-termprogress of patients who have been treated andto better understand Fabry disease and evaluatethe long-term effects of treatment. Enrolment inthis registry is voluntary.

FDA and the manufacturer are also discussing avariety of novel statistical approaches to analysedata and better assess the effectiveness of thetreatment and include measures such as within-patient analyses of trends in creatinine levels (ameasure of kidney function) on placebo and onFabrazyme, and modelling utilizing historicalinformation from matched patients.

In clinical studies, the main safety concern wasinfusion reactions, some of which were severe.These include fever, chest tightness, bloodpressure changes, abdominal pain and headache.Most patients also develop antibodies to theproduct and some patients who experienceallergic reactions may need to be further evalu-ated. Because of the potential for these severereactions, appropriate medical observation andsupport should be available when agalsidase betais administered.

Reference: FDA News, P03–32 (2003).

Imatinib mesylate approved forpaediatric leukaemiaUnited States of America — The Food and DrugAdministration (FDA) has announced the approvalof imatinib mesylate (Gleevec ®) tablets for thetreatment of paediatric patients with Philadelphiachromosome positive (Ph+) chronic myeloidleukaemia (CML) in chronic phase — a rare, life-threatening form of cancer that accounts forapproximately two percent of all leukaemia inchildren.

Imatinib mesylate is indicated for children whosedisease has recurred after stem-cell transplant or

who are resistant to interferon alpha therapy.This drug was approved under the acceleratedapproval programme. As of yet, there are nocontrolled trials demonstrating clinical benefit,such as improvement in disease-related symp-toms or increased survival. Subsequent studiesafter approval will be conducted to confirm thatthe drug has improved survival or other clinicalbenefits in paediatric patients.

In addition to its original approved indication forCML refractory to other treatments in adults, andexpansion to use as a first line treatment for CML,imatinib mesylate was also previously grantedaccelerated approval for the treatment ofgastrointestinal stromal cancer in February 2002.Accelerated approval for paediatric use is basedon extrapolation of results from adults with CMLtogether with good responses in a small numberof children. As a condition of approval, themanufacturer has agreed to conduct paediatricstudies after approval to gain greater insight intothe drug’s use in children.

The most frequently reported adverse eventsreported with the use of imatinib mesylate arenausea, vomiting, diarrhoea, edema (sometimessevere), and muscle cramps. A considerablereduction in white blood cells and platelets wasalso reported.


Drug-eluting stentfor clogged heart arteriesUnited States of America — The Food and DrugAdministration (FDA) has approved the first drug-eluting stent for angioplasty procedures to openclogged coronary arteries. In most cases, a stentis left permanently in the artery to keep the vesselopen after angioplasty. The new stent slowlyreleases a drug, and has been shown in clinicalstudies to significantly reduce the rate of re-blockage that occurs with existing stents.

Drug-eluting stents may have a substantial impacton the occurrence of re-blockages for patientswith heart disease. Each year 800 000 angio-plasty procedures are performed in the UnitedStates to open clogged coronary arteries. Inapproximately 15%–30% of patients, the arterybecomes clogged again (a condition calledrestenosis) within a year, and it must be treatedagain with a procedure such as angioplasty orbypass surgery.


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The product is the Cypher Sirolimus-ElutingCoronary Stent (Cypher Stent)®. It is a tiny metalmesh tube that is covered with the drug sirolimus.The Cypher stent provides a mechanical scaffoldto keep the vessel open while the drug is slowlyreleased from the stent to prevent the build-up ofnew tissue that re-clogs the artery. In studiesconducted by the firm, the stent reduced the rateof restenosis by about two-thirds.

FDA approved the stent based on a review oflaboratory and animal tests and two clinicalstudies of safety and effectiveness conducted bythe manufacturer, as well as a review of manufac-turing procedures for this new combinationproduct. In the SIRIUS study, 1058 patientsreceived either the Cypher Stent® or an uncoatedstainless steel stent. The patients in the SIRIUSstudy had blockages of 15 mm to 30 mm long inarteries that were 2.5 mm to 3.5 mm wide.Results were similar for both types of stents in theweeks immediately following the procedure, butafter nine months the patients who received thedrug-eluting stent had a significantly lower rate ofrepeat procedures than patients who received theuncoated stent (4.2% versus 16.8%). In addition,patients treated with the drug-eluting stent had arestenosis rate of 8.9%, compared to 36.3% ofpatients with the uncoated stent. The combinedoccurrence of repeat angioplasty, bypass surgery,heart attacks and death was 8.8% for drug-elutingstent patients and 21% for the uncoated stentpatients.

The RAVEL study, a smaller study of 238 patientswas similar to the SIRIUS study, but evaluatedpatients with shorter blockage of the coronaryartery. That study also showed significant reduc-tions in repeat procedures and restenosis.This smaller study was the basis for the product’sapproval in Europe, and supported the product’sapproval in the United States. While the RAVELstudy suggested that the Cypher Stent® showedpromise, it was not large enough to assess thepatients most likely to benefit from the device.

Patients who are allergic to sirolimus or tostainless steel should not receive a CypherStent®. Caution is also recommended for peoplewho have had recent cardiac surgery and forwomen who may be pregnant or who are nursing.Patients who receive the drug-eluting stent willlikely need to take certain kinds of anti-plateletdrugs for at least several months.

The FDA is requiring the manufacturer to conducta 2000-patient post-approval study and continueto evaluate patients from ongoing clinical trials toassess the long-term safety and effectivenessand to look for rare adverse events.

Reference: FDA News, P03–31 (2003). Acceleratedapproval for the treatment of gastrointestinal stromalcancer in February, 2002.

Pegvisomant for acromegalyUnited States of America — The Food and DrugAdministration (FDA) has approved pegvisomant(Somavert®) for the treatment of acromegaly, apotentially life threatening disease triggered by anexcess of growth hormone. Pegvisomant, the firstin a new class of drugs called growth hormonereceptor antagonists, is approved for patients whohave had an inadequate response to existingtherapies.

Acromegaly causes headaches, profuse sweat-ing, swelling, joint disorders, changes in facialfeatures, and enlarged hands, feet and jaw.If untreated, patients with acromegaly often havea shortened life span because of heart andrespiratory diseases, diabetes mellitus andcancer. In clinical studies, the most commonlyreported side effects with pegvisomant wereinjection site reactions, sweating, headache andfatigue. Patients should have tests to monitor theirliver function during the first six months of therapywith pegvisomant.



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Fixed-combination medicines:an Australian perspective

Leonie Hunt, Therapeutic GoodsAdministration, Australia

In Australia, the Therapeutic Goods Act 1989provides for a national system of controls for theregulation of therapeutic goods, including bothmedical products and medical devices. TheTherapeutic Goods Act 1989 is administered bythe Therapeutic Goods Administration (TGA), aDivision of the Department of Health and Ageingof the Australian Government. The TGA is locatedin Canberra and undertakes a number of activitiesin administering the regulation of therapeuticgoods in Australia. These include pre-marketassessment of products, pharmacovigilance,enforcement of standards, enforcement of goodmanufacturing practice (GMP) requirements,manufacturing licensing and maintenance of aregister of approved goods.

In carrying out its duties, the TGA adopts a risk-based assessment approach whereby higher-riskmedicines, such as those available on prescrip-tion, are fully assessed for quality, safety andefficacy pre-market whereas goods considered topose a low risk have an emphasis on quality andsafety before market entry. Examples of low-riskgoods include simple vitamin preparations whereit is considered that there is not only an inherentlow risk from use of the product but also thatclaims made about benefits of the product arerestricted.

In undertaking the assessment of higher-riskmedical products, the TGA adopts internationalguidance documents where possible. This is doneto reduce the compliance costs for the industryand to ensure that international best-practice isfollowed. In particular, since 1992, the TGA hasadopted many European Guidelines and Interna-tional Conference on Harmonization (ICH)

Guidelines. TGA’s policy on fixed-combinationmedicinal products is strongly influenced by theEuropean approach to fixed-combination medicalproducts as contained in EudraLex – the rulesgoverning medicinal products in the EuropeanUnion — Rules 1998 (3c) 3a 10a, pp.175–180.

Fixed-combination medicinal products cover theentire spectrum of medicinal products — thoughoften people tend to think of fixed-combinationsas a relatively new introduction. Many traditionalformulations, for example multi-vitamins andminerals or the oral contraceptive pill, are in fact,fixed-combination medicinal products. Therefore,there should be a wealth of experience aroundthe world in the use of these products. Neverthe-less, there are some important factors to considerwhen assessing a new fixed-combination medici-nal product.

Firstly, it is important to assess the potentialadvantages of fixed-combination medicinalproducts. These include an improvement ineffectiveness of treatment, safety profile andsimplification of therapy. There may also be costadvantages if a fixed-combination product can bemanufactured and sold for less than a combina-tion of individual products.

But there are also potential disadvantages. As thedosage is fixed in the combination, the doses ofthe individual substances cannot be easilyadjusted to meet the needs of the individualpatient. There may be unnecessary exposure tothe second medicine for some patients and thecombination may lead to additional adverseevents. It is also not always true that costs will bereduced by a second agent if use of a singleagent alone could have satisfactorily treated thepatient.

It is therefore important that when considering anew fixed-combination medicine, there be ajustification as to why that particular fixed-combination is acceptable and appropriate. Thisjustification needs to address issues relating tothe benefit and risk of the combination. Possiblejustifications for fixed-combination products couldbe that it is more effective. Examples of this

Aspects of Quality Assurance

Based on a presentation delivered by Leonie Hunt at theTenth International Conference of Drug regulatoryAuthorities (ICDRA) held in Hong Kong SAR, China,June 2002.

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could include better control than from eithermedicine used alone at the same or higher dose.

Combinations should also be rational so thatmedicines complement each other in their actionsor potentiate the beneficial effects of each other.It is also important that combinations be rationalin terms of the condition to be treated.

Commonly used fixed-combination productsinclude widely-used cold and flu’ remedies.These often consist of an analgesic, anti-pyretic,a decongestant agent and perhaps an anti-histamine. The combination is logical for self-medication for many patients as the symptomsthat are to be treated in these self-limiting condi-tions often co-exist. In contrast, if a product wasto be developed that simultaneously treated thesymptoms of a respiratory tract infection andmanaged diabetes, the combination would not berational. Although there will be a small sub-set ofpatients with diabetes at any point in time whoalso have the symptoms of an upper respiratorytract infection, the majority of people with anupper respiratory tract infection are not those withdiabetes. The addition of the other treatmentwould lead to an unnecessary exposure to amedicine.

Justifications may also be based on grounds ofsafety. There may be reduced side-effects if twomedicines are used at lower doses than onemedicine used alone at a higher dose. This is anentirely acceptable reason for using a fixed-combination. It may also be that fixed-combina-tions can lead to a reduction in adverse effects ifone of the drugs in the combination reduces theadverse effects of the other medicine. Although,ideally, we would wish to see patients treated withmedicines with no adverse effects, this is notalways possible. Where alternative treatmentswith less adverse effects cannot be found, acombination that leads to a reduction in adverseeffects may be important.

Probably the weakest justification on grounds fora fixed-combination is improved compliance. Thisis often cited as a rationale and is intuitivelyplausible but rarely in the experience of theAustralian regulator do submissions contain datato support claims of improved compliance. It iscertain that some patients are compliant withtherapies but it is not known if someone whocomplies with taking several medicines every fewhours will be less or more compliant if they onlyhave to take the medicines once or twice a day.Similarly, if someone is not compliant when given

clear instructions on taking medicines every fourhours, it is not certain that their compliance willincrease because they are required to take acombination medicine daily.

Development of fixed-combinationmedicinal productsIn developing a fixed-combination product, it isimportant that the sponsor addresses certaincriteria and the regulatory agency assesses thecombination to ensure that these criteria are met.As always, the quality of the pharmaceuticalproduct must be acceptable. It is also importantthat there be a logical combination of medicines inrelation to pharmaceutics. As previously dis-cussed, a combination of therapies for conditionsthat rarely co-exist or that have no obviousconnection to each other is not rational or desir-able.

The pharmacodynamics and pharmacokinetics ofthe drugs used in the combination must be fullyexplored as part of development. Indeed, aninteraction between the two products may in itselfbe a rationale for the combination. It is importantto establish the role of each medicine, alone andin combination. Interactions can and do occurwithin fixed combinations and with other medi-cines used commonly in the target patient group.The potential effects on the pharmacokinetics ofboth medicines must be investigated and under-stood before the product can be approved formarketing.

EfficacyThe indication for which the product is intended tobe approved should be rational. Ideally, theingredients of the product should be used in thesame conditions, but use in usually concurrentconditions may be acceptable as discussedabove. Conservatively, it has generally beenrecommended by many regulatory agencies thatcombination products be used as add-ons tosingle therapy. This would seem to be sensible asusing a single therapy to control a condition isless likely to lead to over-prescribing, unneces-sary adverse events and increased costs. How-ever, there may be circumstances in which it ispossible to demonstrate optimization of treatmentwith a combination as first-line treatment. Thesewould be circumstances where a condition isimportant and serious, where either drug usedsingly at higher doses had significant adverseevents or costs, and it was demonstrated thatthere was a low rate of success of treatment withone product alone.


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The amount of information that the regulatoryagency should require to demonstrate efficacy fora fixed-combination will vary. If two products havea long history of safe and effective use in combi-nation, then it may be possible for documentationto be substantially bibliographic or based on asignificantly reduced data set, relying on previousreviews of the individual products and publishedliterature and other experience of use in combina-tion. This would occur, for example, if two prod-ucts were commonly taken at the same time eachday and were used in the same patient group.Nevertheless, even given this circumstance, it isimportant that there be evidence of effectiveness.If effectiveness for the products used in combina-tion is not greater that the effectiveness for one ofthe products used alone, then it is important thisbe identified for there is little additional benefit tobe gained from such a fixed-combination and it isnot desirable that it be approved for registration.

If a new combination of medicines is proposed,then it is important that a more substantial productdevelopment programme be undertaken and thatsimilar information relating to the combination atvarying doses in the intended patient group begenerated as if the product was a new singleentity. It is particularly important that the dose bewell established. A fixed-combination allows theopportunity for the dose to be minimized andadverse events reduced. In order for this tohappen, it is important that the minimally effectivedose of the medicines, used alone and in combi-nation, be established.

It is also important that the maximal dose re-sponse information is available. This is importantbecause, if a minor increase in dose of onecomponent of the fixed-combination leads to animproved dose response, then development of afixed-combination using marginally lower dose ofthat substance may not be a rational develop-ment. It is also important, when comparing a fixedcombination, to look at effective doses of eithermedicine alone and other reference therapiesused for the treatment of the condition. It mayalso be important to compare the fixed-combina-tion with placebo in some cases.

SafetyAs for any product, it is important that there be asmuch evidence as possible about performance interms of safety of the medicine. For this reason,there should be some animal experience for theuse of both medicines, singly and in combination,and human data should be available from use ofthe medicines, both singly and in combination.Again, if the products have a long history of con-comitant use, documentation may be abridged.

SummaryFixed-combination products can offer significantbenefits to consumers and health systems. It isimportant in assessing the place of a fixed-combination product to consider the justification ofthe combination, as well as information on it’squality, safety and effectiveness in patient man-agement.


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Recent Publications andSources of InformationInternational Travel & Health

The latest edition of International Travel andHealth has been completely redesigned to reflectbetter knowledge about the risks to which travel-lers are exposed and the precautions needed toprotect their health. With new material and arevised structure, the book offers guidance on thefull range of health risks likely to be encounteredat specific destinations and associated withdifferent types of travel. Information is intended tohelp the medical profession be fully alert topotential risks and provide appropriate advice,whether concerning recommended vaccinations,protections against insects and other diseasevectors, or safety in different environmentalsettings.

Details cover effectiveness of mosquito nets andadvice on when and how to treat diarrhoea. Thebook concludes with a country by country list ofrequired vaccinations, togehter with pertinentinformation on the malaria situation for everycountry or territory of the world.

International Travel and Health 2003, ISBN 92 4 2580287. Available from: Marketing and Dissemination, WorldHealth organization, 1211 Geneva 27, Switzerland. e-mail: [email protected]

Affordability of medicinesIn developing countries, most medicines are paidfor out-of-pocket by individual patients rather thanthrough social security systems. High prices aretherefore a barrier to use of medicines and healthproducts. Too little is known about the prices thatpeople pay for medicines in poor and developingcountries.

Medicines Prices: a new approach to Measure-ment, the accompanying workbook and databaseprovide a new approach to measuring the price ofmedicines in response to the need for a standardapproach to measuring medicines prices. Thework proposed can be reliably carried out byacademic centres, consumer groups, or govern-ment departments.

A survey is based on a methodology to evaluatethirty key medicines and results raise questionsabout the relationship between procurementprices and the final price to patients and afford-ability. The impact of policy changes on the priceof medicines can also be assessed using this tool.

Medicines prices: a new approach to measurement.2003 edition. Working draft for field testing and revision.Available from: Marketing and Dissemination, WorldHealth organization, 1211 Geneva 27, Switzerland. e-mail: [email protected]

Drugs and moneySociety attaches great importance to betterhealth, and has witnessed a rising demand forhealth care. The rapid growth of expenditure onmedicines is of particular concern and it hasattracted considerable political attention, partlybecause it seems most amenable to economiccontrol.

The World Health Organization first launcheda study on “Drugs and Money” in 1983, on thefeasibility of measures to control the growth ofexpenditure on medicines. This culminated in acritical overview of the effectiveness of older cost-containment schemes while also paying attentionto innovative ventures. The report was widelyused and repeatedly updated, and this is now itsseventh edition.

This latest edition provides policy-makers andregulators with a compact and practical review ofthe various approaches used to contain the costsof pharmaceutical services and drug treatment.The true art of good housekeeping in this field isclearly to ensure that drugs continue to benefitsociety, while eliminating every form of waste ofpublic funds. This book also addresses issuesconcerning the organization, standards anddelivery of health care. Unlike earlier editions ofDrugs and money, this volume also devotesconsiderable attention to the special problems ofdeveloping countries and those where theeconomy is currently in transition.

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WHO Drug Information Vol 17, No. 2, 2003Recent Publications and Sources of Information

Drugs and money. Prices, affordability and costcontainment. Available from: Marketing and Dissemina-tion, World Health organization, 1211 Geneva 27,Switzerland. e-mail: [email protected]

ABPI launches onlineclinical trials registerAn online register of industry-sponsored clinicaltrials has been launched by the Association of theBritish Pharmaceutical Industry (ABPI). So far, theregister includes details of 65 trials sponsored byfive companies.

Since 2001, the ABPI has encouraged membercompanies to register clinical trials involvingUnited Kingdom patients that form part of alicensing application for a new medicine. Partici-pating countries are asked to register their phaseIII trials within three months of any productreceiving its first licence in a major market.Ongoing trials can also be included.

Trial information listed on the website includesdetails of the sponsor company, design andmethodology used, trial intervention method,planned and actual sample size, start and enddate, and whether trial data have been published.Trial results are not given.

The website can be accessed through PJ Onlineat http://www.pjonline.com/links on a read-onlybasis.

Reference: The Pharmaceutical Journal, 270: 640(2003).

Expert Committee on DrugDependence ReportThe Thirty-third report presents recommendationsfrom the Expert Committee on Drug Dependencewhich is responsible for reviewing information ondependence-producing drugs and assessing theneed for international control by the UN Commis-sion on Narcotic Drugs. It is important to balancethe need for preventing diversion of therapeuticsubstances with abuse potential against the needto ensure access for therapeutic use. WHO hasdeveloped a formal procedure for its review ofdependence-producing psychoactive substanceswhich is described in the first part of the report.

This is followed by a critical review of fivepsychoactive substances (amfepramone,amineptine, buprenorphine, delta-9-tetrahydro-cannabinol and tramadol). The report alsodiscusses the substances that were pre-reviewedby the Committee, four of which (ketamine,zopiclone, butorphanol and khat) were recom-mended for critical review at a future meeting.The final section discusses the problems of theterminology used in reporting abuse-relatedadverse drug reactions and describes howconfusion affects the reporting of adverse effectsusing as an example the selective serotoninreuptake inhibitors (SSRIs).

WHO Expert Committee on Drug Dependence. Thirty-third report. WHO Technical Report Series, No. 915(2003). Available from: Marketing and Dissemination,World Health organization, 1211 Geneva 27, Switzer-land. e-mail: [email protected]

Biomedical researchin human subjectsThe Council for International Organizations ofMedical Sciences (CIOMS) has published therevised International Ethical Guidelines forBiomedical Research Involving Human Subjects.This is the third revision of the guidelines, firstissued in 1982, and consists of 21 core guidelineswith commentaries. Appendices include the WorldMedical Association’s Declaration of Helsinki.

The scope of the guidelines reflects the changes,advances and controversies that have charac-terized biomedical research ethics recently. TheGuidelines are also designed to be of use indefining national policies on ethics, applyingethical standards and establishing or improvingethical review. A particular need is to consider theimplications for research of the specific conditionsand needs of different communities and countries.

International Ethical Guidelines for Biomedical ResearchInvolving Human Subjects. Available from: Marketingand Dissemination, World Health organization, 1211Geneva 27, Switzerland. e-mail: [email protected]

Documents

WHO Drug Information Vol 17, No. 2, 2003 World Health