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WHO Drug Information Vol 22, No. 3, 2008

WHO Drug InformationContents

World Health Organization

International HarmonizationICH Pharmaceutical Quality System

Q10 177African Medicines Regulatory

Harmonization Initiative (AMRHI):a WHO concept paper 182

Safety and Efficacy IssuesMoxifloxacin: adverse hepatic reactions 191Ezetimibe/simvastatin: safety review of

cancer risk 191Norfloxacin-containing medicines not for

use in urinary infections 192Ceftriaxone: fatal outcome with calcium-

containing solutions 193Safety review of tumour necrosis factor

blockers 194Recombinant human bone morphogenetic

protein: life-threatening complications 195Electronic medical devices malfunction:

computed tomography scanning 195Desmopressin and hyponatraemia 196Micro-bubble contrast agents 197Simvastatin used with amiodarone:

rhabdomyolysis 197Naltrexone injection site reactions 197Adalimumab: hepatosplenic T-cell

lymphoma 198Serious Risks/New Safety Information 198Deferasirox: hepatic failure 199Colchicine: fatal interactions and

reactions 200

Abacavir: hypersensitivity reactions 201Fluoroquinolones: risk of tendinitis

and tendon rupture 201

Regulatory Action and NewsWHO Prequalification: GMP deviations

and suspension 203Import alert: Ranbaxy facilities 203Medicines Prequalification Programme:

listed products 204Development of medicines for Alzheimer

and Parkinson disease 205GMP regulations for radiopharma-

ceuticals 205

Pharmaceutical Distributionand TradeWHO Certification Scheme on the

quality of pharmaceutical productsmoving in international commerce

Proposal for improvement of the WHO Certification Scheme 207

Consultation on improvement of theCertification Scheme 214

Recommended InternationalNonproprietary Names: List 60 219

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International Harmonization

The ICH Q10 quality visionIn the 1930s, Walter Shewhart (1) devel-oped Statistical Process Control methodsand the PDSA spiral plan what youwant to do, do it, study the results, makecorrections (total quality management),and start the cycle again (continuousimprovement).Shewharts student, W. Edwards Deming(2) is credited with improving productionin the United States during World War II.From 1950 onwards, he taught topmanagement in Japan on how to improvedesign, product quality, testing and salesin global markets through various meth-ods, including the application of statistics.Deming demonstrated that Shewhartsspiral is roughly analogous to the scien-tific method: one has a theory (or hypoth-esis), and puts it to the test; studies theresults and takes action based on thoseresults. This is the road to scientificlearning. PDSA is the road to organiza-tional learning.

In the 1950s, Dr Joseph M. Juran (3)started a production management systemat Toyota which has continued to evolve

ICH Pharmaceutical Quality System Q10

over the decades. In the 1980s, Toyotacars became the model of global choicebecause they lasted longer than othercars in the same category and requiredmuch less service. About a decade later,it became clear that it was the way Toyotadesigned and manufactured the cars thatled to high consistency in the process andproduct.

In 2003, the ICH Steering Committeeagreed on a new quality vision to empha-sise a risk- and science-based approachto pharmaceutical production in anadequately implemented quality system.As a consequence, the guidelines onPharmaceutical Development (Q8),Quality Risk management (Q9) andPharmaceutical Quality System (Q10)were drafted. As these concepts andprinciples are rather new in the pharma-ceutical area, proper implementation isimportant to bring clarity, further explana-tion and remove ambiguities and uncer-tainties.

Table 1 overleaf lists some frequentlyused terms defined in the ICH Pharma-ceutical Quality System Q10 guideline.

Article submiited by Jnos Pogny, Budapest. Comments to: [email protected]

The International Conference on Harmonization of Technical Requirements for Reg-istration of Pharmaceuticals for Human Use (ICH) guideline Pharmaceutical QualitySystem Q10 was adopted at the ICH meeting in Portland (Oregon, USA) in June2008. Within Step 4 of the ICH Process, the guideline is recommended for adoptionby regulatory bodies of the European Union, Japan and USA. The guideline describesa robust quality management system model that can be implemented throughout thedifferent stages of the product lifecycle.

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Pharmaceutical Quality SystemThe Q10 glossary defines the Pharma-ceutical Quality System (PQS) as amanagement system to direct and con-trol a pharmaceutical company withregard to quality. The PQS describes aset of policies, processes and proceduresrequired for designing (non-clinical andclinical research) and execution (develop-ment, manufacture, distribution andpostmarketing activities) of changes inthe pharmaceutical industries that employscience- and risk-based principles andapproaches related to product quality(ICH Q8 and ICH Q9) at each life cyclestage. This also promotes continualimprovement leading to the fulfilment ofpatient needs and improved businessperformance.The guideline introduction states thatICH Q10 is not intended to create newexpectations beyond current regulatoryrequirements. Consequently, the content

of ICH Q10 that is additional to currentregional GMP requirements is optional.

Scope of the PharmaceuticalQuality SystemPQS applies to all systems supporting thedevelopment and manufacture of phar-maceutical drug substances and drugproducts, including biotechnology andbiological products, throughout theproduct life cycle.

Relationship of ICH Q10 toregional GMPsFigure 1 overleaf drawn from com-ments of the European Union during thedevelopment of the guideline andadapted to this review article illustratesthe principal differences between ICHQ10 and GMPs.

Activities overlap to some extent (e.g.clinical batches are manufactured accord-

Continual Improvement: Recurring activity to increase the ability to fulfil requirementsEnabler: A tool or process which provides the means to achieve an objectiveKnowledge Management: Systematic approach to acquiring, analysing, storing, anddisseminating information related to products, manufacturing processes and componentsPerformance Indicators: Measurable values used to quantify quality objectives to reflectthe performance of an organization, process, or system, also known as performancemetrics in some regionsProduct Realisation: Achievement of a product with the quality attributes appropriate tomeet the needs of patients, health care professionals, and regulatory authorities (includingcompliance with marketing authorisation) and internal customers requirements.Quality Objectives: A means to translate the quality policy and strategies into measurableactivities

Quality Policy: Overall intentions and direction of an organization related to quality asformally expressed by senior management. (ISO 9000:2005)Quality risk management: An active approach to identifying, scientifically evaluating andcontrolling potential risks to qualitySenior Management: Person(s) who direct and control a company or site at the highestlevels with the authority and responsibility to mobilize resources within the company or site(ICH Q10 based in part on ISO 9000:2005 Quality management systems)

Table 1. Pharmaceutical Quality System guideline definitions


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Figure 1. Relationship of ICH Q10 to regional GMPs

ing to GMPs during PharmaceuticalDevelopment, or Human ResourceManagement includes GMP training) butthe diagram permits focusing presenta-tion in this article to the pink rectangles.

Enablers: Knowledge Managementand Quality Risk ManagementKnowledge Management and QualityRisk Management will facilitate achieve-ment of the following objectives of thePQS:

Achieve product realization

Establish and maintain a state of control

Facilitate continual improvement

Management ResponsibilityManagement should establish a qualitypolicy to include expectations of compli-ance with applicable regulatory require-ments. The quality policy should becommunicated to and understood bypersonnel at all levels in the company.Management should provide adequateand appropriate resources (human,financial, materials, facilities and equip-ment) to implement and maintain thePQS and continually improve its effective-ness.

Management should assess the conclu-sions of periodic reviews of processperformance and product quality and ofthe PQS.


ManagementResponsibility

ManagementCommitment

Quality Policy

Quality Objectives Quality Planning

ResourceManagement

QualityCommunication

ManagementReview

Quality Oversight

Organizational processes quality system improvement

Quality System Risk Knowledge Human ResourcesManagement Management Management Management

Support processes product/process managementand improvement

Product/Process Change Control Quality Management ofImprovement Assurance Suppliers and

Contractors

Process CAPA Documentation Management ofValidation Management Equipment and

Facilities

Product life-cycle processes product realization

Pharmaceutical Technology Manufacturing DiscontinuationDevelopment Transfer

P r o d u c t l i f e c y c l e

Covered by ICH10 Covered by GMPs

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Continual improvement ofprocess performance andproduct qualityData collection on performance indicators quality attributes of the drug productand the parameters of the manufacturingprocess starts with the design anddevelopment of pharmaceutical qualityfrom the very beginning of the product lifecycle. In an eternally successful organiza-tion, People routinely do things right firsttime, (Philip Crosby). Product andprocess variability is explored. Pharma-ceutical development results in knowl-edge which establishes that the selectedformulation is suitable for the intendeduse and the manufacturing process canbe scaled up to production level. Processand product monitoring conductedthroughout development can be used toestablish a control strategy for manufac-turing.

The goal of technology transfer activitiesis to pass on product and process knowl-edge [analytical methods, active pharma-ceutical ingredients (APIs) and pharma-ceutical dosage forms] between pharma-ceutical development and manufacturing,and within or between manufacturingsites to achieve product realization.(According to this description, transfer oftechnology takes place within the samequality system. The effective transfer ofknowledge and experience between twoquality systems may not follow the samemethodology, for example, when the APIand the pharmaceutical product aremanufactured by different companies.)This knowledge forms the basis for themanufacturing process, control strategy,process validation approach and ongoingcontinual improvement.

In the third stage, the PQS should assurethat the desired product quality is rou-tinely met, suitable process performanceis achieved, the set of controls areappropriate, improvement opportunities

are identified and evaluated, and thebody of knowledge is continually ex-panded.

In the terminal stage of the productlifecycle, a pre-defined approach shouldbe used to manage activities such asretention of documentation and samplesand continued product assessment (e.g.,complaint handling and stability) andreporting in accordance with regulatoryrequirements.

Pharmaceutical Quality Systemelements

Process performance and productquality monitoring systemAn effective monitoring system providesassurance of the continued capability ofprocesses and controls to produce aproduct of desired quality and to identifyareas for continual improvement.

Corrective Action and PreventiveAction (CAPA) SystemThe pharmaceutical company shouldhave a system for implementing correc-tive action (to prevent recurrence) andpreventive action (to prevent occurrence)resulting from the investigation of com-plaints, product rejections, non-conform-ance, recalls, deviations, audits, regula-tory inspections and findings, and trendanalysis from process performance andproduct quality monitoring. Preventiveaction also includes, e.g., benchmarking,reviews (contracts, purchasing, process-es), process capability studies, StatisticalProcess Control (SPC) analysis, FailureMode Efffects Analysis (FMEA) andemployee training programmes.

This methodology is useful where correc-tive action and preventive action isincorporated into the iterative pharmaceu-tical design and development process.CAPA is mainly used as an effectivesystem for the modification or control of amanufacturing process by its results oreffects (feed-back) or using its anticipated


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results or effects (feed-forward) andcontinual improvement.

Change Management SystemInnovation, continual improvement, theoutputs of process performance andproduct quality monitoring and CAPAdrive change. In order to evaluate,approve and implement these changesproperly, a company should have aneffective change management system.There is generally a difference in formalityof change management processes priorto the initial regulatory submission andafter submission, where changes to theregulatory filing might be required underregional requirements.

Management Review of ProcessPerformance and Product QualityManagement review should provideassurance that process performance andproduct quality are managed over the lifecycle. Depending on the size and com-plexity of the company, managementreview can be a series of reviews atvarious levels of management and shouldinclude a timely and effective communica-tion and escalation process to raiseappropriate quality issues to senior levelsof management for review.

Continual improvement of the pharma-ceutical quality systemManagement should have a formalprocess for reviewing the PQS on aperiodic basis. The review should include,among others, the measurement ofachievement of PQS objectives and theassessment of performance indicators.Management should follow up emergingregulations, guidance and quality issuesthat can impact the PQS. ICH Q10encourages innovations that might

enhance the PQS and product andprocess understanding such as newapproaches to process validation andmonitoring in-process control strategiesthat may lead to real-time release mecha-nisms as well as the use of quality riskmanagement principles (e.g., ICH Q8,ICH Q9 and ICH Q10).

ConclusionThe concepts and principles of qualitymanagement have been widely used inthe car industry since the 1950s but theyare rather new in the pharmaceuticalindustry. Although ICH Q10 is not in-tended to create any new expectationsbeyond current regulatory requirements,pharmaceutical industries also outsidethe ICH regions are expected toimplement the PQS because it is anindispensible condition for those compa-nies that wish to become and/or remaincompetitive in product quality and produc-tivity within global and regional markets.

PQS is equally applicable to innovatorand generic pharmaceutical companiesas well as to drug substances and drugproducts. Implementation of PQS continu-ously increases product and processunderstanding and provides opportunitiesfor science-based dossier assessmentand the increased use of risk-basedapproaches for regulatory inspections.

References

1. http://www.skymark.com/resources/leaders/Shewhart.asp2. http://www.en.wikipedia.org/wiki/Image:W._Edwards_Deming.gif

3. http://www.skymark.com/resources/leaders/juran.asp


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ineffective regulation transcend nationalborders and have global implications (3).Over two-thirds of the worlds populationlive in countries with marginal or inad-equate regimes for assuring drug quality,safety and efficacy. A recent WHO surveyon the quality of antimalarials in sevenAfrican countries revealed that between20 and 90% of products failed qualitytesting (4). Use of poor quality startingmaterials from unreliable sources is anongoing problem in many countries (5).The prevalence of poor quality or evenharmful medicines is a waste of re-sources that undermines already overbur-dened health-care systems, puts publicsafety at risk and increases the likelihoodof drug resistance.Medicines regulation is a complex issue.It is the totality of all measures legal,administrative and technical whichgovernments take to ensure the safety,efficacy and quality of drugs. This alsoinvolves assessment of the relevance andaccuracy of product information.The ability to regulate medicines effec-tively is determined by a number of

Essential medicines save lives and improve health when they are available, afford-able, of assured quality and properly used. However, lack of access to essentialmedicines remains one of the most serious global public health problems (1). Mil-lennium Development Goal number 8 declares that providing access to affordableessential drugs in developing countries is a fundamental human right (2).The objective of the WHO project on Harmonization of Medicines Regulation inAfrica (AMRHI) is to improve health in the African Region by increasing access tosafe and effective medicines of good quality. This can be accomplished by strength-ening the technical and administrative capacity of participating national medicinesregulatory authorities. Collaborative mechanisms can provide a more transparent,streamlined process for the marketing authorization of pharmaceutical productsand follow-up of products already marketed.Comments on this concept paper are most welcome and should be addressed to:Samvel Azatyan, Essential Medicines and Pharmaceutical Policies, World HealthOrganization, 1211 Geneva 27, Switzerland or [email protected]

African Medicines Regulatory Harmonization Initiative(AMRHI): a WHO concept paper

Effective medicines regulationAssuring the quality, efficacy and safetyof medicines is an important task formedicines regulatory authorities (MRA)and is performed through subjecting allpharmaceutical products to pre-marketingevaluation, marketing authorization andpost-marketing review. Countries maydiffer regarding registration systems sincenot all can implement a comprehensivemedicine evaluation and registrationsystem.Currently, approximately 20% of countrieshave fully operational medicines regula-tion. Of the remainder, half have regula-tion of varying capacity, and 30% haveeither no or very limited medicinesregulation. The reality is that many low-income countries cannot ensure thesafety, efficacy and quality of medicinescirculating on their markets because theyare resource constrained in terms ofstaffing, standards, systems, and training.A number of additional factors explainobserved weaknesses of drug regulationwith regard to health systems or socio-economic development. Problems of


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factors, including: the state of economicdevelopment, infrastructure and prevail-ing health-care system. A root problem isthe lack of human and financial resourcesdevoted to regulation and the effective-ness of collaboration with regulatorsabroad. Not all medicines regulatoryauthorities (MRAs) in developing coun-tries have sufficient capacity to performrisk-benefit assessments. Among otherthings, this is often the result of inad-equate political commitment exacerbatedby interest groups that benefit from looseregulation and retaining of the status quoin the pharmaceutical sector. Hence,although the policy options to rectify thissituation are relatively straightforward inprinciple, implementation may well bemuch more complicated.

Countries need resources, both humanand financial. Lack of resources may becompensated to some extent by effectivecollaboration among countries andinformation sharing. Therefore, politicalleadership and commitment is critical.Meanwhile, it is important to mention thateven if more financial resources areallocated to ensuring appropriate regula-tory development within a region, theavailability and expertise of humanresources could remain a challenge overthe medium term.

The need for harmonizationThe circulation of substandard medicinesin the developing world is a seriousconcern (6). The problem of substandardmedicines include inadequate or over-concentration of ingredients, contamina-tion, poor quality ingredients, poor stabil-ity and inadequate packaging. Reasonsfor the existence of substandard medi-cines are multiple: medicines manufac-tured for export are not regulated to thesame standards as those for domesticuse, while regulatory agencies in the less-developed world are poorly equipped toassess and address this problem.

A number of recent initiatives have beensuccessful, most notably the establish-ment of the WHO Medicines Prequalifica-tion Programme (7). However, muchmore action is required in order to im-prove the operation of medicines regula-tory authorities in resource-constrainedcountries to detect and contain substand-ard medicines. The formation of effectivenetworks between regulatory authoritiesnationally and internationally facilitatessharing of scarce resources and elimi-nates duplication of effort. Networking ofinstitutions in developing and developedcountries, both formal and informal, is animportant element in building regulatorycapacity and trust, especially with regardto innovative products (8). Harmonizationof medicines regulation is a desirablegoal for many reasons (9). Companies have to generate only one

data set for all regions and, conse-quently, the amount of human andanimal experimentation is reduced.

The cost of development of new drugsand their regulatory documentation isreduced, which would logically lead tolower prices.

Common regulatory standards forevaluation and inspection facilitateregulatory communication and informa-tion sharing.

Local products are more likely to beacceptable for export to other countries.

Faster access to medicines of highpublic health value (paediatric medi-cines, medicines for major diseases orfor emergencies in national settingsetc.).

Increased competitiveness resultingfrom newly developed common mar-kets.

Existing harmonization initiativesHarmonization in a broad sense meansharmonization of technical requirements


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for medicines regulation, i.e., legislation,guidelines, procedures, etc. Theserequirements relate to the quality, safetyand efficacy of medicinal products andcan differ in complexity from one type ofmarketing authorization application toanother (i.e., innovator drugs vs. gener-ics). In implementing medicines regula-tion, it should be noted that this will onlybe effective if all aspects of regulation areaddressed. The results of a WHO multi-country study showed that several areasin drug regulation receive relatively littleattention in the implementation process.The informal sector, post-marketingsurveillance (quality and safety) andcontrol of drug information were the mostimportant of these (10).Various international and regional initia-tives exist in which regulators fromdeveloping countries participate. WHOconvenes the biennial InternationalConferences of Drug Regulatory Authori-ties (ICDRA) where many importantpolicy options, technical issues andactions related to harmonization havebeen debated, recommended and imple-mented as a result.

The International Conference on Harmo-nization (ICH) has core members fromthe research-based industry and regula-tory authorities from the European Union,Japan and USA, with observers fromCanada, EFTA and WHO. The ICH hasmade significant progress in harmonizingtechnical requirements used in thedeveloped world, thus mitigating some ofthe problems associated with differingrequirements of the three regulatoryblocks.

Although in recent years the ICH GlobalCooperation Group has intensified itswork and has opened up to non-ICHcountries, the ICH has been less suc-cessful in involving and having an impacton developing countries. This is because,in particular, harmonization implies areasonable parity in existing regulatory

capacity and a certain level of socioeco-nomic development. It should also benoted that ICH was created for newinnovative medicines and the ICH partiesare highly industrialized nations control-ling the majority of the innovative industry,whereas most developing countries havegeneric markets with generic manufac-ture, or with no local manufacture at all.

Regional harmonizationCooperative action at the regional levelhas proved more effective in many casesin strengthening regulatory capacity at thenational level. Regional initiatives in-volved in harmonization include theAssociation of South-East Asian Nations(ASEAN), the Andean Community, theGulf Cooperation Council, Mercosur andthe Southern African DevelopmentCommunity (SADC). These offer differentworking models, ways of exchangingregulatory information and creatingcommon technical requirements, poolinginformation on drugs in actual circulation(since markets have substantial regionaland country differences in terms of originand nature of products). In certain casesthey share facilities (e.g. testing laborato-ries), and compare experience of side-effects of particular drugs in the post-marketing phase, identify substandardand counterfeit drugs, and so on. Practi-cal and pragmatic steps to share regula-tory resources, information and evenfacilities offer the most effective means toprotect public health from substandardproducts in developing countries.New regulatory pathwaysConsidering the reality of inadequateregulatory capacity in many developingcountries, and also in smaller wellresourced/developed countries, harmoni-zation initiatives often rely on the ap-proval or opinions emitted by regulatoryauthorities in well-resourced countries.This could carry some concerns becausethe risk/benefit balance in developingcountries may be different from those indeveloped countries. As there is little


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available evidence of differences in therisk/benefit profile of the majority ofessential medicines in various environ-ments, consideration of the assessmentscarried out in well resourced and fullyoperational MRAs in developed countriesis a better option than no guidance at allor limited assessment with no addedvalue.

There exist several examples of howregulators in developing countries maybenefit from assessments carried out bywell resourced regulatory authorities.These initiatives include, but are notlimited to, US FDA tentative approvalprocess for antiretroviral medicines,European Union Article 58 process forpriority medicines in developing countries,Canadian Access to Medicines Scheme(known as the Jean Chrtien Pledge) andothers. These initiatives could provide thesupport needed for capacity building ofnational regulatory authorities of develop-ing countries through partnerships, orscientific and technical assistance.

WHO Medicines PrequalificationProgrammeThe WHO Medicines Programme formedicines was set up in 2001 to provideUnited Nations procurement agencies,such as UNICEF, with a range of goodquality products that meet internationalstandards of quality, safety and efficacy. Itdoes not intend to replace nationalregulatory authorities or national authori-zation systems for importing medicinesbut draws on the best national regulatoryexpertise available while pro-activelyincluding and involving regulators fromdeveloping countries. Since its beginning,capacity building has been a majorobjective of the Prequalification Pro-gramme.Over time, the growing list of productsfound to meet international standards hasproved useful for anyone purchasing bulkmedicines, including countries them-selves and other organizations. For

instance, the Global Fund to Fight AIDS,Tuberculosis and Malaria gives prefer-ence to medicines that have been pre-qualified by the WHO process, as well asby stringent regulatory authorities. Thishas proved useful to developing countrieswithout the necessary resources toconduct similar level assessments andinspections, with the added potential ofbeing actively involved in the prequalifica-tion process through their national regula-tory experts.Active involvement in the WHO MedicinesPrequalification Programme has contrib-uted to building national regulatorycapacity and improving regulations andregulatory processes. Several Africancountries can serve as good examples.However, the responsibility for decision-making, and the processes required forthat decision-making, as well as post-marketing surveillance, must remain amatter of national sovereignty.

African MedicinesRegulatory HarmonizationInitiative (AMRHI)The overall objective of AMRHI is toimprove health in the African Region byincreasing access to safe and effectivemedicines of good quality for the treat-ment of priority diseases. This can beaccomplished by strengthening thetechnical and administrative capacity ofparticipating national medicines regula-tory authorities. Collaborative mecha-nisms can be established to create amore transparent, streamlined process forthe marketing authorization of pharma-ceutical products and follow-up of prod-ucts already marketed.

Collaborative mechanisms for drugregulatory systems and processes at theregional/sub-regional levels shouldtranslate into improved regulatory ap-proval processes and operationalefficiencies at the national level. In this


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regard, the project aims to increase thecapacity of national medicines regulatoryauthorities and specifically strengthen theadministrative, structural and technicalelements of medicines regulation. Indoing so, the project will help countries toenhance and facilitate their decision-making processes regarding the registra-tion of medicines, as well as exercisemore control over medicines circulatingon the market. Regulatory capacitybuilding and facilitation of informationexchange are thus indispensable compo-nents of the project.Specifically, the project objectives in-clude:

1. To create a collaborative networkthrough partnership between regula-tory authorities of participating coun-tries and/or selected sub-regionaleconomic blocks.

2. To harmonize technical requirementsfor the regulation of medical productsand build confidence so that agreedharmonized standards are respectedby participating authorities.

3. To establish a framework for jointevaluations of application dossiers andinspections of medicine manufacturingsites.

4. To strengthen the capacity for regula-tory oversight.

5. To develop information managementsystems and promote the exchange ofregulatory information.

Political commitmentA fundamental issue is the politicalcommitment of Member States to partici-pate in the harmonization process. Theexperience of existing harmonizationinitiatives has shown that all such proc-esses have led to upgrading of publicservices. In less resourced counties,unfortunately, consumers still continue to

pay out-of-pocket for most medicines.Improved regulation, with more sophisti-cated requirements, usually eliminatessubstandard cheap medicines from themarket but could lead to an increase inprices. In this regard, it is suggested thataction should focus initially on mutuallyagreed standards, technical assistanceand capacity building issues and aim forgradual and carefully balanced harmoni-zation of actual markets.

The willingness of sub-regional secretari-ats and potential member countries toparticipate in the harmonization processshould be assessed beforehand. It is alsovery important that participating countriesdemonstrate their commitment to con-tinue the harmonization process and tocarry the financial burden of maintainingthe secretariat, investing in developingand maintaining technical capacity of theirstaff, paying for travel to joint assessmentmeetings, inspections, etc. The Initiativeshould also operate as a catalyst forsustainable processes.

Leadership and maintenanceOne important question is whether apermanent secretariat of the harmoniza-tion process needs to be established. Ifyes, how should it be managed andoperated and whether it should be basedin one of the countries or should rotate atspecified intervals of time. Experiencehas shown that well qualified, effectiveand stable secretariats are crucial for thecontinuity and success of regulatorynetworks.

Rotating secretariats may have disadvan-tages as opposed to stable, permanentsecretariats. However, rotating nationalstaff in terms of time-limited secondmentmay be an option to consider. The secre-tariat could also be reinforced by inviting,on a secondment basis, competent andexperienced regulators from well-estab-lished authorities from outside the region.Additionally, the secretariat must haveaccess to highly qualified legal advice


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from potential participating countries. Theorganization of meetings of legal adviserswould be highly appropriate as a mecha-nism to discuss and share commonalitiesand differences in the respective legisla-tive areas.

Of particular value would be the estab-lishment of a steering committee ofrepresentatives of participating membercountries to give oversight and act as acoordinating body. Representatives ofdonor organizations could have observerstatus. Governing bodies and proceduresof the project should, as far as possible,represent a sustainable model for longterm management of a collaboratingnetwork.

The issue of availability of sufficientresources in MRAs is of importance forthe project. Most resource-constrainedcountries currently base their regulatorydecisions for NCE applications on theopinion taken by other well-resourcedcountries. Evaluation of new innovativemedicines specific for country needs such as medicines for neglected diseasesand certain paediatric medicines maynecessitate creating special collaborativemechanisms for assessment and ap-proval.

The African medicine market is basicallya generic market and local manufactur-ing, where it exists, is also limited togeneric medicines (with perhaps someexceptions in countries such as SouthAfrica). Limiting the scope of the projectto generic applications in the first instancemay help to fast track the initiative be-cause this will restrict the number ofguidelines that need to be harmonized.

Such action could be considered a firstphase, followed by harmonization ofregulatory guidelines specific to newmedicines whose safety, efficacy andquality requirements, at least in the longterm, should be the same. It also shouldbe decided to what extent harmonization

maintenance of already authorizedproducts will be covered, includingvariations and renewals. A number ofWHO guidelines that are directly relevantto these questions exist and are updatedregularly. These guidelines are adoptedby many countries both for local use andfor reasons of international harmonization(10).Differences in regulatory capacityand national legislationThe issue of differences in capacitybetween national regulatory authorities ofdifferent countries is also very important.The results of a recent WHO pilot projecton a registration technical package havedemonstrated that even in a relativelyhomogenous group of participatingcountries, from a socioeconomic develop-ment perspective, there are seriousdifferences in regulatory capacity.Most participating countries have exper-tise and experience in evaluating thequality aspects of an application dossierbut only one or two had expertise inevaluating the clinical (efficacy andsafety) parts. In recent years, WHO hasconducted an assessment of the medi-cines regulatory systems in some AfricanMember States using the WHO assess-ment tool. However, for many countries,information is either absent or out of date.

WHO role in implementing AMRHIThere may be many ways of introducingmedicines harmonization to Africa.However, WHO proposes focusing on twoscenarios that seem the most feasible.In the first scenario, WHOs involvementcould be limited to assisting foundations,funding agencies, or any other partner indeveloping and finalizing the proposaland then hand over the project to anappropriate party such as a professionalinternational organization, or regional orsubregional agency for implementation.The implementing agency, in this case,would take full responsibility for selection


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of the partners, for performance of theplanned activities and for reportingoutcomes of the project to the donors.WHO would provide technical expertise inthe preparatory phase of the project butinvolvement would not go beyond thispoint.

In the second scenario, WHO would takethe lead in the project, from both amanagerial and organizational point ofview, would develop and finalize theproject proposal and select partners forthe implementation phase in collaborationwith Member States. WHOs competitiveadvantage in running such an initiative isexpressed by its constitutional mandateand role in medicines regulation standardsetting. In the framework of this mandate,and during decades of work in the field,WHO has gained valuable experienceand, with its regional and country offices,has established a global network ofresearch institutions, collaborating cen-tres and individual experts upon which itcan draw.

Historically, WHO has actively supportedseveral harmonization initiatives such asASEAN and SADC. In the case of thePan American Network for Drug Regula-tory Harmonization (PANDRH), thesecretariat is provided by the WHORegional Office for the Americas.

Providing technical support to countriesto strengthen national drug regulatorycapacities is one of WHOs key activities.To ensure that good quality pharmaceuti-cals are available, WHO sets norms andstandards, develops guidelines andadvises Member States on issues relatedto quality assurance of medicines innational and international markets. WHOassists countries in building nationalregulatory capacity through networking,training and information sharing. Further,no other organization is involved in acomparable amount of capacity buildingworldwide.

WHO has well-established workingrelations with medicines regulatoryauthorities, nongovernmental organiza-tions and many other partners and majorplayers. WHO can also build on thecompetence and know-how of other UNorganizations such as UNICEF, UNIDO,or UNDP and the International AtomicEnergy Agency (IAEA) for issues relatedto radiopharmaceuticals. Such partnersconstitute valuable resources in thesuccessful implementation of the harmo-nization initiative together with the WHORegional Office for Africa and WHOcountry offices in African Member States.

Implementation of AMRHI1. Mapping exerciseA logical start to the initiative is assess-ment of the situation in potential partici-pating countries with regard to:

regulatory capacity and experience ofthe MRA;

volume and structure of the pharmaceu-tical market; and

existing respective regulations andlegislation (including internationaltreaties and agreements).

With better understanding of the situation,appropriate future activities can beplanned. This mapping exercise shouldalso look beyond the regulatory frame-work to all environments and legal re-quirements impacting medicines regula-tion, regulatory harmonization and inter-national cooperation. Countries withlegislation not enabling participation inthe project will also be identified. Thismapping exercise could be followed bytwo consecutive meetings.

2. Brainstorming kick-off meetingThis meeting with responsible representa-tives of potential participating MRAswould assess commitment to participatein the project. Representatives of the


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harmonization initiatives that are alreadyoperational (EU, ICH, ASEAN, GulfCooperation, SADC and others) couldattend this meeting to share experienceon expected buy-in for the participatingcountries.

3. Regional stakeholders meetingThis meeting would involve other inter-ested parties including, but not limited to:

Local industry associations; Importers/wholesalers of medicines; Representatives of medical community; Representatives of pharmacist commu-

nities;

Consumer groups;

Other interested ministries (finance,trade);

Representatives of customs authorities;

Representatives of regional and sub-regional economic blocks;

Other interested parties identified duringthe kick-off meeting.

4. RoadmapAs a result of these meetings, a roadmapshould be proposed describing the scopeand speed of implementation of theproject and the sequence of proposedactivities, as well as expected outcomes,country buy-in, and support and effortrequired to achieve successful functioningof the initiative. Decisions on secretariat,management structure and principleprocedures should be adopted. Mecha-nisms for legally acceptable handling andsharing of commercially-sensitive infor-mation should be proposed. A draftconsensus document setting out a basisfor further development of the projectshould be drafted and agreed.

5. Establishment of the AMRHI secre-tariat and Steering CommitteeAs an outcome of the regional stakehold-ers meeting, an AMRHI secretariat,Steering Committee and expert bodiesshould be established. The secretariat willcarry out routine implementation work,while the Steering Committee will beacting as a coordinating body for theharmonization initiative.

6. Common technical requirements(guidelines) for regulation of medicinalproducts and starting joint activitiesAccording to an agreed scope and speedof harmonization, technical documentsidentified for harmonization and a workingplan would be agreed. As a principle,preference should be given to the adop-tion or amendment of existing regulatoryguidelines rather than development of acompletely new set.The working plan should be regularlyupdated to reflect newly arising needsand developments. Step-by-step coop-eration should be based on progressmade in the harmonization of technicalrequirements for individual regulatoryactivities, e.g. following the harmonizationof GMP requirements, the exchange ofinspection reports, confidence buildingexercises for inspectors, and recognitionof inspection findings may start.7. Development of a training andconfidence building plan for regulatorsA Training plan should be developed inline with harmonized standards andprocedures. Training should, as far aspossible, respect the following principles.

Trainers external to the participating MRAwill support the developmental capacity oflocal trainers recruited from the expertstaff of participating MRAs. Training atnational level both of regulators andother stakeholders will be led by staffof participating authorities. Training will beoriented to acquiring practical knowledgeand confidence building. Learning by


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doing will be promoted. In order tostrengthen confidence between participat-ing MRAs, rotation of staff should bepromoted and organized. An option to beconsidered is the establishment of aregional centre to provide sustainabletraining in regulatory affairs and relatedmatters. Some preparatory work in thisdirection has already been undertaken byWHO in Africa.

8. Joint evaluation of applicationdossiers and inspection ofmanufacturing sitesA framework for assessment of applica-tion dossiers should be developed whichrespects the agreed scope of harmonizedprocedures and experience from existingregulatory networks. Each participatingauthority will be given the opportunity toparticipate in the assessment processand inspections according to availablecapacity. Harnessing available outcomesof regulatory assessments and a risk-based approach to the assessment willbe promoted. Procedures will be pro-posed for communication of assessmentoutcomes at different stages of drugevaluation between participating authori-ties and applicants. Publicly availableevaluation outcomes will be identified andprocedures will be proposed for dealingwith objections from applicants againstevaluation outcomes.

9. Information managementand exchange systemsFocal communication points and informa-tion exchange mechanisms will beproposed to support regular regulatoryactivities and processes and to manageemergencies. This will include communi-cation among participating MRAs, com-munication with the secretariat and withapplicants/authorization holders. Internetcommunication could be used as theprinciple communication platform. Atten-tion should be paid to the security ofcommercially confidential data.

References

1. World Health Organization. Equitableaccess to essential medicines: a frameworkfor collective action. WHO Policy Perspectiveson Medicines no. 8. March 2004.

2. World Health Organization. Health and theMillennium Development Goals. 2005. http://whqlibdoc.who.int/publications/2005/9241562986.pdf.

3. World Health Organization. Effectivemedicines regulation: ensuring safety, efficacyand quality. WHO Policy Perspectives onMedicines no. 7. November 2003.

4. World Health Organization. World HealthOrganization steps up action against sub-standard and counterfeit medicines. Asian andAfrican countries move to improve the qualityof their medicines. Press Release, 11 Novem-ber 2003.

5. Rgo L. Global disequilibrium of quality. In:Prince R, ed. Pharmaceutical quality. DavisHorwood International Publishing, 2005.

6. J.-M. Caudron, N. Ford, M. Henkens, C.Mace, R. Kiddle-Monroe and J. Pinel. Sub-standard medicines in resource-poor settings:a problem that can no longer be ignored.Tropical Medicine and International Health.2008. 13: 8,10621072.

7. World Health Organization. PrequalificationProgramme. http://healthtech.who.int/pq/

8. World Health Organization. Public health,innovation and intellectual property rights:report of the Commission on IntellectualProperty Rights, Innovation and Public Health.2006.

9. World Health Organization. Marketingauthorization of pharmaceutical products withspecial reference to multisource (generic)products: A manual for drug regulatoryauthorities. WHO/DMP/RGS/98.5.

10. World Health Organization. Effective drugregulation. A multicountry study. 2002.


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Safety and Efficacy IssuesMoxifloxacin: adversehepatic reactionsEuropean Union Finalizing a reviewof the safety of moxifloxacin-containingmedicines for oral use, the EuropeanMedicines Agency (EMEA) has concludedthat these medicines should only beprescribed in the treatment of acutebacterial sinusitis, acute exacerbation ofchronic bronchitis and community-acquired pneumonia when other antibiot-ics cannot be used or have failed. TheAgency also recommended strengtheningthe warnings for oral moxifloxacin medi-cines.

Moxifloxacin is a fluoroquinolone antibi-otic for the treatment of acute exacerba-tion of chronic bronchitis, community-acquired pneumonia, acute bacterialsinusitis and, in some Member States,for mild to moderate pelvic inflammatorydisease.

At its July 2008 meeting, the Committeefor Medicinal Products for Human Use(CHMP) concluded that the benefits oforal moxifloxacin medicines continue tooutweigh its risks. However, due to safetyconcerns, mainly related to an increasedrisk of adverse hepatic reactions, theCHMP recommended restricting their usein these indications. For acute bacterialsinusitis and acute exacerbations ofchronic bronchitis, they should only beprescribed when other antibiotics cannotbe used or have failed. For communityacquired pneumonia, they should onlybe given when treatment with otherantibiotics cannot be used.The CHMP also recommended that thewarnings of oral moxifloxacin-containing

medicines should be strengthenedconcerning the risk of diarrhoea, heartfailure in women and older patients,severe skin reactions and fatal liver injury.Doctors are advised to prescribe oralmoxifloxacin-containing medicinesaccording to the updated product informa-tion and to consider the official guidanceon the appropriate use of antibiotics andthe local prevalence of resistance.The CHMP opinion will now be forwardedto the European Commission for theadoption of a decision applicable to alloral moxifloxacin-contain medicinesauthorized in the EU.

Reference: European Medicines AgencyPresss Release, Doc. Ref. EMEA/CHMP/382927/2008. 24 July 2008. http://www.emea.europa.eu

Ezetimibe/simvastatin: safetyreview of cancer riskUnited States of America The Foodand Drug Administration (FDA) is investi-gating a report from the SEAS trial(Simvastatin and Ezetimibe in AorticStenosis) of a possible associationbetween the use of Vytorin (a combina-tion of simvastatin plus ezetimibe) and apotentially increased incidence of cancer.

Simvastatin (Zocor), a statin classdrug approved in 1991, decreasesproduction of cholesterol by the liver andis indicated to reduce LDL-cholesterollevels and reduce the risk of cardiovascu-lar events such as heart attack andstroke. Ezetimibe (Zetia), approved in2002, inhibits the absorption of choles-terol in the intestine and is indicated toreduce LDL-cholesterol levels. Vytorin,the combination product approved in

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2004, is indicated to reduce LDL-choles-terol levels.

Recently, FDA obtained preliminaryresults from the SEAS trial. This clinicaltrial tested whether lowering LDL-choles-terol with Vytorin would reduce the riskof major cardiovascular events, includingaortic valve replacement, congestiveheart failure, and ischemic cardiovascularevents in individuals with aortic stenosis.A lower overall cardiovascular risk wasnot found with Vytorin. However, therewas an additional observation that alarger percentage of subjects treated withVytorin were diagnosed with and diedfrom all types of cancer combined (includ-ing skin cancer) when compared toplacebo during the 5-year study.

Interim data from two large ongoingcardiovascular trials of Vytorin theStudy of Heart and Renal Protection(SHARP) and the Improved Reduction inHigh-Risk Subjects Presenting with AcuteCoronary Syndrome (IMPROVE-IT) show no increased risk of cancer with thecombination of simvastatin plus ezetim-ibe. The SHARP trial is expected to becompleted in 2010. The IMPROVE-IT trialis scheduled for completion around 2012.Safety data from both of these trials arebeing evaluated on a regular basis byindependent data safety monitoringboards. FDA has determined that, to date,these findings in the SEAS trial plus theinterim data from ongoing trials shouldnot prompt patients to stop takingVytorin or any other cholesterol loweringdrug.

FDA is aware of previous reports sug-gesting a link between low on-treatmentcholesterol levels and an increased risk ofcancer. A 2007 pooled analysis of 16studies with 23 statin drug arms, pub-lished in the Journal of the AmericanCollege of Cardiology, reported an asso-ciation between the level of LDL-choles-

terol achieved and incident cancer inpatients receiving a statin.

However, most large prospective studiesof statin drugs have reported no differ-ence in cancer incidence between theactive and placebo arms. For simvastatin,the Heart Protection Study randomized20 000 patients to a daily dose of simvas-tatin 40 mg or placebo for up to 5 years.The incidence rate for cancer was 7.9%in the simvastatin group and 7.8% in theplacebo group, and the deaths fromcancer occurred at similar rates in bothgroups.

References

1. Alsheikh-Ali A et al. Effect of the magnitudeof lipid lowering on risk of elevated liverenzymes, rhabdomyolysis, and cancer. J AmColl Cardiol 2007;50: 409-18.

2. Heart Protection Study Collaborative Group.MRC/BFH Heart Protection Study of choles-terol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002;360: 7-22.

3. FDA Early Communication about anongoing safety review of ezetimibe/simvastatin(marketed as Vytorin), simvastatin (marketedas Zocor) and ezetimibe (marketed asZetia). 21 August 2008 at http://www.fda.gov/medwatch

Norfloxacin-containingmedicines not for use inurinary infectionsEuropean Union The EuropeanMedicines Agency (EMEA) has recom-mended restricting the use of oral nor-floxacin-containing medicines in urinaryinfections. The Agencys Committee forMedicinal Products for Human Use(CHMP) has concluded that the market-ing authorizations for oral norfloxacin-containing medicines, when used in thetreatment of acute or chronic complicatedpyelonephritis (kidney infection), should

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be withdrawn because the benefits ofthese medicines do not outweigh theirrisks in this indication. This is based onthe fact that the efficacy has not beenadequately demonstrated for this type ofinfection.

Norfloxacin is a fluoroquinolone antibiotic.Medicines containing norfloxacin areauthorized in all European Union (EU)Member States under various tradenames for the treatment of infections,including simple or complicated urinarytract infections, infection of the prostate,uncomplicated gonorrhoea, several typesof gastroenteritis and conjunctivitis.The CHMP review of norfloxacin medi-cines was initiated on the request ofthe Belgian medicines regulatory agency.They questioned the efficacy of oralformulations of the medicine for compli-cated pyelonephritis, in comparison withother fluoroquinolones. In current prac-tice, this disease is usually treated usingeither injectable antibiotics, or otherfluoroquinolones taken by mouth or givenby injection.Following evaluation of informationprovided by the companies, the CHMP,at its July 2008 meeting, noted that therewas not enough clinical data to demon-strate the efficacy of oral treatment withnorfloxacin-containing medicines incomplicated pyelonephritis. Therefore,the CHMP concluded that the use of oralnorfloxacin-containing medicines in thetreatment of acute or chronic complicatedpyelonephritis could no longer be sup-ported.The recommendation of the CHMP doesnot have an impact on the use of oralnorfloxacin-containing medicines in othertypes of infection.

Doctors should not prescribe oral nor-floxacin for complicated pyelonephritisand should consider switching patients

already taking oral norfloxacin for thistype of infection to an alternative antibi-otic. Patients who are taking oral formula-tions of norfloxacin-containing medicinesto treat complicated pyelonephritisshould discuss their treatment with theirdoctor if they continue to have symptomsor at their next scheduled visit.

Reference: European Medicines AgencyPress Release. Doc. Ref. EMEA/380260/2008. 24 July 2008. http:/www.emea.europa.eu

Ceftriaxone: fatal outcomewith calcium-containingsolutionsCanada There is a risk of precipitationwhen ceftriaxone and calcium are admin-istered concurrently via intravenous route.Cases of fatal reactions with ceftriaxone-calcium precipitates in lung and kidneyshave been described in neonates andinfants (14).Ceftriaxone is a long-acting broad spec-trum cefalosporin antibiotic for parenteraluse indicated for treatment of lowerrespiratory tract infections, renal andurinary tract infections, bacterial septi-cemia, skin and wound infections, boneand joint infections, gonorrhoea, intra-abdominal infections, and meningitiswhen caused by susceptible organisms.Ceftriaxone is also indicated for prophy-laxis in patients undergoing certainsurgical procedures.

Although there are no reports to date ofintravascular precipitations in patients,other than neonates, the theoreticalpossibility exists for an interaction be-tween ceftriaxone and calcium-containingsolutions in other patients. In patients aged less than 10 weeks, IV

Ceftriaxone and IV calcium-containingsolutions should not be administeredwithin 5 days of each other.

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In all other patients, IV Ceftriaxone andIV calcium-containing solutions shouldnot be administered within 48 hours ofeach other.

Ceftriaxone and calcium-containingsolutions, including continuous calcium-containing infusion such as parenteralnutrition, should not be mixed or co-administered to any patient irrespectiveof age, even via different infusion linesat different sites

Although most cases occurred withsimultaneous administration of the twoproducts, the interaction has also beenreported when ceftriaxone and calcium-containing products were administeredat different times and through differentinfusion lines. This explains the recom-mended interval between the administra-tion of the two products becauseceftriaxone remains in circulation for acertain time after its administration (5).References

1. Rapp RP, Kuhn R. Clinical pharmaceuticsand calcium ceftriaxone. Ann pharmacother2007;41:2072. Epub 6 nov 2007. DOI10.1345/aph.1K410.

2. Gin AS, Wheateon H, Dalton B. Comments:Clinical pharmaceutics and calcium-ceftriaxone. Ann pharmacother 2008;42:450-51. Epub 29 January 2008. DOI 10.1345/aph.1K410a.

3. Minutes of Commission Nationale depharmacovigilance meeting, January 31,2006. http://afssaps.sante.fr/htm/1/pharmaco/cr060101.pdf. Accessed 2008-06-23.

4. Information for healthcare professionals.September 2007. www.fda.gov/cder/drug/InfoSheets/HCP/ceftriaxone.htm. Accessed2008-06-23.

5. Communication from Medeffect, 31 July2008. http://www.hc-sc.gc.ca

Safety review of tumournecrosis factor blockersUnited States of America The Foodand Drug Administration (FDA) is investi-gating the possible association betweenuse of tumor necrosis factor (TNF)blockers (marketed as Remicade,Enbrel, Humira, and Cimzia) and thedevelopment of lymphoma and othercancers in children and young adults.These individuals were treated with TNFblockers for Juvenile Idiopathic Arthritis(JIA), Crohn disease or other diseases.JIA is the new name for what was calledJuvenile Rheumatoid Arthritis (JRA).FDA is investigating approximately 30reports of cancer in children and youngadults submitted to FDAs Adverse EventReporting System over a ten-year inter-val, beginning in 1998 after approval ofthe first TNF blocker, and extendingthrough 29 April 2008. These reportsdescribed cancer occurring in childrenand young adults who began taking TNFblockers (along with other immuno-suppressive medicines such as meth-otrexate, azathioprine or 6-mercaptopu-rine), when they were aged 18 or less, totreat Juvenile Idiopathic Arthritis (JIA),Crohn disease or other diseases. Ap-proximately half the cancers were lym-phomas and included both Hodgkin andnon-Hodgkin lymphoma. Lymphoma isnot a recognized complication of JIA or ofCrohn disease. Other cancers reportedincluded leukaemia, melanoma, and solidorgan cancers.

FDA is also aware of the risk of hepato-splenic T cell lymphoma in children andyoung adults with Crohn disease treatedwith Remicade and immunosuppressivedrugs such as azathioprine or 6-mercap-topurine. This risk was described in theRemicade prescribing information in2006.

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FDA has requested the manufacturers toprovide information about all cases ofcancer reported in children taking TNFblockers. The manufacturer of Cimzia isrequired to conduct a study to assesslong-term risks of the product, includinglymphoma and other cancers.

Reference: FDA Advise of safety review, 4June 2008. http://www.fda.gov/medwatch/

Recombinant human bonemorphogenetic protein: life-threatening complicationsUnited States of America The Foodand Drug Administration (FDA) hasreceived reports of life-threateningcomplications associated with recom-binant human bone morphogeneticprotein (rhBMP) when used in the cervicalspine. It is of note that the safety andeffectiveness of rhBMP in the cervicalspine have not been demonstrated andthese products are not approved by FDAfor this use.

FDA has received at least 38 reports ofcomplications during the last 4 years withthe use of rhBMP in cervical spine fusion.These complications were associatedwith swelling of neck and throat tissue,which resulted in compression of theairway and/or neurological structures inthe neck. Some reports describe difficultyswallowing, breathing or speaking.Severe dysphagia following cervical spinefusion using rhBMP products has alsobeen reported in the literature.Anatomical proximity of the cervical spineto airway structures in the body hascontributed to the seriousness of theevents reported and the need for emer-gency medical intervention. The mecha-nism of action is unknown, and character-istics of patients at increased risk havenot been identified.Most complications occurred between 2and 14 days post-operatively with only a

few events occurring prior to day 2. Whenairway complications occurred, medicalintervention was frequently necessary.Treatments needed included respiratorysupport with intubation, anti-inflammatorymedication, tracheotomy and mostcommonly second surgeries to drain thesurgical site.

Since the safety and effectiveness ofrhBMP for treatment of cervical spineconditions has not been demonstrated,and in light of the serious adverse eventsdescribed above, FDA recommends thatpractitioners either use approved alterna-tive treatments or consider enrolling asinvestigators in approved clinical studies.Both rhBMPs are contraindicated for alluses in patients who are skeletallyimmature (

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pumps. In these reports, the followingadverse events were likely to have beencaused by x-rays from CT scans:

Unintended shocks (i.e., stimuli) fromneurostimulators

Malfunctions of insulin infusion pumps Transient changes in pacemaker output

pulse rate

Note that malfunctions of this kind, whichcan result from direct exposure of themedical device to the high x-ray doserates generated by some CT equipment,are different from those related to MRIscanning, which are caused by strongelectric and magnetic fields.

Reference: FDA Preliminary Public HealthNotification: Possible Malfunction of ElectronicMedical Devices Caused by ComputedTomography (CT) Scanning, 14 July 2008 athttp://www.fda.gov/cdrh/safety.html.

Desmopressin andhyponatraemiaAustralia Desmopressin (Minirin,Octostim) is a synthetic analogue ofthe natural antidiuretic hormone (ADH)arginine vasopressin and is currentlyavailable in nasal spray, nasal solution,tablet, sublingual wafer, and injectionform. Desmopressin nasal spray andtablets are indicated for primary nocturnalenuresis (where an enuresis alarm hasfailed or is contraindicated) and cranialdiabetes insipidus; desmopressin nasalsolution and tablets are indicated forcranial diabetes insipidus and certainblood disorders.Desmopressin acts on the ADH receptorsin the kidneys, mimicking the effects ofADH and therefore preventing excessiveloss of water. In the presence of exces-sive fluid intake in patients taking desmo-pressin, dilutional hyponatraemia canoccur. If this occurs quickly then lack of

adaptation can result in a shift of waterintracellularly and cerebral oedema,which may present with anorexia, nauseaand vomiting, difficulty concentrating,confusion, lethargy, agitation, headache,and seizures.

The risk of hyponatraemia is greater withdesmopressin intranasal preparationsthan with the oral forms. In 2007, the TGAamended the indications for desmo-pressin nasal spray to restrict use onlywhen it is not feasible to use an oralformulation. Sponsors were also requiredto amend all desmopressin productinformation documents to strengthenprecautionary statements relating to thepotential for hyponatraemia and toprovide information on this potentiallyserious reaction (1).To date, ADRAC has received 68 reportsof adverse reactions associated with theuse of desmopressin, including 17 reportsof convulsions (with or without reportedhyponatraemia), and 10 further reports ofhyponatremia alone. Of 12 reports ofconvulsions or hyponatremia following theuse of desmopressin nasal spray, 7involved children under 13 years of age.

Prescribers are reminded that desmo-pressin nasal spray and tablets should beused in the treatment of nocturnal enu-resis only when an enuresis alarm hasfailed or is contraindicated, and thattablets should be used in preference tointranasal preparations because of apossible increased risk of hyponatremia.Avoidance of excessive fluid intakeshould be advised during treatment withdesmopressin. The ongoing need forthese products should be reviewedperiodically in patients taking desmo-pressin long-term.

Extracted from the Australian AdverseDrug Reactions Bulletin, Volume 27,Number 4, August 2008

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Reference

1. Ferring Pharmaceuticals Pty Ltd. ProductInformation for: Minirin Nasal Spray, MinirinTablets, Minirin, Octistim.

Micro-bubble contrast agentsUnited States of America The Foodand Drug Administration (FDA) hasissued an alert to healthcare profession-als about changes that were made to theprescribing information for micro-bubblecontrast agents.

The revised boxed warning and warningscontinue to highlight the risk of seriouscardiopulmonary reactions during orwithin 30 minutes following the adminis-tration of these products and recommendthat high risk patients with pulmonaryhypertension or unstable cardiopulmo-nary conditions be closely monitoredduring and for at least 30 minutes postadministration of these contrast agents.Concurrent with these labelling changes,the FDA has required that manufacturersof micro-bubble contrast agents conductclinical studies to more thoroughly assessthe risks for serious cardiopulmonaryreactions.

Reference: Information for HealthcareProfessionals. Micro-bubble Contrast Agents(marketed as Definity (Perflutren LipidMicrosphere) Injectable Suspension andOptison (Perflutren Protein-Type AMicrospheres for Injection). FDA Alert, 17 July2008 at http://www.fda.gov/medwatch

Simvastatin used withamiodarone: rhabdomyolysisUnited States of America The Foodand Drug Administration (FDA) hasissued an alert to healthcare profession-als about the risk of a rare condition ofmuscle injury called rhabdomyolysis,which can lead to kidney failure or death,when simvastatin is used with amiodar-one.

This risk is dose-related and increaseswhen a dose of simvastatin greater than20 mg per day is given with amiodarone.A revision of the simvastatin labelling in2002 described an increased risk ofrhabdomyolysis when amiodarone istaken with simvastatin doses greater than20 mg daily.

However, the FDA continues to receivereports of rhabdomyolysis in patientstreated concurrently with amiodarone andsimvastatin, particularly with simvastatindoses greater than 20 mg daily. Prescrib-ers should be aware of the increased riskof rhabdomyolysis when simvastatin isprescribed with amiodarone, and theyshould avoid doses of simvastatin greaterthan 20 mg per day in patients takingamiodarone.

Reference: Information for HealthcareProfessionals. Simvastatin (marketed asZocor and generics), Ezetimibe/Simvastatin(marketed as Vytorin), Niacin extended-release /Simvastatin (marketed as Simcor),used with Amiodarone (Cordarone,Pacerone). FDA Alert, 8 August 2008 athttp://www.fda.gov/medwatch

Naltrexone injectionsite reactionsUnited States of America The Foodand Drug Administration (FDA) hasissued an alert to healthcare profession-als about the risk of adverse injection sitereactions in patients receiving naltrexone(Vivitrol). Physicians should instructpatients to monitor the injection site andcontact them if they develop pain, swell-ing, tenderness, induration, bruising,pruritus, or redness at the injection sitethat does not improve or worsens withintwo weeks. Physicians should promptlyrefer patients with worsening injection sitereactions to a surgeon.

FDA has received 196 reports of injectionsite reactions including cellulitis, indura-

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tion, haematoma, abscess, sterile ab-scess, and necrosis. Sixteen patientsrequired surgical intervention rangingfrom incision and drainage in the cases ofabscesses to extensive surgical debride-ment in the cases that resulted in tissuenecrosis.

Naltrexone is indicated for the treatmentof alcohol dependence in patients whoare able to abstain from alcohol in anoutpatient setting prior to initiation oftreatment. Naltrexone is administeredas an intramuscular (IM) gluteal injection.Naltrexone should not be administeredintravenously, subcutaneously, or inad-vertently into fatty tissue. Healthcareproviders should ensure that the nal-trexone injection is given correctly withthe pre-packaged needle that is specifi-cally designed for this drug.

Reference: Information for HealthcareProfessionals. Naltrexone Injection SiteReactions [naltrexone for extended-releaseinjectable suspension (marketed as Vivitrol)].FDA Alert, 12 August 2008 at http://www.fda.gov/medwatch

Adalimumab: hepatosplenicT-cell lymphomaUnited Kingdom The manufacturerof adalimumab (Humira) is advisinghealthcare professionals of new safetyinformation. Adalimumab is a TNF alphablocker authorized in adult patients for thetreatment of rheumatoid arthritis, psoriaticarthritis, ankylosing spondylitis, Crohndisease and psoriasis.

From launch in December 2002, threepostmarketing reports of hepatosplenicT-cell lymphoma (HSTCL), which is arare aggressive form of non-Hodgkinlymphoma with a poor prognosis, havebeen reported in patients receivingadalimumab.

Two of these three patients were youngmen also receiving azathioprine or 6-

mercaptopurine for inflammatory boweldisease. A risk for the development ofhepatosplenic T-cell lymphoma inpatients treated with adalimumabcannot be excluded.

HSTCL should be considered in theevent that a patient receiving adalimu-mab develops symptoms of lymphomasand / or hepatosplenomegaly with orwithout peripheral lymphadenopathy orsignificant peripheral blood lymphocyto-sis.

A warning will be added to the productinformation (SPC/Package Leaflet) as arisk minimization measure.

Reference: Direct Healthcare ProfessionalCommunication on reports of hepatosplenic T-cell lymphoma in patients treated withHumira (adalimumab). Abbott Ltd. at http://www.mhra.gov.uk

Serious Risks/New SafetyInformationUnited States of America The Foodand Drug Administration (FDA) haspublished a table listing the names ofproducts and potential signals of seriousrisks/new safety information that wereidentified for these products during theperiod January March 2008 in theAdverse Event Reporting System (AERS)database (see table on page 199).The appearance of a drug on this listdoes not mean that FDA has concludedthat the drug has the listed risk. It meansthat FDA has identified a potential safetyissue, but does not mean that FDA hasidentified a causal relationship betweenthe drug and the listed risk. If after furtherevaluation the FDA determines that thedrug is associated with the risk, it maytake a variety of actions including requir-ing changes to the labelling of the drug,requiring development of a Risk Evalua-tion and Mitigation Strategy (REMS), orgathering additional data to better charac-terize the risk.

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FDA wants to emphasize that the listingof a drug and a potential safety issue onthis Web site does not mean that FDA issuggesting prescribers should not pre-scribe the drug or that patients taking thedrug should stop taking the medication.Patients who have questions about theiruse of the identified drug should contacttheir health care provider. FDA willcomplete its evaluation of each potentialsignal/new safety information and issueadditional public communications asappropriate.

Reference: 5 September 2008 at http://www.fda.gov

Deferasirox: hepatic failureUnited Kingdom In agreement withEuropean Union regulatory authorities,the manufacturer of deferasirox(Exjade) has advised healthcare profes-sionals of updated safety information.Deferasirox is indicated for the treatmentof chronic iron overload due to frequentblood transfusions, or when desferriox-amine (Desferal) is contraindicated orinadequate:

Postmarketing cases of hepatic failure,sometimes fatal, have been reported inpatients treated with deferasirox. Therole of deferasirox as a contributing oraggravating factor cannot be excluded.

Potential Signals of Serious Risks/New Safety Information Identified by theAdverse Event Reporting System (AERS), January March 2008

Product Name: Active Ingredient Potential Signal of Serious Risk/(Trade), New or Product Class Safety InformationArginine Hydrochloride Injection Paediatric overdose due to labelling / (R-Gene 10) packaging confusionDesflurane (Suprane) Cardiac arrestDuloxetine (Cymbalta) Urinary retentionEtravirine (Intelence) HaemarthrosisFluorouracil Cream (Carac) and Adverse events due to name Ketoconazole Cream (Kuric) confusionHeparin Anaphylactic-type reactionsIcodextrin (Extraneal) HypoglycaemiaInsulin U-500 (Humulin R) Dosing confusionIvermectin (Stromectol) and Warfarin Drug interactionLapatinib (Tykerb) HepatotoxicityLenalidomide (Revlimid) Stevens Johnson SyndromeNatalizumab (Tysabri) Skin melanomasNitroglycerin (Nitrostat) Overdose due to labelling confusionOctreotide Acetate Depot Ileus (Sandostatin LAR)Oxycodone Hydrochloride Controlled- Drug misuse, abuse and overdose Release (Oxycontin)Perflutren Lipid Microsphere (Definity) Cardiopulmonary reactionsPhenytoin Injection (Dilantin) Purple Glove SyndromeQuetiapine (Seroquel) Overdose due to sample pack labelling

confusionTelbivudine (Tyzeka) Peripheral neuropathyTumor Necrosis Factor (TNF) Blockers Cancers in children and young adults

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It is recommended that serum trans-aminases, bilirubin and alkaline phos-phatase are checked before the initia-tion of treatment, every 2 weeks duringthe first month and monthly thereafter. Ifthere is a persistent and progressiveincrease in serum transaminase levelsthat cannot be attributed to othercauses, deferasirox should be inter-rupted (see section 4.8 of revised SPC,attached).

Upper gastrointestinal ulceration andhaemorrhage have been reported inpatients, including children and adoles-cents, receiving deferasirox. Physiciansand patients should remain alert forsigns and symptoms of gastrointestinalulceration and haemorrhage duringdeferasirox therapy and promptly initiateadditional evaluation and treatment ifa serious gastrointestinal adverse eventis suspected.

Cases of renal tubulopathy (Fanconisyndrome) have been reported inpatients treated with deferasirox. Dosereduction or interruption may be consid-ered if there are abnormalities in levelsof tubular markers and/or if clinicallyindicated.

Reference: Communication from NovartisPharmaceutical UK Ltd, EXJ08000052, July2008 at http://www.Mhra.gov.uk

Abacavir: hypersensitivityreactionsUnited States of America The Foodand Drug Administration (FDA) hasissued an alert to healthcare profession-als about serious and sometimes fatalhypersensitivity reactions (HSR) causedby abacavir therapy which are signifi-cantly more common in patients with aparticular human leukocyte antigen (HLA)allele, HLA-B*5701. Abacavir HSR is amulti-organ syndrome characterized by 2or more clinical signs or symptoms thatcan include fever, rash, gastrointestinal

symptoms, respiratory symptoms andconstitutional symptoms.FDA has reviewed data from 2 studiesthat support the recommendation for pre-therapy screening for the presence of theHLA-B*5701 allele and the selection ofalternative therapy in positive subjects.Genetic tests for HLA-B*5701 are alreadyavailable and all patients should bescreened for the HLA-B*5701 allelebefore starting or restarting treatment withabacavir or abacavir-containing medica-tions. Avoidance of abacavir therapy inHLA-B*5701 positive patients will signifi-cantly decrease the risk of developingclinically-suspected abacavir HSR. ForHLA-B*5701-positive patients, treatmentwith an abacavir-containing regimen isnot recommended and should be consid-ered only under exceptional circum-stances when the potential benefit out-weighs the risk.

Development of clinically-suspectedabacavir HSR requires immediate andpermanent discontinuation of abacavirtherapy in all patients, including patientsnegative for HLA-B*5701. This new safetyinformation will be reflected in updatedproduct labelling.

Reference: Information for HealthcareProfessionals. Abacavir (marketed asZiagen) and Abacavir-containing Medica-tions. FDA Alert, 24 July 2008 at http://www.fda.gov/medwatch

Fluoroquinolones: risk oftendinitis and tendon ruptureUnited States of America The Foodand Drug Administration (FDA) hasnotified manufacturers that a boxedwarning is necessary in the labelling forfluoroquinolones concerning the in-creased risk of tendinitis and tendonrupture. The agency also determined thatit is necessary for manufacturers of thedrugs to provide a Medication Guide topatients about possible side effects.

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The risk of developing fluoroquinolone-associated tendinitis and tendon ruptureis further increased in people older than60, in those taking corticosteroid drugs,and in kidney, heart, and lung transplantrecipients.

Reference: FDA News, 8 July 2008. http://www.fda.gov/medwatch

Colchicine: fatal interactionsand reactionsAustralia Colchicine is indicated forthe treatment of acute gout, but it has anarrow therapeutic index with significantpotential for toxicity and severe druginteractions. In mid-2007, the TherapeuticGoods Administration (TGA) requiredupdates to the Colgout and Lengoutproduct information to limit colchicineusage to only where NSAID treatment iscontraindicated, has failed or has causedunacceptable side effects; and to limit themaximum cumulative dose to 6 mg over 4days in otherwise healthy adults (withwashout intervals of at least 3 days ifadditional treatment is needed). Alterna-tive treatments should be considered inthe elderly and those with renal or hepaticimpairment, but if colchicine is to be usedin these patients the cumulative doseshould not exceed 3 mg over 4 days.

The Adverse Drug Reactions AdvisoryCommittee (ADRAC) has previouslywarned of the potential for severe or fataltoxicities with colchicine especially inoverdose and in those with renal impair-ment (1). Toxic effects of greatest con-cern include blood dyscrasias due tobone marrow suppression, multi-organfailure and, more rarely, myopathy andrhabdomyolysis (which tend to occur inpatients with impaired renal or hepaticfunction on long-term treatment withprophylactic doses of colchicine).Since colchicine is metabolized mainly byCYP3A4, prescribers should be aware

that drugs that inhibit this enzyme mayincrease blood colchicine concentrationsand therefore increase the potential forcolchicine toxicity. The CYP3A4 inhibitor,clarithromycin, was used concomitantly in4 cases of severe colchicine toxicityreported to the TGA, 3 of which describeda fatal outcome. In one of the fatal cases,clarithromycin was being used as part oftriple therapy for Helicobacter pylorieradication in a patient undergoingtreatment for gout with colchicine; thispatient subsequently developed massivemyelosuppression and multi-organ failure.Cases of fatal interactions betweencolchicine and clarithromycin have alsobeen published (2, 3).To date, the TGA has received 243reports for colchicine, including 53 de-scribing blood dyscrasias such as neutro-penia (15 reports), thrombocytopenia(10), pancytopenia (10), leukopenia (8)and agranulocytosis (4 reports), and anadditional report describing sepsis andextensive severe maculopapular rash.Of these cases, 21 had not recovered atthe time of reporting and 9 described afatal outcome associated with renalfailure, multi-organ failure or overwhelm-ing sepsis. Colchicine was the solesuspected drug in 16 of the reports ofblood dyscrasia but other drugs werealso suspected in all of the reports thatdescribed a fatal outcome.Prescribers are reminded that colchicinecan be associated with significant toxicityand the risk-benefit should be consideredon a case-by-case basis. In most cases,it should be used for short-term periodsand only where NSAID therapy is con-traindicated or has failed. Colchicine isbest avoided if patients are taking drugsthat inhibit CYP3A4 or have significantrenal or hepatic impairment.

Extracted from the Australian AdverseDrug Reactions Bulletin, Volume 27,Number 5, October 2008

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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 adverse eventand a drug, the relationship being unknown or incompletely documented previously. Usually, more than a single reportis required to generate a signal, depending upon the seriousness of the event and the quality of the information". Allsignals must be validated before any regulatory decision can be made.

References

1. ADRAC and Kubler PA. Fatal colchicinetoxicity. MJA 2000; 172: 498-490.2. Cheng VC, Ho PL and Yuen KY. Twoprobable cases of serious drug interactionbetween clarithromycin and colchicine.Southern Med J 2005; 98: 811-813.

3. Hung IF, Wu AK, Cheng VC, et al. Fatalinteraction between clarithromycin andcolchicine in patients with renal insufficiency:A retrospective study. Clin Infect Dis 2005; 41:291300.

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Regulatory Action and NewsWHO Prequalification: GMPdeviations and suspensionWorld Health Organization WHOsMedicines Prequalification Programmehas issued a Notice of Concern letter toSandoz South Africa Ltd. based on theresults of inspections performed at theirmanufacturing facility in Kempton Park,South Africa. Additionally, one product(isoniazid 150 mg + rifampicin 300 mgtablet) which is manufactured at thefacility was suspended from the WHO Listof Prequalified Medicines.

These actions were taken as a conse-quence of problems documented withmanufacturing processes, where signifi-cant deviations from good manufacturingpractices (GMP) were documented in themanufacture and control of antituber-culosis medicines during the WHO in-spection in May 2008. A follow-up inspec-tion by WHO was refused by the com-pany, thus it was not possible to verify theimplementation of corrective action andcome to a conclusion on the level of GMPcompliance currently on site.

These actions are proactive measuresthat WHO is taking to ensure that allprequalified medicinal products aremanufactured according to GMP require-ments. A Notice of Concern is issued toremind a manufacturer or researchorganization of their obligations to assurequality and to inform suppliers andprocurement agencies of potential risksassociated with a given product, manu-facturer or organization.A Notice ofConcern is not cause for public concern.If WHO identifies a public health risk,appropriate additional steps are taken toadvise health professionals and thepublic.

Suspension from the WHO List of Pre-qualified Medicinal Products will haltprocurement by international and nationalprocurement agencies of the productsconcerned until the Medicines Prequalifi-cation Programme is satisfied that allcorrective actions have been taken by themanufacturer and verified by WHO.Based on the information currentlyavailable, the documented deficiencies inmanufacturing do not relate to the specificfailure of the concerned Sandoz productto meet its required specifications or totreat human illness.

WHO is advising consumers to continuetaking their Sandoz medications until theycan be replaced with quality assuredproducts from other manufacturers.However, where no alternative treatmentoptions are available, WHO stronglyadvises consumers not to interrupt theirdrug therapy, which could have seriousimplications for their health.Reference: Sandoz PQ note, 25 September2008 at http://www.who.int/prequal

Import alert: Ranbaxy facilitiesUnited States of America The USFood and Drug Administration (FDA) hasissued two Warning Letters to RanbaxyLaboratories Ltd and simultaneouslyestablished an Import Alert for drugsmanufactured or using materials from twoRanbaxy facilities in India at Dewas orPaonta Sahib. This means that anyfinished product or active pharmaceuticalingredient manufactured at these sitesoffered for import into the United Stateswill be detained at the border.The reason for these actions followsproblems involving drug manufacturing

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WHO Drug Information Vol 22, No. 3, 2008Regulatory Action and News

in addition to its routine monitoringactivities to confirm if products prequali-fied by WHO from Ranbaxy continue tomeet all the necessary requirements toensure quality, safety and efficacy.Additionally, the WHO Medicines Pre-qualification Programme: has written to Ranbaxy requesting

clarification of the issues raised by FDA; is in close contact with FDA concerning

the Ranbaxy products based on theconfidentiality agreement between thetwo institutions;

is in contact with other national regula-tory authorities to follow the matterclosely;

is taking steps to identify any potentialirregularities or deficiencies that mayaffect Ranbaxy products, either underevaluation or prequalified by WHO;

is liaising with other UN agencies (suchas UNICEF) and partners.

In the current situation, where no alterna-tive treatment options are available, WHOstrongly advises consumers not to inter-rupt their drug therapy, which could haveserious implications for their health.Switching to non-prequalified products isnot recommended as their quality has notbeen documented by WHO.

References

1. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01886.html

2. Ranbaxy PQ note, 17 September 2008 athttp://www.who.int/prequal

Medicines PrequalificationProgramme: listed productsWorld Health Organization The WHOMedicines Prequalification Programme, inclose cooperation with national regulatoryagencies and partner organizations,was established to make quality priority

processes where significant deviationfrom good manufacturing practices(GMP) have been documented in manu-facture and control of both finishedproducts and active pharmaceuticalingredients during FDA inspections inearly 2008 (1).These are proactive measures that theFDA is taking to ensure that all drugs thatreach the American public are manufac-tured according to GMP requirements.Based on the information currentlyavailable, the FDA documented deficien-cies in manufacturing do not relate to thespecific failure of any Ranbaxy product tomeet its required specifications or to treathuman illness. FDA is not recalling anyproduct presently in distribution in theUSA, but is advising consumers tocontinue taking their medications untilthey can be replaced with products fromanother manufacturer.

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