Good Pharmaceutical Trade and Distribution Practices

8/6/2019 Good Pharmaceutical Trade and Distribution Practices

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WHO Drug Information Vol. 15, No. 1, 2001

WHO Drug Information

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Contents

Quality Assurance IssuesGood pharmaceutical trade and distribution

practices 1

Personal PerspectivesRisk assessment as an element of drug control 6

Current TopicsThe WHO Model List of Essential Drugs:

latest developments 12Sequencing of the Anopeles gambiaegenome 14Multilateral initiative on Malaria: benefits to

the global community 15China revises its pharmaceutical law 16

Regulatory and Safety MattersNew formulation of DTP vaccine 17Bupropion safety reminder 17

Propofol: reactions to long-term high doses 17Propofol: not for paediatric use 18Leflunomide: hepatic reactions 18Rapacuronium bromide voluntarily withdrawn 18Levacetylmethadol withdrawn 19

Levacetylmethadol: labelling changes 19Isotretinoin and depression 19New glucose test for adult diabetics 19Anti-inflammatory analgesics: hepatic reactions 20Gentamicin ear drops: toxicity 20Tetracycline and benign intracranial

hypertension 20Ergotamine and erythromycin interaction 21Celecoxib and warfarin interaction 21

Cerivastatin: rare effect of rhabdomyolysis 22SSRIs and increased ocular pressure 22Amfepramone: new cases of primary

pulmonary hypertension 23Bufexamac and contact eczema 23Droperidol: prolongation of the QT interval 23Mofezolac: revised data sheet 24Monoethanolamine oleate: revised data sheet 24Rivastigmine: revised product information 24Sarpogrelate: revised data sheet 25

ATC/DDD ClassificationATC/DDD methodology: a country perspective 26

Recommended International

Nonproprietary Names: List 45

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WHO Drug Information

is now available at:

http://www.who.int/druginformation
http://www.who.int/druginformationhttp://www.who.int/druginformation


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Quality Assurance Issues

Good pharmaceutical tradeand distribution practices

H. Leblanc, The European Chemical IndustryCouncil (CEFIC)F. Milek, International PharmaceuticalExcipients Council (IPEC)

Over the past sixty years, there have been over 500reported cases of fatal incidents due to the acciden-tal but also fraudulent incorporation of diethyleneglycol into pharmaceuticals (1). About 80 childrendied in Haiti in 1996 as a result of contaminatedparacetamol syrup containing diethylene glycol inglycerol used as an excipient. A similar case ofdiethylene glycol poisoning was identified in Indiabetween April and June 1999 (2). The WHO DrugInformationhas also published articles on othercases reported worldwide (3).

WHO has developed guidelines on good manufac-turing practices (GMP) for both finished pharma-ceutical dosage forms and starting materials (4),while other regulations and guidelines continue tobe issued. A Guideline on Good Manufacturing

Practice for Active Pharmaceutical Ingredients hasalso been approved by the International Confer-ence on Harmonization (ICH) (5). Other bodies,such as the International Pharmaceutical ExcipientsCouncil or the United States Pharmacopeia, havepublished recommendations (67). WHO Guide-lines for the Manufacture of Pharmaceutical Excipi-ents were published in 1999 (8) although noequivalent ICH guideline yet exists. Although highquality production standards will guarantee a goodquality product, they do not confirm that high qualitystarting materials are indeed delivered to the phar-maceutical manufacturers.

Industry has engaged in a voluntary programme ofresponsible care and product stewardship, as setout on the following page. Such programmesshould ensure that only safe products are used.However, the best programmes cannot defeat allfraudulent practices. Unscrupulous individualsconcerned with making quick and easy money willcontinue to seek out any loopholes in regulations

and circumvent systems in particular when regula-tions are absent or not enforced (9).

How do these productsreach the consumer ?When company A buys from manufacturing com-pany B, does company A really receive a productmade by company B? Hopefully, yes. But this is notalways the case. The commercial practices de-scribed below are considered normal transactionsin many countries and demonstrate the difficultiesencountered in operating effective control systems.

Producer A has more orders on the books foractive ingredients than he can handle. Therefore,he orders products from company B to be deliv-ered in neutral drums (no labels, or peelablelabels). He will then relabel these drums with hisown labels and reissue the certificate of analysis.

Export company XYZ exports products bearingwith its own labels, without reference to the origi-nal producer. Additionally, the company maysource from several different producers at thesame time.

A distributor repackages a product in smallercontainers under its own name, without traceabil-ity to the original producer. Such practice is alsofairly common in some European companieswhich are not obliged to communicate the origin ofthe goods.

A technical product or a food-grade product is re-analysed by the broker/distributor and foundcompliant with a given pharmacopoeia, andrelabelled as being of pharmaceutical quality.

The above practices, and many more, have apotential impact because these products are even-tually administered to humans for sometimes quiteserious health conditions. In all the cases above,there is no way to guarantee that the productoriginates from a plant where appropriate GMPstandards have been implemented. Absent clean-ing validations, the use of low quality water, the use

*Authors alone are responsible for views expressed in signed contributions.


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of unacceptable solvents such as benzene, orprocess changes which go unreported andunvalidated, can result in unsafe medicinal prod-ucts. Recent FDA warning letters indicate thatsome facilities who claim GMP compliance havenever carried out the corrections they committed tomake in writing. Are these exceptions to the rule, orare they the tip of the iceberg?

Furthermore, if there is lack of traceability, a vari-able or unknown origin of the goods, all processvalidation files of the medicinal producer are bydefinition meaningless, and this includes all thestability data. Processing conditions may varydepending on the source of the starting materials,which has a direct impact on bioavailability andhence on the efficacy of the medicinal product.

Another frequent observation is that products arebeing offered against obsolete pharmacopoeial

standards. For example, at the end of the year2000, acetylsalicylic acid was reported to havebeen offered, with compliance stated against BP80 although the British Phamacopoeia monographwas changed in 1986 and again in 2000. Themonograph change concerned related substances,suspected to be mutagenic and now limited at0.1%. The samples of the product offered had over

0.2 % of the principal impurity.

These are not the only recurring fraudulent prac-tices by far. Several constructions are known, oftenrelated to the registration process or patent in-fringement. A lot of money can be made by commit-ting fraud, and the risks taken are sometimessignificantly lower than those, for example, ofnarcotics dealers for which capital punishment isoften the penalty. Yet fraud with medicinal productscan be as devastating to the end user as narcot-ics!

PRODUCT STEWARDSHIP*

Product stewardship is the responsible and ethical management of health, safety and environmentalaspects of a product throughout its total life cycle. Product Stewardship is Responsible Careappliedto products.

Product stewardship improves market confidence. By defining and pursuing common goals throughoutthe supply chain, we can achieve benefits for all businesses involved.

No company operates in isolation. Everyone involved in the production, handling, use and disposal ofchemicals has a shared responsibility to ensure their safe management and use.

By adopting a programme of Product Stewardship, every company can play its part in protecting humansand the environment from potential harm.

WHY PRODUCT STEWARDSHIP?

Every company, up and down the supply chain, should be concerned about the impact of chemicals on

human health and the environment, throughout their life cycle.

Each of us is confronted with a multitude of safety, health, and environmental issues regarding ourproducts. These may be voiced by our customers, environmental groups, and regulatory authorities.They may arise from special expectations and public concern or from the industrys own internalassessment.

Implementing Product Stewardship helps us to manage these issues more effectively, taking intoaccount health, safety and environmental as well as technical and economic aspects to ensure bestcustomer value.

Chemical products must be managed and used safely along the supply chain, through manufacture,packaging, distribution, use and ultimate disposal.

*The European Chemical Industry Council (CEFIC) definition,


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Supply chain characteristicsof excipientsDuring the past decade, the excipient market haschanged from a regional to a global market. Com-panies have become international, manufacturing

products from only a small number of sites for thewhole global market. New competitors have ap-peared, especially in Eastern Europe and Asia. Thissituation has led to a movement of excipientsthroughout the world. In this environment, distribu-tors become more involved in the supply chain.

The incident in Haiti of contaminated paracetamolillustrates the extent and dramatic consequences ofimproper handling of excipients by supply chainbrokers. Several distributors were involved in thisincident, the product was shipped all around theworld from Asia via Europe to Haiti, with no

traceability, insufficient controls and documentationlacking. Other similar incidents have also beenreported (10).

In many countries, distributors are in charge of theexcipients business because pharmaceutical com-panies have low consumption of these productscompared to the large quantities used in foodproduction, or for cosmetic and technical applica-tions. Of course, some exemptions exist concerningparticular excipients used exclusively for pharma-ceutical applications. However, most distributorsdealing with excipients are involved in trading to

businesses with technical applications and oftensupply similar products for different uses. In theseother business lines, processes involving mixing orminor cross contamination, are not viewed with thesame precision as they are in pharmaceuticalproduction. Traceability and documentation are notstrictly required, nor do customers wish to pay forthis service when using such materials for techni-cal, food or cosmetic applications.

Given this situation, managing the distribution ofpharmaceuticals requires sensitivity of the issuesand knowledge of how to deal with the differentrequirements for the many similar products andtheir different applications. Incidents with contami-nated excipients in the past showed that there is alack of good practice in this area but no detailedregulation yet exists that provides standards forindustry and regulatory authorities.

Current legislation and guidelineson good distribution practices (GDP)The latest harmonized ICH Guideline:Good Manu-facturing Practice for Active Pharmaceutical Ingre-

dients (Q7a), approved in November 2000 includesa chapter entitled Agents, brokers, traders, dis-tributors, repackers, and relabelers. Within thatchapter, special requirements for distributors aredefined regarding traceability, stability, repackag-

ing, transfer of information, complaints and recalls(5).

The French Medicines Agency (AFSSAPS) iscurrently preparing an exhaustive guide for gooddistribution practices covering both active pharma-ceutical ingredients and excipients. This is still adraft working document, but it is likely to be pub-lished and implemented before the end of 2001.The International Pharmaceutical Excipients Coun-cil (IPEC) has also issued an audit-style question-naire specifically designed for assessing distribu-tors of excipients and is based on IPEC GMP

Guidelines for Bulk Pharmaceutical Excipients(11).This document is intended to be used by pharma-ceutical companies for auditing their supply distribu-tors as part of their supplier evaluation system, aswell as certifying distributors against IPEC stand-ards. It should be used as a tool to assess theactual GMP/GDP level of distributors, to raiseawareness and improve knowledge of supply chainactors, and thereby improve GMP compliance.

The European Association of Chemical Distributors(FECC) and other traders organizations have alsopublished a discussion paper entitled GMP forActive Pharmaceutical Ingredients in DistributiveTrade(12). However, there is so far no final agree-ment amongst traders and brokers on these re-quirements and on the implementation of the princi-ples set out in the document. Furthermore, therehave been substantial comments made by sometrader's organizations on the GDP requirements ofICH Draft Q7a, claiming that these requirementswill lead to substantial price increases in Europe.

The European Chemical Industry Council (CEFIC)has published Guidelines for Handling and Distribu-

tion of Propylene glycol USP/EP(13) as part oftheir Responsible Care Program. The Guidelineswere created by European manufacturers of propyl-ene glycol USP/EP and contain relevant instruc-tions and procedures to ensure safety and quality ofpropylene glycol from the manufacturing site downto the end user, bearing in mind special applica-tions in pharmaceuticals, and consumer healthprotection measures. Similar ideas and strategiesare included in the European Single AssessmentDocument for Chemical Distributors (ESAD), adocument published by CEFIC and FECC in 1999


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(14). In this document, specific guidance is givenfor the distribution of excipients, food and cosmeticingredients. It can be used either by manufacturersto assess their distribution partners, or by custom-ers to find out what level of GMP/GDP distributors

of excipients have achieved.

Do these regulations sufficeto safeguard public health?Maintaining quality standards and product safetyhas a price, but negating the need for requirementswith purely commercial arguments is unacceptablewhen the implicit risks to human health are consid-ered. The need for global recommendations andcontrol is crucial: if the expense of applying qualityand safety practices risks forcing the compliantcompanies out of business because they chargehigher prices than their unscrupulous rivals, thenthis is obviously a horrifying prospect! It is possiblethat the current GMP practices dealing with activepharmaceutical ingredients (API), excipient tradingand distribution are not sufficient to guaranteeproduct quality and safety.

Several guidance documents require full traceabilityback to the original producers. However, a repackeror re-labeller is also often considered to be a manu-facturer, so that traceability to the last manufactur-ing step is clearly insufficient. Other guidelinesrequire a reference to the original producer on the

certificate of analysis. The traceability requirementclearly needs to be bi-directional and is best re-flected in section 17.60 of ICH Q7a which states:"Agents, brokers, distributors, re-packers, or re-labellers should transfer all quality or regulatoryinformation received from an active pharmaceuticalingredient (API) or intermediate manufacturer to thecustomer, and from the customer to the API orintermediate manufacturer."

The API industry endorses these requirements.However, as long as there are no stringent verifica-tion and enforcement regulations in place, it is likely

that fraudulent practices will continue to prosper.Europe intends to amend its Starting MaterialsDirective (75/319 EC) which will create a legal basisfor the implementation of these GMP / GDP re-quirements. This will also create a legal basis forinspections covering manufacturers that are export-ing products into the European Union, or intend todo so. However, in the current draft text of theAmendment, the decision to inspect is being left tothe discretion of each Member State. Consideringcurrent budget restrictions in several countries,industry fears that substandard products, or prod-

ucts made by different processes to those declaredin regulatory filings, will continue to enter into theEuropean Union. This particularly concerns gener-ics and over-the-counter (OTC) products, for whichcontrols are minimal.OTC products are generally

not even inspected, so similar concerns apply toimports of these products.

Recently, market prices of pharmaceutical ingredi-ents for generics and OTC products have beenforced to below economic levels. The inroad ontothe market of products manufactured under inad-equate or even in the absence of systemsthat should secure their quality and safety seems tobe one important causative factor for this develop-ment. Omitting the use of such systems allows forlower manufacturing costs and therefore offers animportant competitive edge. The implicit risks to

humans are evident: such products are often soldto very large populations. For example, it is esti-mated that annually about 70,000 tons of paraceta-mol (acetaminophen) are consumed worldwide,representing a total of 150 billion tablets. A sub-standard product could have a more lethal impactthan an atom bomb in such cases!

Similar requirements will certainly also be neededwith regard to trade in pharmaceutical ingredientsworldwide. The first steps that have been taken inthis direction by WHO will hopefully lead to in-creased safety of medicines on a global scale.

In conclusion, the API manufacturing industry looksforward to presentation of a final text for Amend-ment of 75/319/EC for approval by the EuropeanCouncil and European Parliament. After all, it is thesafety of patients which is at stake.

References

1. Wax, H. et al. Clinical Toxicology, 34(5): 517520(1996).

2. Bulletin of the World Health Organization, 79(2): 8895

(2001).3. WHO Drug Information, 11(3), 123 (1997).

4. World Health Organization. Quality Assurance ofPharmaceuticals. Volume 2: Good Manufacturing Prac-tices and Inspection. Geneva, 1999.

5. International Conference on Harmonization (ICH)documents available on http://www.ifpma.org

6. International Pharmaceutical Excipients Council. GoodManufacturing Practices Guide for Bulk PharmaceuticalExcipients(1997).


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7. United States Pharmacopeia. Good ManufacturingPractices for Bulk Pharmaceutical Excipients, USPXXIV24, General Chapter 1078: 20402049, 2000.Pharmeuropa, 9(2): 302322 (1997).

8. World Health Organization. GMP: Supplementary

Guidelines For The Manufacture of PharmaceuticalExcipients. WHO Technical Report Series, No. 885,(1999).

9. International Federation of Pharmaceutical Manufactur-ers Associations (IFPMA). Counterfeiting. Download fileon http://www.ifpma.org

10. World Health Organization/US Food and Drug Admin-istration/US Centers for Disease Control. Report of theDiethylene Glycol Contamination Prevention Workshop,Washington, D.C. (1997).

11. GMP Audit Guideline for Distributors of Bulk Pharma-ceutical Excipients; International Pharmaceutical Excipi-ents Council, (2000).

12. The European Association of Chemical Distributors(FECC). GMP Guide for Active Pharmaceutical Ingredi-

ents in Distributive Trade (1998).

13. The European Chemical Industry Council (CEFIC),Propylene Oxide / Propylene Glycols sector group.Guidelines for Handling and Distribution of PropyleneGlycol USP/EP, (1999)

14. The European Chemical Industry Council (CEFIC) andThe European Association of Chemical Distributors(FECC). European Single Assessment Document forChemical Distributors (ESAD), January 1999.


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Personal Perspectives

Risk assessment as anelement of drug control

Professor Witold Wieniawski, Chairman,Polish Pharmacopoeia CommissionWarsaw, Poland

The responsibility of governments to establishsystems which assure that all pharmaceuticalproducts used in a given country are both safe andeffective is now generally accepted, even if theextent of such responsibility may differ between

countries. The operation of such systems may besupervised by a special department within theMinistry of Health or delegated to a drug regulatoryauthority. In either case, such activities are carriedout in close collaboration with those parties in-volved in drug manufacture and distribution, includ-ing manufacturers, wholesalers, hospitals, retailpharmacies and other drug distribution outlets.

The main purpose of a drug regulatory system is toprevent the occurrence of harmful drug relatedevents which may have the potential to attaincatastrophic proportions. Because of the need tomaintain public confidence in pharmaceuticalproducts for the general health of the population, asystem of government-imposed regulations is oftenin operation, while responsible institutions andenterprises endeavour to ensure that no harmfulnegligence occurs during manufacture, distributionand use of medicinal products. Such additionalactivities ensure that all precautions are faithfullyimplemented by all those involved.

Medicines have important consequences for healthand their regulation may involve decisions with

international implications. As such, the advice ofWHO in relation to these issues is consideredhighly relevant. Drug regulatory systems operatewithin the economic environment of the country asa whole and the level of development differs enor-mously between countries, with regard to theparticularities of the restrictions encountered.

Drug-related hazardsWhile harmful events and risks are inherent in thenature of drugs, many risks can be avoided or at

least minimized through implementation of effectivepreventive measures. For the purposes of thepresent article, three types of risk may be distin-guished.

1. Risks related to theintroduction of new medicinesRisks related to the introduction of new medicinesare linked to the possibility that an unknown harmfuleffect of a new substance will appear when theproduct is used extensively in the general popula-tion. Elaborate systems have now been developed

for the prevention of such risks based on earlydetection of harmful effects in the course of pre-clinical testing or during clinical studies. Separatesets of requirements are established for new chemi-cal entities and for new products obtained frombiotechnology where additional kinds of risks canbe expected. However, even highly elaboratesystems cannot be completely foolproof, as isevidenced from cases where rapid withdrawal fromthe market of recently approved products wasnecessary (1).

2. Risks related to drug production

Risks that are related to the production of drugsinclude events resulting from improper manufactur-ing processes or cases of mix-ups and mislabellingduring production. This type of hazard is not relatedto the intrinsic pharmacological property of theactive substance or excipient but to the manufactur-ing process. Improper production includes the useof inadequate (substandard) starting materials aswell as deficiencies in the technological processesof drug formulation. Such deficiencies could result,for example, in the manufacture of products ofinadequate bioavailability, or may lead to the ap-pearance of unexpected contaminants in the final

product.

Risks related to the use of incorrect starting materi-als may have serious adverse consequences, as inthe well-known cases of ethylene glycol being usedin place of glycerol or as an admixture to an excipi-ent (2). Similarly, the risk of contamination byadventitious impurities has also to be considered inthe case of starting materials. Risks related to mix-ups may also occur within the drug distributionchain if re-packaging or re-labelling of products is


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undertaken by traders, wholesalers or at retail level.Fraudulent production of counterfeit or adulterateddrugs is a serious problem which should be consid-ered separately (3). This criminal activity is linked toimmense health risks.

3. Risks related to improper use of drugsThe improper use of drugs may lead to scenarioswhere harm is caused instead of expected relief.This includes mistakes made by physicians in theselection of drugs, irrational prescribing, over-prescribing (leading to over-consumption, particu-larly of antibiotics) (4), mistakes by auxiliary staffwhen administering medicines, lack of patientcompliance, or mistakes made when taking medica-tion. Some of those situations may also be createdby unethical promotional practices which influenceprescribing and consumption decisions. Effective

drug information and education is essential tocounter such practices. It is debatable to whatextent drug regulatory authorities are able to takeremedial action, since rational prescribing is prima-rily the responsibility of institutions which supervisemedical practitioners.

Drug regulatory authoritiesThere have been few attempts to establish a classi-fication of drug regulatory authorities into specificgroups, although the notion of a small drug regula-tory authority has been introduced by the WHOdocument Guiding Principles for Small National

Drug Regulatory Authorities(5). The three followinglevels of drug regulation were identified in a recentreport on global harmonization of regulatory re-quirements of pharmaceuticals (6). These catego-ries often reflect the degree of economic develop-ment of countries, which confirms that the impor-tance of economic factors in the health area ex-tends also to drug regulation.

1. A sophisticated level of drug regulationCountries with sophisticated drug regulatory activi-ties are generally well equipped to prevent mosttypes of risks related to medicines. Appropriate

drug regulatory institutions exist to confirm thesafety and efficacy of new drug entities. The major-ity of these activities are now carried out accordingto guidelines established by the International Con-ference on Harmonization of Technical Require-ments for the Registration of Pharmaceuticals forHuman Use (ICH). A brief review of ICH activitieswas recently published in WHO Drug Information(6).

High-income countries with sophisticated drugregulatory activities have properly functioning

systems for the establishment of drug quality re-quirements. This will include activities of pharmaco-poeia commissions and well established surveil-lance systems on the manufacture and distributionof pharmaceuticals such as pharmaceutical inspec-

tion and national drug control laboratories. Allinstitutions function effectively in order to reduce toa minimum the risks related to drug production anddistribution.

Administrative regulations related to the introduc-tion of new medicines and control of drug produc-tion can be properly implemented in high-incomecountries because the pharmaceutical industry, towhich they are addressed, is well developed anddrug distribution services are staffed by fully quali-fied personnel. Full implementation of the rules ofgood manufacturing practices (GMP) is also much

simpler in facilities with high manufacturing stand-ards and having at their disposal well-equipped andwell-staffed analytical laboratories. The same canbe said of institutions providing information on druguse for health professionals and the general public.

2. Drug regulation at the intermediate levelThe medicines control situation is less sure incountries at the intermediate level. Countries in thisgroup rely heavily on the evaluation of new drugentities carried out in countries with a sophisticatedlevel of regulatory activity, avoiding, to some extent,the risks associated with unexpected harmful

effects of new medicines. However, as the mainsource of pharmaceutical products will normally bethe domestic manufacture of generic pharmaceuti-cals, the main risk encountered is that related toproduction processes.

Because of the country's economic situation, drugregulatory authorities have only moderate financialmeans at their disposal. Activities are mainly basedon the use of national resources, not on outside aid,even if a measure of external advice is usuallyavailable. Local pharmaceutical manufacture in the

majority of countries in this group, with a few nota-ble exceptions, is based on the importation of rawmaterials, which gives rise to particular kinds ofrisk. Furthermore, the technical equipment of localpharmaceutical enterprises may be more rudimen-tary in comparison with pharmaceutical manufac-ture in the high-income countries. Drug distributorsmay also be more moderately equipped. Somecountries in this group are also victims of fraudulentproduction of adulterated drugs. There is, therefore,a whole range of combinations of risk areas withindrug regulation that exists in countries of this group.


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3. Inadequate drug regulationCountries with inadequate regulatory activity arequite numerous and comprise nearly all low-incomecountries where there is no infrastructure for regula-tory activity or, where such infrastructure does exist

, it is too weak to achieve effective regulation.Typically, there is little local pharmaceutical manu-facture, the drug distribution chain is only moder-ately equipped, while conditions at drug retail levelcan be described as quite rudimentary. Thesecountries, using mostly imported pharmaceuticals,are highly vulnerable to risks that can occur duringdrug distribution including fraudulent distribution ofadulterated drugs. As countries in this group are notable to create independent, effective drug regula-tion, they require strong external assistance.

The influence of drug risks

on control strategiesAs an intergovernmental institution responsible forall matters related to health, the World HealthOrganization provides advice to its Member Statesfrom both the international and national perspec-tive. This is carried out through recommendationsand suitable documentation for implementation bycountries. Such advice is intended for global appli-cation and has been founded on an underlyingnotion that similar approaches can be applied allover the world in many health related areas. Such anotion also includes issues concerning drug regula-tion. This integral approach has gradually becamediffused through the creation, for example, ofessential drug programmes intended primarily forlow-income countries. Furthermore, countries atdifferent levels of economic development havebecome more and more conscious of the varioustypes of risks inherent in providing medicines totheir populations.

The lack of proper evaluation of potential hazardsand the effectiveness of administrative counter-measures remains a serious obstacle for the selec-tion of an appropriate strategy. Data collection that

could help such evaluations is poorly organized, if itexists at all, and is further complicated by the needfor greater transparency.

Control strategies ofhigh-income countriesThe activities of drug regulatory authorities in high-income countries are directed towards prevention ofall types of risks, both those relevant to the intro-duction of new medicines and those that can occurduring manufacture and distribution. To maintain a

sophisticated level of drug regulation, considerablefinancial outlays are necessary from governmentsand the pharmaceutical industry with the result thatrisks related to the production of drugs and drugdistribution are kept at the lowest level. Major

activities are now focused on a comprehensivemaintenance strategy of prevention of hazardslinked to the introduction of new medicines. Conse-quently, less attention is being paid to risks linkedto drug production and distribution since this wasachieved at earlier stages of development.

Control strategies for other countriesUnfortunately, the favourable situation existing inhigh-income countries does not exist in countrieswhere risks linked to the production and distributionof drugs remain a problem. It may even be that thesituation is becoming worse in part due to the

presence of counterfeit products. Appropriateadvice is needed from WHO because, for economicreasons, a direct transposition of institutions andprocedures which operate in high-income countriesis not possible.

In countries at an intermediate level, the operationof drug regulatory institutions is reflected by na-tional resources rather than outside aid operatingwithin the constraints imposed by the economicsituation of the country in question. In countries atmedium and low-income level, such constraints aremuch more restrictive than those existing in eco-nomically developed countries. In such circum-stances, to be fully effective, activities should beoriented where the risks are highest. The assess-ment of risks is therefore of primary importance inestablishing effective drug control strategies.

Assessment of risks linked to the production ofdrugs should be based on a separate review ofeach of the main elements of the drug supplysystem as follows.

local manufacture;

sources of raw materials;

production facilities;

importation;

products in final containers; and

products to be repackaged and re-labelled.


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Existing literature on quality assurance of pharma-ceuticals, which includes numerous WHO docu-ments, describes in detail the activities related todrug quality assurance in respect of each of theseelements. The advice given in that literature is fully

appropriate in a sitution where adequate resourcesare available. What is usually missing, however, isa listing of priority risk areas to be considered incases when insufficient economic resources do notpermit a full implementation of all recommenda-tions.

Alternative control strategiesAn assessment of individual risks related to specificproducts and raw materials, and recognition ofhazards at specific stages of production or distribu-tion would permit national regulatory authorities tobetter plan a drug control strategy and render its

activities more effective within available resources.The main element to be considered is the extent ofreliance on documentary evidence concerning thequality of products against confirmation of theirquality (identity, purity and strength) through testingof samples. This applies equally to preparationsand to raw materials, either of domestic or foreignorigin.

Documentary evidence is much cheaper to procure,but it confirms nothing more than the results ob-tained by the manufacturer's analytical laboratory atthe time the product was released onto the market.

Obviously, it requires an additional assurance that itindeed pertains to the product in question. A con-firmatory testing of samples is much more expen-sive, as it requires the maintenance of a suitabletesting laboratory added to the costs of analysis.Such confirmatory testing is therefore only carriedout on a random basis. None the less, testing ofactual samples taken from the market can confirmwhether regulatory authority action is adequate andit will remind the manufacturers and importers ofthe existence of control. A proper combination ofthe two approaches should also take into accountthe specificity of risk situations, examples of which

are given below.

In many countries, local manufacture of pharma-ceutical preparations is based on imported rawmaterials, both for active materials and excipients.Assurance of the identity and purity of these materi-als can be based either on certificates of analysisissued by the manufacturer or trader, or on theresults of confirmatory testing done locally by themanufacturer of the pharmaceutical preparation.When such confirmatory testing is done locally, thesize of the consignment is of importance as in most

cases raw materials are shipped in a number ofcontainers, not a single one. The risks that mayoccur here include those due to natural deteriora-tion of the substance, to mix-ups caused by mis-takes in labelling of containers or to contamination

of the material by foreign substances. Such pres-ence of adventitious impurities may occur by acci-dent or may be intentional.

When assessing the level of risk of an individualsubstance, numerous factors have to be consid-ered: the stability intrinsic properties, or improve-ments made by the use of stabilizers or adequatecontainers; price of materials expensive sub-stances are particularly the target of fraudulentactivity; and any other possible dangers related touse. The high-risk category also includes suchdeceptively innocuous substances as polyols (e.g.

glycerol), where mix-ups or inept use as excipientshave, as already mentioned, been the cause ofmany tragedies (1).

Requirements concerning production facilities andprocesses are the subject of recommendationsrelated to good manufacturing practices (GMP).The assessment of risk is also needed here toindicate those elements of the production processwhere mistakes can have the most harmful conse-quences. For example, the risks related to mix-upsare the highest during the labelling stage, while therisk of cross-contamination (but also of mix-ups) is

highest at weighing areas. Risk assessment shouldalso take into account the type of products that aremanufactured in a given production facility.

Situation of low-income countriesThe existence of countries with insufficient drugregulation is an unfortunate situation which hasbeen deplored by many authors (6). In such coun-tries, the prevention of risks cannot be achievedthrough local efforts and appropriate strategieshave to be developed to draw on outside assist-ance. This is especially valid in relation to imported

pharmaceuticals on which these countries areusually heavily dependent. In the case of donatedproducts, the assurance of quality should be theresponsibility of the donor organizations. The use ofcertificates issued according to WHO CertificationScheme on the Quality of Pharmaceutical ProductsMoving in International Commerce is a possiblesolution and special procedures exist also forassessing the acceptability of vaccines for pur-chase by United Nations agencies. Unfortunately,low-income countries are also highly vulnerable torisks related to counterfeited products.


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ConclusionsRecognition of the risks that may occur in the drugarea is fundamental for the establishment of effec-tive preventive strategies. Although some risks areinherent in the utilization of pharmaceutical prod-

ucts, the majority of such risks are avoidable. Drugregulatory authorities need to match control require-ments to the available resources. In high-incomecountries, resources for drug control activities areconsiderable, hence eventual risks can be effec-tively kept at a very low level. In other countries,where more limited resources are at the disposal ofregulatory authorities, the assessment of risks anddesignation of high-risk products, areas and situa-tions will be a priority in designating priorities forcontrol measures. WHO recommendations on drugregulatory and control activities should indicate, tothe extent possible, the level of risk linked to spe-

cific elements and stages of the production anddistribution of pharmaceuticals as this could im-prove the modalities of their implementation inpractice.

References

1. Fung, M.C., Thornton, A., Mybeck, K. et al. Evaluationof the characteristics of safety withdrawal of prescriptiondrugs from worldwide pharmaceutical markets 1960 to1999. Drug Information Journal, 35: 293317 (2001).

2. Singh, J., Dutta, A.K., Khare, S. et al. Diethylene glycolpoisoning in Gurgaon, India, 1998. Bulletin of the WorldHealth Organization, 79: 8894 (2001).

3. World Health Organization. Observations and recom-mendations on counterfeit drugs. Quality Assurance ofPharmaceuticals: A compendium of guidelines and relatedmaterials, Volume 1. Geneva, 1997.

4. Report of the International Narcotics Control Board for2000. United Nations, New York (2001).

5. World Health Organization. Guiding principles for small

national drug regulatory authorities. Quality Assurance ofPharmaceuticals: A compendium of guidelines and relatedmaterials, Volume 1. Geneva, 1997.

6. Global Harmonization and ICH. WHO Drug Information,14(3): 145159 (2000).

7. Folb, P., Olliaro, P. Pharmaceutical policies and regula-tory control. WHO Drug Information, 14: 82-84 (2000).


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Message to drug regulatory authorities:

Tenth International Conference of

Drug Regulatory Authorities (ICDRA)

The Tenth International Conference of Drug Regulatory Authorities (ICDRA) will be

hosted and co-sponsored by the People's Republic of China (PRC) in collaboration with

the World Health Organization from 5-8 November 2001 in Hong Kong, China. The

Department of Health of the Government of the Hong Kong Special Administrative

Region of PRC is the organizer of the Conference. Information materials and registra-

tion form of the 10th ICDRA are available at the website: http://www.mvdmc.com/icdra

Please note that this conference is reserved exclusively

for drug regulatory officials from WHO Member States.

The following travel agent has been appointed to handle registration and arrange hotel

accommodation for participants. For further information please contact:

MV Destination Management Ltd.

Room 1405, Golden Gate Commercial Building,

136138 Austin Road,

Tsim Sha Tsui,

Kowloon, HONG KONG.

Tel. No: (852) 2735 8118

Fax. No: (852) 2735 8282

E-mail Address: [email protected]


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Current Topics

The WHO Model List of Essential

Drugs: latest developments

The WHO Model List of Essential Drugs has beensuccessful in establishing and promoting the con-cept of essential drugs. For more than twentyyears, it has served as the gold standard for coun-tries wishing to develop their own lists and hasbeen adapted for use in more than 150 WHOMember States. From a public health perspective,priorities for the pharmaceutical system can beidentified through the use of an essential drugs list.For example, national lists are often linked tonational standard treatment guidelines used fortraining of health workers, and can serve as a guidefor the procurement of needed drugs, for reim-bursement purposes in health insurance schemesand for encouraging local pharmaceutical produc-tion.

The WHO Model List has been updated every twoyears since it was first published in 1977. Thecurrent Model List contains a little over 300 activeingredients and is divided into a main list and a

complementary list. At the last meeting of the WHOExpert Committee on the Use of Essential Drugsheld in November 1999, several recommendationswere made concerning the process of updatingboth the methodology for selecting drugs for inclu-sion in the Model List and the List itself. Theserecommendations included linking the selection ofdrugs on the Model List to standard treatmentguidelines developed by WHO. It was also agreedthat decisions on selection of essential drugsshould be based on properly-identified evidence. Itwas recommended that the Model List shouldprioritize those conditions and drugs for which

equitable availability and affordability should beensured before resources are spent on other treat-ments. A recommendation on the need for moreexplicit criteria was also made.

Updating and disseminating the WHOModel List of Essential DrugsAs a result of these recommendations, a draftdiscussion paper Updating and disseminating theWHO Model List of Essential Drugs: the way for-

ward was prepared. This was the subject of dis-cussion at an informal consultation held by WHO inMarch 2001. The discussion paper highlightedvarious perceived problems.

The range of diseases for which essential drugsare selected is not clearSome drugs for very rare diseases are included onthe Model List, while some second-line drugs formore common diseases are not. For example,should the Model List include essential drugs forcystic fibrosis?

The selection criteria are insufficiently clearThere is much confusion about the extent to whichcost, cost-effectiveness and affordability criteria arebeing used during selection. For example, thedecision not to include antiretroviral drugs (ARVs)for HIV/AIDS has provoked global discussion. TheCommittee had decided not to include ARVs for thetreatment of HIV/AIDS because there was insuffi-cient evidence of their long-term effectiveness inresource-poor settings. Others believed that exclu-sion was based on cost considerations, and haveargued that inclusion of ARVs on the Model List

would create the necessary pressure to bring pricesdown.

Selection has been based on experiencerather than evidenceIn the past, the Committee has taken a decisionbased on the material presented and on their ownprofessional experience. However, there is nostandard format application and no systematicsearch for and review of evidence prior to submis-sion before the Committee in support of decisions.Furthermore, there is no external review of theCommittees draft recommendations.

There are discrepancies between the WHOModel List and WHO treatment guidelinesAbout 250 of the 306 active ingredients on thecurrent Model List are also recommended in vari-ous treatment guidelines published by differentWHO programmes and departments. There are afew therapeutic categories where no WHO treat-ment guidelines exist (e.g. cytotoxics, hormones,diagnostic agents and gastrointestinal drugs).


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However, 155 drugs recommended in the total bodyof WHO treatment guidelines are not on the WHOModel List of 1999. If WHO recommends thatnational essential drugs lists should be based onnational treatment choices and guidelines, the

WHO Model List could be developed in a similarway.

Drugs are included for which there is nopharmacopoeial standard, or no supplierIn 1997, there were several substances on theModel List for which there was no pharmacopoeialstandard. Examples are eflornithine hydrochloride,heparin sodium, methylene blue, permethrin andprimaquine.1 There are several drugs on the ModelList for which there is only one supplier, or for whichthe supply of quality products has always beenproblematic. Examples of such abandoned essen-

tial drugs are oily chloramphenicol injection,suramin injection, ether and eflornithine.

The reasons underlying the decisions of thecommittee are insufficiently recordedThe reasons for the recommendations of the Com-mittee are summarized in footnotes to the report.However, these extensive footnotes are not repro-duced in WHO Drug Informationor on the WHOMedicines Website (http://www.who.int/medicines),which implies that this information is only availableto the public through the Technical Report Serieswhich is published by WHO much later. In addition,notes from earlier meetings are only availablethrough copies of old Committee reports and are inpractice difficult to find. Recently, WHO has made adata base of the recorded reasons for recent Com-mittee decisions which is available on request.However, for many earlier decisions no records areavailable.

The recommendations of the committeeare final and not open for reviewAccording to the rules and procedures for WHOexpert committees, the report of the Committee is

prepared and approved before the end of themeeting. There are no provisions for internal andexternal review of the report or recommendationsafter the meeting. The Chair of the Committee maydecide to omit a statement from the report but mayonly change the wording on the basis of written

agreement by all members. In practice, the recom-mendations of the Committee and the text of thereport are rarely changed after the meeting and areaccepted by the Director-General of WHO.

The official report of the Committeeis published latePublication of each of the last three official reportsin English in the WHO Technical Report Series hastaken over a year. As the Committee meets everytwo years, the report of the previous meeting andthe new WHO Model List therefore came out justbefore the next meeting, which seriously under-mines the usefulness of the report and even of themeeting itself. The French, Spanish and Russiantranslations of the 1997 report came out even later.

In recent years, this problem has partly been solved

by publishing the Model List (without notes, andonly in English) in WHO Drug Informationand onthe WHO Medicines Website.

Recommendations from theinformal consultationA series of questions was presented during theinformal consultation in March 2001 and the follow-ing recommendations were issued.

1. The definition of essential drugs is still adequateand does not need to change: Essential drugs are

those drugs that satisfy the health care needs of themajority of the population. They should therefore beavailable at all times in adequate amounts and inappropriate dosage forms, at a price the individualand the community can afford (1).

2. The WHO Model List should continue to bepresented in two levels. The core list should indi-cate the minimum drug needs for a basic healthcare system, listing the most cost-effective drugsfor priority conditions; while the complementary listshould consist of drugs for priority diseases whichare cost-effective but not necessarily affordable, or

which may need specialized health care facilities,and should include essential drugs for less frequentdiseases. The section on reserve anti-infectiveagents could thus be integrated into the comple-mentary list.

3. The process of updating the Model List should bemore systematic and transparent. A revised stand-ardized format for applications should be drawn up,to include a systematic review of comparativeefficacy, safety and cost-effectiveness. An externalreview of these draft applications and systematic

1 The full list quoted by WHO in 1997 was: asparaginase,dasozin mesilate, eflornithine hydrochloride, heparincalcium and heparin sodium, methylene blue, permethrin,polygeline, potassium ferric hexacyaniferrate, and pri-maquine.


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reviews should be undertaken prior to submittingthem to the Expert Committee.

4. The report of the Expert Committee shouldspecify the reasons for the decision, link the drug to

the relevant WHO treatment guideline and summa-rize the evidence. The report and the Model Listshould be published both electronically and in hardcopy.

5. Several sections of the current Model List needto be reviewed systematically and as a whole; thisprocess should be undertaken in close collabora-tion with the disease programmes concerned,drawing on the expertise of all the relevant WHOExpert Advisory Panels. Development of this proc-ess will require several meetings of the ExpertCommittee over the next two years.

6. An essential drugs library should be created onthe WHO Website, which should include at least:summaries of WHO clinical guidelines for prioritydiseases; the Model List, with reasons for inclusionof drugs, and linked references to systemic reviews;WHO clinical guidelines and cost information; theWHO Model Formulary; and quality assuranceinformation such as Basic Tests, The InternationalPharmacopoeia and reference standards.

7. The health care industry and patient advocacygroups could contribute to the work of the ExpertCommittee with relevant technical and other infor-mation as needed. Consideration should be givento the question of whether their representativescould attend the meetings of the Committee asobservers.

Outline of the review processThe discussion paper with full details of the aboverecommendations, including the proposed proce-dures and information requirements, has beenissued for wider consultation among WHO MemberStates and national essential drug programmes,

United Nations agencies, the World Bank, membersof WHO Expert Advisory Panels, and interestednongovernmental organizations.

All comments will be taken into consideration andthe final recommendations will be reviewed by theWHO Global Cabinet later in 2001.

Reference

1. The Use of Essential Drugs. WHO Technical ReportSeries, No. 895 (2000).

Sequencing of the

Anopheles gambiaegenome

Representatives of an international network ofAnopheles gambiaeresearchers and genomesequencing centres met at the Pasteur Institute inParis in March 2001 and agreed on the generalprinciples and method of operation for sequencingthe genome of Anopheles gambiae the mosquitoresponsible for the spread of malaria in sub-Saha-ran Africa and for making this information freelyavailable through a public data base, together withall ancillary genomic, genetic and biological infor-mation concerning the mosquito. The mosquitogenome sequence will join those of the Plasmo-diumparasite and the human host to provide ma-laria researchers with the opportunity to identify

new mechanisms for controlling the malaria diseasecycle and transmission of the malaria parasite to itshuman host. Each year, this cycle results in threehundred million cases of malaria and approximatelyone and a half million deaths, primarily Africanchildren.

The network operates under the auspices of theUNDP/WORLD BANK/WHO Special Programmefor Research and Training in Tropical Diseases andincludes the Pasteur Institute, the European Mo-lecular Biology Laboratory (EMBL, headquarteredin Germany), the University of Notre Dame (USA),

the French National Sequencing Center(Genoscope, France), Celera Genomics (USA),The Institute for Genomic Research (TIGR, USA),the Institute of Molecular Biology and Biotechnology(IMBB, Greece), the ONSA network (Sao Paolo,Brazil) and leading mosquito researchers fromaround the world.

The participating organizations are collaborating ina programme to sequence the entire A. gambiaegenome, with the first version to be completed in2001. The network looks forward to expanding thiscollaborative approach to the genomic analysis ofother Anophelesspecies that are important malariavectors in other parts of the world. The FrenchGovernment has guaranteed financial support for aportion of this international sequencing project andadditional funding is being sought from othersources including the National Institute of Allergyand Infectious Diseases, National Institutes ofHealth (NIH), an agency of the United States De-partment of Health and Human Services.

The proposed project will sequence the 260 millionbase pair Anopheles gambiaegenome using theWhole Genome Shotgun technique perfected by


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Multilateral Initiative on Malaria:

benefits to the global community

Malaria is responsible for enormous disease andeconomic burdens in malaria-endemic regions. Ahigh percentage of those who die of malaria areAfrican children under the age of five. Unfortu-nately, cases of malaria are on the rise due toinsecticide resistance, antimalarial drug resistance,and environmental changes. Unless new strategiesare developed, death and illness due to malaria willincrease, and the disease will continue to be asubstantial barrier to the economic and socialdevelopment of malaria-endemic regions as well asa threat to the millions of people who travel to thoseregions each year.

In 1997, an international alliance of research andpublic health agencies and African scientistslaunched the Multilateral Initiative on Malaria (MIM).MIM is stimulating collaborative research to answerthe needs of public health programmes in malaria-endemic countries, modernizing communicationsystems used by the African research community,and strengthening research capacity and humanresources where malaria takes its greatest toll sub-Saharan Africa. MIM supports 23 collaborativemalaria research projects between African laborato-ries that are also in partnership with laboratories inEurope and the United States (1).

MIM will hold its Third MIM Pan-African Conferenceon Malaria in November, 2002, in Arusha, Tanza-nia. This conference will bring together malariaresearchers who battle Plasmodium falciparummalaria, which causes the most severe illness andwhich is the dominant form of malaria in sub-Saharan Africa. In addition, MIM is organizing aconference to focus on a second form of malaria,Plasmodium vivax, in January 2002 in Bangkok,Thailand, together with partners in Asia. Plasmo-dium vivaxmalaria significantly contributes tomalaria morbidity in Africa, Asia, and Latin America.

Both conferences will bring together malaria re-searchers and malaria control experts with the aimof transferring malaria research advances intocritically needed control, prevention, and treatmentprogrammes. Malaria research and capacity build-ing in malaria-endemic regions are essential,integrally linked components in an effective ap-proach to addressing malaria.

Celera Genomics. The initial sequencing would bedone by Celera Genomics and Genoscope, theFrench National Sequencing Center and assembledat Celera Genomics while sequence closure andfinishing would be provided by Genoscope, The

Institute for Genomic Research (TIGR) and others.Sequence annotation would be carried out byparticipating organizations.

The genome sequencing effort will build on theinitial genomic research. Participation of additionalagencies, laboratories and sequencing centres tocontribute to genome finishing and annotation willbe sought. All interested public and private sectorparties active in the field of Anophelesgenomics,are welcome to participate, subject to technicalfeasibility and quality assurances. The EuropeanUnion programme for action on HIV/AIDS, malaria

and tuberculosis in the context of poverty reductionmay also provide support.

Malaria, with one and a half million deaths per year,and 300 million clinical cases in sub-SaharanAfrica, is a serious medical, economic and socialproblem. Rather than decreasing, the incidence ofmalaria is mounting due to increased insecticideresistance in mosquitoes and drug resistance in theparasites. Malaria spreads when the parasite ispassed from an infected person to an uninfectedperson by the bite of an Anophelesmosquito.Control of human exposure to the insect vector hasbeen and continues to be the surest way to controlmalaria. In sub-Saharan Africa, Anopheles gambiaeis the major mosquito vector and Plasmodiumfalciparumis the principal malaria parasite. Thehope of eliminating malaria through the applicationof insecticides to destroy the mosquito vector hasreceded as the mosquito population has becomemore and more resistant to chemical agents. Newmethods of controlling the disease vector areneeded and the Anopheles gambiaegenomeproject is the fastest way to obtain the basic infor-mation which, when combined with field research,

can lead to control of malaria transmission.

Reference: Dr Ayo Oduola, UNDP/WORLD BANK/WHOSpecial Programme for Research and Training in TropicalDiseases, World Health Organization, Switzerland.Email : [email protected]


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The Fogerty International Center (FIC) of the Na-tional Institutes of Health (NIH) currently serves asthe MIM Secretariat (1). NIH, primarily through theNational Institute of Allergy and Infectious Diseases(NIAID), supports malaria research to address

critical needs related to vaccine development,vector biology and control, health economics,health information systems, and other researchareas, while FIC promotes capacity buildingthrough its malaria research training programmesfor scientists from malaria-endemic countries. Inaddition to the two international scientific confer-ences announced today, other activities of the MIMSecretariat at NIH includes:

Expanding the capabilities of malaria researchers,through the International Malaria Research andTraining Program (IMRTP). The scarcity of trained

malaria researchers in the regions most severelyimpacted by the disease is a major impediment tosuccessful malaria research. In 2000, the IMRTPbegan supporting collaborative training pro-grammes between US institutions and malariaresearchers in endemic countries (2).

Addressing malarial anaemia by fostering re-search on the interaction between malaria andanaemia. MIM, NIAID, FIC and the National Heart,Lung, and Blood Institute (NHLBI) organized meet-ings of haematologists, nutritionists, and malariaresearchers to discuss these interactions. Subse-quently, NIAID and FIC developed a joint researchand training programme to support research inmalaria-endemic countries on the pathogenesis ofsevere malarial anaemia (3, 4).

References

1. More information about the IMRTP is available on theFIC website at http://www.nih.gov/fic/programs/malaria.html.

2. More information about this programme, which iscurrently accepting applications, is available on the FICwebsite at http://www.nih.gov/fic/programs/malaria.html.

3. Information about NIAID malaria research activities isavailable at http://www.niaid.nih.gov/dmid/malaria.

4. Information about MIM is available on the MIM Websiteat http://mim.nih.gov

China revises

its pharmaceutical law

The Chinese National Peoples Congress adopteda new pharmaceutical law on 28 February 2001aiming to standardize China's pharmaceutical drugprocurement and distribution system, to furtherencourage open market competitiveness inthe pharmaceutical industry, and to combat drugcounterfeiting. The new law provides for strictercontrols on price management, manufacturingregistration, import inspections, and law enforce-ment.

A centralized administration will promote a uniformcode of conduct for manufacturers and importersand strengthen law enforcement. One of the newchanges being introduced is a clear and wide

ranging definition of counterfeit drugs. This nowincludes drugs prohibited by official order, expireddrugs, and drugs whose advertised benefits do notreflect their actual efficacy. Drug production anddistribution will now be more aggressively managedand the licensing system for manufacturers hasbeen simplified. It is hoped that this will have apositive impact on imported drugs. Although im-ported drugs must go through new cumbersomeapproval procedures before being released on theopen market, once approved, pharmaceuticalcompanies will enjoy unrestricted access to theChinese market.

The new legislation cancels batch inspection ofdrugs except for drugs that will be sold in China forthe first time, biological products, and for drugsdesignated by the State Drug Administration.Importers will now require a registration certificate,import permit, and customs entry permission at adesignated port. The new law has also given stronglegal powers to drug inspectors based at ports andairports. It is expected that the inspectors to have astrong impact on the legal and illegal drug markets.Routine sample inspections of imported drugs andmandatory inspections will also be clearly deline-ated under the new law. Previously, manufacturerspaid fees for each inspection but new regulationshave eliminated the fee paying system for routineinspections. Now, a graded scale of inspectionfees will be imposed on manufacturers and import-ers of drugs and biological products.

Reference: The Lancet, 357: 942 (2001).


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Regulatory and Safety Matters

New formulation of DTP vaccine

United States of AmericaThe Food and DrugAdministration (FDA) has approved a new, pre-servative-free formulation for a diphtheria andtetanus toxoid and acellular pertussis (DTaP)vaccine (Tripedia). The reformulated productcontains less than 0.3 g mercury per dose (asthiomersal), which is less than 5% of the amount ofthiomersal in the original version that the FDAapproved in 1992.

Although no harmful effects have been reportedfrom thiomersal in vaccines when used at therecommended dosages, Federal public healthagencies, the American Academy of Pediatrics, andvaccine manufacturers have agreed to reduce oreliminate its use in vaccines to protect childrenagainst the potential cumulative health risks ofmercury.

Since 1999, the FDA has approved paediatricformulations of hepatitis B vaccines that contain nothiomersal (Recombivax HB) or only traceamounts of the ingredient (Engerix B). Thiomer-

sal-containing Haemophilus influenzaetype bconjugate vaccine (HibTITER) has been replacedby a thiomersal-free, single-dose formulation. Withthe reformulated DTaP vaccine, all routinely recom-mended paediatric vaccines in distribution will soonbe free of thiomersal or will contain it in only traceamounts.

References

1. FDA News, P01-07 (2001).

2. http://www.cdc.gov/nip/vacsafe.

Bupropion safety reminder

United Kingdom Bupropion (Zyban) waslicensed in June 2000 as an aid to smoking cessa-tion in combination with motivational support innicotine-dependent individuals aged 18 years orover. The initial dose is 150 mg twice daily. Themaximum single dose should not exceed 150 mgand the total daily dose should not exceed 300 mg.

It is estimated that approximately 276 000 patientshave received bupropion in the United Kingdom inthe first six months of marketing. A total of 3457reports of suspected adverse reactions have beenreceived. The most frequently reported reactionsinclude:

CNS reactions (e.g. insomnia, dizziness, depres-sion, tremor, anxiety, agitation); and

skin and hypersensitivity reactions (urticaria, rash,pruritus).

Other reported recognized reactions includeangioedema, chest pain, increased blood pressure,erythema multiforme and Steven-Johnson syn-drome.

It is important to note that the reactions are sus-pected and may relate to other factors. Eighteenreports have had a fatal outcome although thecontribution of bupropion is unproven.

Bupropion is associated with a dose-related risk ofseizure with an estimated incidence of approxi-

mately 0.1% based on doses up to the recom-mended daily dose of 300 mg. There have been 74reports in the United Kingdom of seizures sus-pected as being associated with the use ofbupropion.

Bupropion inhibits metabolism of cytochrome P4502D6. Caution is therefore advised when othermedicines predominantly metabolized by theseenzymes are co-administered. These includecertain antidepressants, antipsychotics, beta-blockers and type 1C antiarrythmics.

Reference: Current Problems in Pharmacovigilance,Volume 27 (2001).

Propofol: reactions

to long-term high doses

United Kingdom Propofol (Diprivan) is ashort-acting intravenous anaesthetic also used forsedation of ventilated adults receiving intensivecare.


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A recently published study (1) suggests an associa-tion between long-term high-dose infusion used forsedation and cardiac failure in adult patients withhead injuries. Seven patients are described whodeveloped metabolic acidosis, hyperkalaemia or

rhabdomyolysis. Similar reports, including hyper-lipaemia and hepatomegaly have previously beenreported in children administered propofol infusionfor sedation in intensive care units (2).

Doctors are reminded that the recommended doserange for sedation (up to 4 mg/kg/hour) should notbe exceeded (3).

References

1. Cremer, O.L. Long-term propofol infusion and cardiacfailure in adult head-injured patients. Lancet, 357: 117

118 (2001).

2. Current Problems in Pharmacovigilance, Volume 18(1992).

3. Current Problems in Pharmacovigilance, Volume 27(2001).

Propofol: not for paediatric use

United States The manufacturer of propofol(Diprivan) has informed Health Care Providers ofthe safety concerns of propofol injectable emulsion

if used for sedation of intensive care paediatricpatients.

Propofol is currently not approved for sedation inintensive care paediatric patients in the USA andshould not be used for this purpose.

Reference: Letter from AstraZeneca Pharmaceuticals LP,USA, dated 26 March 2001.

Leflunomide: hepatic reactions

European Union The Committee for ProprietaryMedicinal Products (CPMP) of the EuropeanAgency for the Evaluation of Medicines (EMEA) hasevaluated reports of serious liver injuries, includinghepatitis, hepatic failure and rare cases of acutehepatic necrosis, some with fatal outcome, inpatients treated with leflunomide (Arava). Lefluno-mide is a disease-modifying antirheumatic drugwhich inhibits the enzme dihydro-orotate dehydro-genase and exhibits antiproliferative activity.

Prescribers are reminded that leflunomide shouldonly be prescribed by specialists experienced in thetreatment of rheumatoid diseases. The EMEAwishes to draw attention to the following informa-tion.

Leflunomide is contraindicated in patients withimpaired liver function.

Rare cases of severe liver injury, including caseswith fatal outcome, have been reported duringtreatment. Most cases occurred within 6 months ofinitiation of treatment. Although confoundingfactors were present in many cases a causalrelationship with leflunomide cannot be excluded.

Concomitant treatment with methotrexate and/orother hepatotoxic medications is associated with

an increased risk of serious hepatic reactions.

The full revised product information is available onthe EMEA Website (2).

References

1. EMEA Public Statement on Leflunomide. 12 March2001. EMEA/H/5611(01/v4/en/adopted).

2. http://www.eudra.org/humandocs/humans/epar/arava/arava.htm.

Rapacuronium bromidevoluntarily withdrawn

United States of America The injectable drugrapacuronium bromide (Raplon) is being voluntar-ily withdrawn from the market following reports, fiveof which were fatal, that the drug may by associ-ated with bronchospasm.

Rapacuronium bromide is used as a muscle relax-ant for breathing tube placement and surgery.Other drugs are on the market which may be pre-

scribed for the same purpose. Although the ap-proved labelling does note the occurrence of bron-chospasm in a small percentage of clinical trialpatients, post-marketing reports indicate that therisk of injury may be greater than suggested.

Reference: FDA Talk Paper, T01-11 (2001).


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Levacetylmethadol withdrawn

European Union The European Agency for theEvaluation of Medicinal Products (EMEA) hasissued a public statement regarding the suspension

of the marketing authorization for levacetylmethadol(Orlaam), a long-acting opiate used for the treat-ment of drug addition.

Levacetylmethadol is known to cause QTc prolon-gation. Ten cases of life-threatening heart rhythmdisturbances have been reported since July 1997.The Committee for Proprietary Medicinal Products(CPMP) has given an opinion, based on a review ofrisk benefit, that levacetylmethadol should besuspended.

Health professionals involved in the care of patients

currently receiving levacetylmethadol have beenadvised to immediately review patients who shouldbe switched to alternative treatment. It is recom-mended that methadone should be started on adaily dose of 80% of the levacetylmethadol dosewith subsequent adjustments of 5 to 10 mg accord-ing to the clinical status of each patient. The initialmethadone dose must be given no sooner that 48hours after the last levacetylmethadol dose. Pa-tients are advised not to stop levacetylmethadolsuddenly without seeking medical advice.

Pharmacists have been advised that existing drugsupplies should be disposed of in accordance withprocedures relating to controlled drugs.

Reference: Committee on Safety of Medicines. http://www.gov.uk/mca

Levacetylmethadol:

labelling changes

United States of America The Food and DrugAdministration (FDA) is strengthening warnings to

physicians about serious cardiac adverse eventsassociated with levacetylmethadol (Orlaam), adrug for opiate addiction treatment.

In addition, the approved indication for levacetyl-methadol will be revised to indicate that the drug isnot for use as first line therapy. Levacetylmethadolshould be reserved for treatment of opiate-addictedpatients who fail to show an acceptable response toother adequate treatments for addiction. Levacetyl-methadol can be given less often than methadone.

At the time of approval, there was a possibility thatthe drug could prolong cardiac conduction andprecautions about cardiac adverse events areincluded in the labelling. However, increasingnumbers of reports have been received from both

USA and Europe.

Reference: FDA Talk Paper, T01-15 (2001).

Isotretinoin and depression

Canada An increasing number of reports sug-gest a temporal association between isotretinoin(Accutane) and depression and/or suicidal idea-tion in young people. As a result, additional infor-mation is being provided to patients and the safetyinformation reinforced.

The majority of patients with severe acne are youngpeople. This group is also at increased risk ofdepression, suicidal ideation and suicide. However,some young people treated with isotretinoin havebeen reported with depression which has subsidedafter discontinuation of isotretinoin therapy. Al-though a causal relationship has not been estab-lished, all patients should be monitored for depres-sion and if symptoms develop during treatment, thedrug should be discontinued and the patient re-ferred for appropriate psychiatric treatment if neces-sary.

Complete information on prescribing Accutane isavailable on www.rochecanada.com.

Reference: Health Canada, Therapeutic Products Direc-torate Safety Information at http://www.hc-sc.gc.ca

New glucose test for adult diabetics

United States of America The Food and DrugAdministration has approved a wristwatch-likedevice that provides adult diabetics with moreinformation for managing their disease. It is in-tended for use along with, not as a replacement for,finger-prick blood tests to monitor glucose.

The GlucoWatch Biographer extracts fluid throughthe skin by sending out tiny electrical currents.Glucose levels are measured using this fluid every20 minutes for 12 hours even during sleep. Thedevice sounds an alarm if the patient's glucosereaches dangerous levels.


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Clinical studies conducted by the manufacturershow that GlucoWatch measurements are gener-ally consistent with the results from traditionalfinger-prick blood tests. However, up to 25% of thetime the results differed by more than 30% and

sometimes gave erroneous readings. TheGlucoWatch also caused mild to moderate skinirritation in at least 50% of patients. Because of thispotential for error, patients should never use anindividual GlucoWatch reading alone to makechanges in insulin doses. The device has not beentested in children.

Reference: FDA News, P01-08 (2001).

Anti-inflammatory analgesics:

hepatic reactions

Finland Liver damage caused by anti-inflamma-tory analgesics is very rare and the incidence ofsymptomatic liver damage is estimated to be lessthan 0.05%. However, a symptom-free, mild in-crease in hepatic enzymes is more common andmay occur in as many as 515% of patients. Thefrequency and pattern of liver damage varies be-tween the different anti-inflammatory analgesicsand damage is classified as hepatocellular, choles-tatic or a mixture of these.

The mechanisms of liver damage caused by anti-inflammatory analgesics are not well known. Thereactions may be idiosyncratic, host-dependent andlacking precise correlation with the dose. Thedamage may be caused by a reactive/toxic metabo-lite formed from the drug. Sometimes the liverdamage may be associated with symptoms indica-tive of a hypersensitivity reactions (e.g. fever,eosinophilia, rash, arthralgia).

The register of adverse reactions maintained by theNational Agency for Medicines has received a totalof about 15 200 reports between 1973 and Novem-

ber 2000 concerning suspected adverse reactionsin association with the use of drugs. About 1000(6.6%) of these reports involved a variety of effectson the liver. A total of 59 cases have been reportedin association with the use of anti-inflmmatoryanalgesics. The majority of cases only involved achange in liver function tests.

Reference: TABU, No. 6, 3738, 2000.

Gentamicin ear drops: ototoxicity

Canada The Canadian Adverse Drug ReactionMonitoring Program (CADRMP) warns thataminoglycoside ear drops can cause ototoxicity

when used in patients with tympanic membraneperforation.

Between 1981 and October 2000, the CADRMPreceived 18 reports of suspected ototoxicity associ-ated with use of gentamicin + betamethasone(Garasone) ear drops in patients with tympanicmembrane perforation or tympanoplasty tubes; 16of these reports involved vestibular disorders and 2involved hearing loss. At the time of reporting, 15patients had not recovered from their ototoxicity. Inaddition to these 18 reports, the CADRMP hasreceived 1 report of dizziness and vertigo associ-

ated with use of gentamicin ear drops and anotherreport of temporary hearing loss in a patient withMnire disease following treatment with gen-tamicin ear drops and high-dose infusion. TheCADRMP reminds prescribers that the labellingwas changed in 1996 to limit the indications andclinical uses, to expand the contraindications toinclude patients with absent or perforated tympanicmembranes, and to recommend patient monitoringduring treatment.

Reference: Canadian Adverse Drug Reaction Newsletter11 (1): 2-3, January 2001.

Tetracycline and benign

intracranial hypertension

New Zealand Benign intracranial hypertension(BIH) is a rare but potentially serious condition. BIHhas been documented in association with a varietyof medications, particularly the tetracyclines.

The New Zealand Centre for Adverse ReactionsMonitoring (CARM) has received its second report

of benign intracranial hypertension (BIH) related touse of minocycline involving a 14-year old girl whowas being treated for acne. Other prescribed medi-cines were fluticasone and salbutamol inhalers. Thepatient presented with headache unrelieved byanalgesics, and had intermittent vomiting. Onadmission to hospital she suffered from slurredspeech, reduced sensation and left sided weak-ness, with mild lateral rectus palsy on the right.Minocycline, which had been taken for thirteendays, was discontinued. A diagnosis of hemiplegic


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migraine was made, and she recovered. The head-ache then recurred after restarting minocycline.Papilloedema was observed and the diagnosis ofbenign intracranial hypertension (with hemiplegicmigraine) was made. Treatment included aceta-

zolamide. The patient had not fully recovered at thetime of reporting.

Physicians should regularly enquire about head-ache in patients receiving tetracycline therapy inview of the potential risk of benign intracranialhypertension (BIH). BIH has been reported inassociation with a variety of medications, particu-larly the tetracyclines and minocycline is the agentmost frequently cited. The lipophilic properties ofminocycline may be an explanation for the highernumber of reported cases.

If drug-induced BIH is suspected, the implicateddrug should be discontinued. Tetracyclines shouldnot be prescribed concomitantly with retinoids (e.g.isotretinoin), another drug class associated withBIH.

Reference: Kingston H. Tetracyclines and Benign Intrac-ranial Hypertension a headache rare but real. PrescriberUpdate No. 21, January 2001. http://www.medsafe.govt.nz/profs.htm.

Ergotamine and erythromycin

interactionAustralia Ergotism is manifested by symptomsand signs of peripheral ischaemia due to constric-tion of vascular smooth muscle caused by directaction of an ergot derivative. Headache, intermit-tent claudication, muscle pain, numbness, coldnessand pallor of the extremities may occur, and gan-grene has been reported. Ergotism is usuallyassociated with excessive dosing of ergot prepara-tions but has also been reported with normal dosesof ergotamine preparations when there wasconcommitant use of macrolides (particularly eryth-

romycin). The mechanism of the interaction is notestablished but may involve an inhibition of ergot-amine metabolism or an increased gut absorptionresulting in an increase in serum ergotamine con-centration.

In recent years, the Australian Adverse Drug Reac-tions Committee (ADRAC) has received two reportsdescribing severe ergotism in association with thecombined use of ergotamine and erythromycin.

ADRAC has also received reports of ergotismarising from the combination of ergotamine withritonavir and verapamil and has noted publishedreports of similar interactions with HIV proteaseinhibitors, particularly ritonavir (1, 2). These reports

suggest that the basis of the interaction is inhibitionof either cytochrome P4503A4 in the liver or gutP-glycoprotein with subsequent increase in ergot-amine concentrations. As most inhibitors ofCYP3A4 also inhibit P-glycoprotein, the concomi-tant use of erythromycin and other known inhibitorsof CYP3A4 with ergotamine preparations should beavoided.

References:

1. Phan, T.G., Agaliotis, D., White, G. et al. Ischaemicperipheral neuritis secondary to ergotism associated withritonavir therapy. Medical Journal of Australia,171: 502503.(1999).

2. Blanche, P., Rigolet, A., Gombert, B. et al. Ergotismrelated to a single dose of ergotamine tartrate in an AIDSpatient treated with ritonavir. Postgraduate MedicalJournal,75: 546547 (1999).

3. ADRAC Bulletin, Volume 19, No 4, December 2000.

Celecoxib and warfarin interaction

Australia Since the introduction of celecoxib

(Celebrex) onto the market in October 1999, theAustralian Adverse Drug Reactions Committee(ADRAC) has received 2218 reports of suspectedadverse drug reactions. Of these, 21 cases de-scribe an increase in the INR of patients on treat-ment with warfarin. In the 16 cases where thevalue of the INR was specified, it rose from a stablevalue of around 2.0 to a peak ranging from 4.2 to12.2 (median: 5.3). In two other cases the INR wasdescribed as high and very high. While most ofthe reports did not describe complications, bleedingwas reported in 6 cases. These included severeoral bleeding, intracranial haemorrhage, epistaxis

and gastrointestinal haemorrhage. In most cases,the problem occurred within two weeks of theaddition of celecoxib. Of the patients in whom theoutcome was known, all recovered after withdrawalof celecoxib and, in some cases, withholding orreducing the dose of warfarin.

In addition to these 21 cases, there have been 11cases of bleeding in patients taking concomitantcelecoxib and warfarin. These reports describedpurpura (3 cases), gastrointestinal haemorrhage


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(2), haematuria (1), haematemesis (1), melaena(1), subdural haematoma (1), unspecified haemor-rhage (1) and stroke (1). There was no referenceto the INR in these reports except for one in whichthe INR was reported as unchanged. It is not clear

in these cases whether the bleeding was the resultof an interaction, an additive effect, an effect ofcelecoxib alone, or unrelated to the use ofcelecoxib.

The product information for celecoxib states that inpostmarketing experience, bleeding events havebeen reported, predominantly in the elderly, inassociation with increases in prothrombin time inpatients receiving celecoxib concurrently withwarfarin. In the cases of increased INR and bleed-ing reported to ADRAC, 5 of the 26 patients inwhom the age was stated were less than 50 years

old.

The product information also describes a study inhealthy volunteer subjects given 2 mg to 5 mgwarfarin daily in whom celecoxib had no effect onthe prothrombin time. However, since warfarin ismetabolised mainly by CYP2C9 and this enzymecan be inhibited by celecoxib, it is possible that insome individuals, inhibition of CYP2C9 may besignificant, producing higher blood concentrationsof warfarin. There have been two recent publica-tions describing this interaction. (1, 2)

References

1. Mersfelder, T.L., Stewart, L.R. Warfarin and celecoxibinteraction. Annals of Pharmacotherapy, 34: 325327.

2. Hasse, K.K., Rojas-Fernandez, C.H., Lane, L et al.Potential interaction between warfarin and celecoxib.Annals of Pharmacotherapy,34:666667 (2000).

3. ADRAC Bulletin, Volume 20, No 1, February 2001.

Cerivastatin: rare effect

of rhabdomyolysisAustralia Cerivastatin (Lipobay) is the fifth ofthe HMG-CoA reductase inhibitors (statins) to bemarketed in Australia. Rhabdomyolysis is a knownbut rare effect of the statins and is more likely tooccur when a fibrate is taken concomitantly. Itsoccurrence in association with cerivastatin appearsgreater than with other statins. Up to January

2001, the Australian Adverse Drug ReactionsCommittee (ADRAC) had received a total of 95reports associated with cerivastatin, of which 17(18%) have described rhabdomyolysis. This can becompared with the other statins for which the

percentages range from 0.3 to 1.2%.

The 17 cases of rhabdomyolysis associated withcerivastatin occurred from just over a week to 18months after the introduction of cerivastatin butmost occurred in the first month of therapy. Sevenof the 15 cases in which the dose was statedoccurred with daily dosages of 400 micrograms orgreater and two cases occurred shortly after thedose was increased to 800 micrograms daily.

Of particular interest is the fact that 10 of the 17patients were also taking gemfibrozil. The sponsor

has made the concomitant use of cerivastatin andgemfibrozil a contraindication. ADRAC wishes toalert prescribers to the possibility of rhabdomyolysiswith all statins. Cerivastatin should no

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