WHO Drug Information Vol. 22, No. 1, 2008

W H O DRUG

INFORMATION V O L U M E 2 2 N U M B E R 1 2 0 0 8

R E C O M M E N D E D I N N L I S T 59 I N T E R N A T I O N A L N O N P R O P R I E T A R Y N A M E S F O R P H A R M A C E U T I C A L S U B S T A N C E S

W O R L D H E A L T H O R G A N I Z A T I O N G E N E V A

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WHO Drug Information Vol 22, No. 1, 2008

WHO Drug Information

Contents

World Health Organization

Challenges in BiotherapeuticsRegulatory pathways for biosimilar

products 3

Pharmacovigilance FocusWHO Programme for International Drug

Monitoring: annual meeting 6

Safety and Efficacy IssuesRecall of heparin products extended 10Contaminated heparin products recalled 10DacartTM development terminated and

LapdapTM recalled 11Varenicline and suicide attempts 11Norelgestromin-ethynil estradiol: infarction

and thromboembolism 12Emerging cardiovascular concerns with

rosiglitazone 12Disclosure of transdermal patches 13Statement on safety of HPV vaccine 13IVIG: myocardial infarction, stroke and

thrombosis 14Erythropoietins: lower haemoglobin levels 15Erythropoietin-stimulating agents 15Pregabalin: hypersensitivity reactions 16Cefepime: increased mortality? 16Mycophenolic acid: pregnancy loss and

congenital malformation 17Carbamazepine and skin reactions 17Canada Vigilance: a new name and data-

base 18Desmopressin and hyponatraemia 18

Regulatory Action and NewsInfluenza virus vaccines: northern

hemisphere winter 19Lumiracoxib-containing medicines:

withdrawal 19Thalidomide approved for multiple

myeloma 19New genetic test for breast cancer 20Natalizumab for moderate-to-severe

Crohn disease 20First test to detect and identify 12 res-

piratory viruses 21

Miglustat: withdrawal by manufacturer 21Voluntary withdrawal of clobutinol cough

syrup 22

Current TopicsProposed harmonized requirements:

licensing vaccines in the Americas 23Sixteen types of counterfeit artesunate

circulating in South-east Asia 24Eastern Mediterranean Ministers tackle

high medicines prices 24

ATC/DDD ClassificationATC/DDD Classification (temporary) 26ATC/DDD Classification (final) 28

Consultation DocumentInternational PharmacopoeiaCycloserine 30Cycloserine capsules 33

Recent Publications,Information and EventsAssessing the quality of herbal medicines:

contaminants and residues 36Launch of procurement and supply

management website 36Malaria research collection published 36New pricing bulletin 37How to improve the use of medicines by

consumers 37Model quality assurance system for

procurement agencies 38Training courses in management and

supply 38Pharmacists work to improve use of

generics 39

Recommended InternationalNonproprietary Names: List 59 41

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Challenges in Biotherapeutics

Regulatory pathways forbiosimilar productsInnovative biotherapeutic products suchas insulin, human growth hormone anderythropoietin offer promise for treatingmany of the life threatening chronicdiseases that present major challenges topublic health programmes in both devel-oped and developing countries.

Until now, the high cost of biotherapeuticshas often limited their use, particularly inlow income countries. However, many ofthe current patents on these products arenow expiring, offering an opportunity tomanufacturers to produce and marketgeneric products. This will improveavailability and contribute to increasedaccess at a more affordable price. De-pending on the jurisdiction, biotherapeuticproducts produced and marketed in thisway are referred to as similar biologicalmedicinal products (bio-similars), follow-on protein products, subsequent-entryproducts or biogenerics.

Worldwide, varying degrees of regulatorypreparedness exist for the approval ofbiosimilars. In order to consolidatethinking on the current situation, a WHOinformal consultation was organized inApril 2007 by the Quality, Safety andStandards Team of the WHO Departmentof Immunization, Vaccines and Biologi-cals. The consultation was attended bynational regulatory authorities fromdeveloping and developed countries,innovator and generic biopharmaceuticalindustries, and academia. The objectivesof the meeting were to discuss the currentstatus of so-called similar biologicalmedicinal products biosimilars andto review regulatory pathways and

challenges in evaluating the quality,safety and efficacy of these products.

It was soon realized that marked differ-ences exist in the definitions and regula-tory pathways for biosimilar products inmany countries. For example, in someAsian countries, a number of biosimilarproducts such as interleukins, interferons,erythropoetins, growth factors, hormones,enzymes and even monoclonal antibod-ies, are available on the market. How-ever, they are not defined as a class norare they approved within a distinct regula-tory framework. In the European Union(EU), a few biosimilar products have beenapproved so far through the EuropeanMedicines Agency (EMEA), which has themost well developed regulatory frame-work for biosimilars so far and which issupported by specific guidelines (13).

The existence of divergent approaches tothe regulatory oversight of biosimilars indifferent countries has revealed a needfor defining globally acceptable regulatoryexpectations for these products. It wasagreed that WHO should develop a globalregulatory guideline for biosimilar prod-ucts to help WHO Member States meetthe challenge of establishing appropriatenational oversight (4).

Consequently, a drafting group has beenorganized and is developing a WHOguideline on Biosimilar/Follow-on protein/Subsequent-entry products. A number ofkey issues for future discussion were alsohighlighted during the meeting.

TerminologyTerminology currently used is not consist-ent between the various countries andjurisdictions. In the EU, the term similar

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biological medicinal products, commonlyreferred to as biosimilars, is defined inthe legislation. EU terminology and theEMEA regulatory guidelines for bio-similars have been adopted in Australiaalso. In the USA, biosimilars are termedfollow-on protein products, and in Japanfollow-on biologicals. In Canada they arereferred to as subsequent entry bio-logics. In India and Iran, they are usuallyreferred to as biogenerics. WHO aims toestablish globally acceptable terminology.This issue is the starting point for definingthe scope of the international guideline,therefore, it will hopefully be resolvedduring the development of the draft. Forconvenience, the term biosimilars isused in this document.

Concept of biosimilarsThe term generic medicines refers tochemically-derived products which aretherapeutically equivalent to the agreedreference or originator product. For suchgenerics, demonstration of bioequiva-lence with the originator product is usuallyappropriate to infer therapeutic equiva-lence. However, it is unlikely thatbiotherapeutics can generally follow thisstandard approach for generics becauseof their relatively large and complexmolecular structures, which are moredifficult to adequately characterize in thelaboratory.

Based on current analytical techniques,two biologicals produced by differentmanufacturing processes cannot beshown to be identical, but similar at best.For these reasons, the standard genericapproach is scientifically not applicable todevelopment of biosimilar products andadditional non-clinical and clinical dataare usually required.

Principally, two different strategies fordeveloping biosimilar products can beenvisaged. The first scenario can betermed a full comparability approach andcorresponds to the EU pathway, which

requires a thorough comparability exer-cise to generate evidence substantiatingthe similar nature, in terms of quality,safety and efficacy, of the new biosimilarproduct and the chosen reference orcomparator product.

The second scenario considers that athorough comparability exercise may notbe required but rather reliance on publiclyavailable information coupled with addi-tional non-clinical and clinical studies todemonstrate similarity could be used. Inthe second approach, reliance on thereference product may not be as essen-tial and a new biosimilar product ap-proved with this approach would not begranted all the indications of the refer-ence product. At the current time, it isconsidered that further clarity and realexamples are needed to assist in devel-opment of this second scenario as aregulatory pathway.

Proof of similarityIn general, a biosimilar product may beapproved following an abbreviatedregulatory process based on the claimthat it is similar to an existing licensedproduct. The key issue to agree is howmuch data are required to demonstratesimilarity. There was consensus in theWHO meeting that a comparabilityprogramme should involve all aspects ofdevelopment, with full analytical compara-bility of quality, and abridged studies forthe non-clinical and clinical componentsof a licence application.

But there were clear differences betweencountries in the approach to non-clinicaland clinical studies for biosimilars. Al-though there was a strong view thatcomparative studies remain central to anabbreviated regulatory process, in somecountries non-clinical studies might bereduced to non-comparative studies fortoxicity (single and/or repeat-dose),where the goal is solely to establish thenon-clinical safety of biosimilars. For


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clinical assessment, there was agreementthat reduced studies compared to a fulllicence application for a biological medi-cine or novel biotherapeutic would beacceptable; however there was no clearconsensus on the details of a reducedclinical assessment package.

Generally, confirmatory phase III studiesfor safety and efficacy involving pharma-cokinetic and pharmacodynamic testswould be required, along with safe doseranging. However, views varied as to theextent to which these studies need to becomparative or not. It was also unclearwhether the studies should demonstratenon-inferiority or equivalence. It was alsoacknowledged that in some cases theeffort that would be required to performthe comparability study might be greaterthan to seek licensure of the biothera-peutic as a stand-alone medicinal prod-uct. It would be the responsibility of thesponsor of biosimilars to choose thedesired licensure pathway.

The reference or comparator productA common feature in this process is thereference or comparator product. Gener-ally, countries expect this to be a locallyregistered product, but it has to beconsidered that a company might wish toregister the biotherapeutic in a countrywhere the reference product is not (and isunlikely ever to be) licensed. The optionof accepting reference products notlicensed by the national regulatoryauthority (NRA) would increase opportu-nities for access to alternatives to innova-tor biologics and/or entry of biosimilars tosome markets.

It is conceivable that scientific issues thatlimit their use could be addressed through

the use of publicly available information,data provided by the manufacturers, and/or information obtained by the NRA viainformation sharing with other NRAs.However, this consideration may causelegal problems unless careful approachesare made.

All these issues will be discussed at thenext WHO consultation on biosimilar inSeoul, Republic of Korea, May 2008.Progress in the development of the WHOguideline on biosimilar products will bereported to the Expert Committee onBiological Standardization (ECBS) at itsmeeting in October 2008.

References

1. EMEA guideline on similar biologicalmedicinal products. London, 2005 (CHMP/437/04)

2. EMEA guideline on similar biologicalmedicinal products containing biotechnology-derived proteins as active substance: Qualityissues. London, 2006 (CHMP/BMWP/49348)

3. EMEA guideline on similar biologicalmedicinal products containing biotechnology-derived proteins as active substance : non-clinical and clinical issues. London, 2006(CHMP/BMWP/42832).

4. Meeting report available at http://www.who.int/biologicals/areas/biological_therapeutics /Final Biosimilarmeeting Report for web 13 September2007.pdf.

5. European Generic Medicines Association(EGA) Handbook on Biosimilar Medicines.Brussels, 2007

6. United States Food and Drug Administra-tion, Office of Generic Drugs, http://www.fda.gov/cder/ogd/index.htm#Introduction


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WHO Programme forInternational DrugMonitoring: annual meetingThe annual meeting of representativesfrom national centres participating in theWHO Programme for International DrugMonitoring was recently convened inBuenos Aires, Argentina. Working groupswere set up during the meeting to discusspoints of immediate interest and toprovide recommendations. A summary ofthe proceedings is set out below.

WHO adverse drug reactions data-base: public access

Requests for information are received atall twelve national centres representedin the working group but not all haveprocedures available for dealing withsuch inquiries.

Users of the data base have been identi-fied as physicians, researchers, epidemi-ologists, lawyers, general public andpatient organizations or the generalpublic, media, and politicians. Queriesrange from very basic information(number of reports; number of fatalcases) to more detailed information, e.g.for specific rare adverse drug reactions,signals, or comparative data. NationalCentres need to improve their capacity torespond and to be more transparent byallowing the public access to decision-making processes. Such access wouldstrengthen public trust.

There was no objection to informationfrom the adverse drug reactions (ADR)data bases being provided to interestedthird parties, but it was felt that theresponses should be tailored to the

individual/organization requesting thedata. It was important for data privacy tobe rigorously preserved in accordancewith national legislation, and it wasrecommended that rules and proceduresbe established to deal with third partyrequests. A caveat should also be createdto set out the basic principles applicableto the practice of sharing information. Tomaintain data privacy, narratives shouldnever be given to third parties, but maybe given to the market authorizationholder. Alternatively, a third party can beasked what specific fields they wouldneed, while physicians often prefersummaries.

The Netherlands National Centre hasalready opened its database to thegeneral public and was able to offeruseful feedback (www.lareb.nl). Foreexample, information provided by theCentre is restricted to age groups ratherthan specific ages since a specific agecould be an identifier.

Extending open accessto the signal document

A signal document is a publication ofpotentially interesting pharmacovigilancesignals drawn from the WHO globalindividual case safety reports (ICSR)database, Vigibase. Signals are noted bythe Uppsala Monitoring Centre ReviewPanel and distributed to a restrictedaudience of national pharmacovigilanceauthorities.

There are many advantages to providingopen access to the signal document:information will reach a wider audience,will provide greater transparency, in-crease public confidence in pharma-covigilance, contribute to scientific re-

Pharmacovigilance Focus

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search, and give feedback to the report-ers. Disadvantages include misinterpreta-tion of information and possible creationof unnecessary concern. In providingopen access to the document, it would beuseful to describe how the reports arecollected, how a signal is detected andhow the results should be interpreted.

In conclusion, it was proposed that allsignals should be published in the samejournal, that marketing authorizationholders should be allowed to commentand that national centres should benotified of signals in advance in order tobe prepared. Signals could be graded tobetter assess impact, which may as-sessed by noting a change in number ofreports or increased number of studies.

Exchange of information

It was agreed that there is a need toinvolve consumers and patients in phar-macovigilance practices. Concernsregarding patient reporting include themixed quality of reports, incompleteinformation, which sources of informationare being used by patients, and patientaccess to prescribers.

International experience indicates that inthe majority of countries, patients areadvised to make a report to their physi-cian or to go to a pharmacist. Somepatients are allowed to report directly tonational centres. Although many nationalcentres are not interested in acceptingreports from patients/consumers, somemay accept reports from special interestgroups. In developing countries, patientsneed the assistance of a health profes-sional to make a report. An InformationHotline is also available in some coun-tries. EudraVigilance, in the EuropeanUnion, does not accept reports frompatients because they require reports tobe medically confirmed.

Consumers/patients have rights and areacknowledged as end users. By involving

patients, it is hoped to improve compli-ance, and by accepting patient reportsone gets a closer view of patient safety.Mechanisms for reporting by patientsmust be suitable and user friendly. Em-powering patients by providing informa-tion is an opportunity for national centresto improve their public health role. Con-sumer reports accepted by nationalcentres should be reported to the WHOadverse drug reactions database at theUppsala Monitoring Centre.

Direct to consumer advertising

With regard to direct-to-consumer adver-tising of pharmaceuticals, the groupunanimously recommended prohibitingdirect-to-consumer advertising.

Risks in special populations:women and children

Few data are available on the safety ofmedicines used in pregnant and lactatingwomen. Women may be inadvertentlyexposed to unsafe products and there isa particular lack of information, educationand guidance in resource-limited settings.Intensive monitoring systems could leadto creating pregnancy registries whichwould serve as a useful tool. Congenitalabnormalities registers could also beused to collect information on congenitalabnormalities, stillbirths, birth defects, etc.

In relation to medicines use in women ofchildbearing age there is an urgent needto educate health professionals, thegeneral public and the media on safetyissues. Establishment of a medicalinformation centre would be desirable.

Children are vulnerable because theyhave unique physiological features andhandle medicines differently. Extrapola-tion of adult data to children is often notappropriate nor backed by solid evidence.In resource poor settings, children areoften malnourished and conditions suchas marasmus and kwashiorkor are


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common. Many medicines have not beendeveloped in paediatric doses and areused off-label, so that dosage in childrenis often inaccurate. Fortunately, clinicaltrials in children are now required in someregions before marketing approval.Global networking and sharing of informa-tion, or pooling of data could contribute tobetter knowledge of the true extent ofadverse drug reactions in children.Poison Centres are often a useful sourceof information for adverse drug reactionsin children.

WHO has published a booklet promotingsafety of medicines in children and, at thenext International Conference of DrugRegulatory Authorities (ICDRA) in Swit-zerland, a two-day satellite meeting willfocus on better medicines for children.

Medication errors: expanding thescope of pharmacovigilance centres

The role of pharmacovigilance centres inmonitoring medication errors (ME) needsto be expanded and the ability to detectcases increased. Existing systems arelimited by unharmonized terminology andunhelpful presentation of information.Pharmacovigilance centres are not yetresponsive enough for root cause analy-sis and corrective action.

A proposal for a combined ADR and MEreport form needs to be discussed further.There are areas which can be identifiedfor focused analysis, or which mayconcentrate on patients presenting withallergy due to ME.

It was recommended that:

national centres interact with relevantnational bodies to ensure integration ofactivities related to ME

national centres complete and returnquestionnaires to facilitate a compre-hensive overview of data.

the Uppsala Monitoring Centre shoulddevelop a web-page for ME activities,with links to relevant information.

a special ad-hoc meeting should takeplace to review progress.

co-operation should continue with theWorld Alliance for Patient Safety.

Communication andcrisis management

Management of crises includes handlingthe impact of rumours, defining the role ofthe media, and managing the publicperception of disasters. This is veryimportant where coincidental adverseevents following immunization occur or inthe event of premature withdrawal orsuspension of a product. Patients andprofessionals need to interact on theinterpretation of science.

National centres need to oversee proc-esses through guidelines, standardoperating procedures and protocols toenable them to predict, prepare and planfor future events. These protocols shouldidentify communications priorities andexplain how to address a communicationscrisis. Trusted opinion leaders could beidentified and recruited to help managethe crisis, and communication materialsshould be designed to target the issues.Training should focus on process man-agement and communication skills.

In dealing with potential groups that arequestioning the decisions of a publichealth authority, it is important to considerthe context of culture and allow equalopportunities for these groups to articu-late their concerns. When explaining thefacts of a crisis, compassion and empathywere cited as critical components of acredible messenger.

Cohort Event Monitoring

Cohort event monitoring (CEM) is amethodology which analyses cohorts by


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various means based on prescriptionrecords, public health programmes, andother health records and is a disciplinewhich should be included in pharmaco-vigilance training. CEM has many addi-tional needs in the area of terminologybecause CEM uses terms that are neverreported or rarely used in spontaneousreporting. However, such terminology hasto be in the context of local culture andprogrammes. A complete dictionary ofadverse events with a hierarchicalstructure should be developed.

The working group proposed to mapWHO-ART terminology and the eventsdictionary developed by New ZealandsIntensive Medicines Monitoring Pro-gramme, to update WHO-ART corre-spondingly, with provisions on ongoingmaintenance in accordance with progressin medical sciences, and to have theterminology available within a datamanagement tool such as the Vigiflow(see www.who-umc.org). The datamanagement tool should be adapted toreceive reports from CEM.

Stimulated passive reporting

Stimulated passive reporting (SPR) hasbeen used in South Africa as a way of

encouraging reporting of adverse drugreactions to antiretrovirals. The objectiveof this working group was to determinewhether SPR could be used as a method-ology to improve spontaneous adversedrug reactions reporting.

The general consensus was that SPRwas not a methodology per se, but couldbe used to encourage spontaneousreporting of adverse drug reactions. SPRcould be used to suit country and/orproduct specific needs, to encouragespontaneous reporting of adverse drugreactions, and to increase awareness andculture of reporting. It could be effective ifused appropriately to complement exist-ing pharmacovigilance activities/systems.

However, SPR does not necessarilyincrease the quality of reporting, it canlimit reporters to reporting specifiedadverse drug reactions only. It does notdetermine the incidence of adverse drugreactions and may limit information forsignal generation.

Reference: Pharmaceuticals Newsletter,Number 6, 2007. http://www.who.int/medicines


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Safety and Efficacy Issues

Recall of heparinproducts extendedUnited States of America On 11February 2008, the Food and DrugAdministration (FDA) informed healthcareprofessionals of important warnings andinstructions for heparin sodium injectionuse. On 28 February 2008, the FDAissued an update to inform the public thatthe manufacturer has extended its recallof multi-dose vials of heparin sodium forinjection to also include single-dose vialsof heparin sodium for injection.

There have been reports of seriousadverse events including allergic orhypersensitivity-type reactions, withsymptoms of oral swelling, nausea,vomiting, sweating, shortness of breath,and cases of severe hypotension. Mostevents developed within minutes ofheparin initiation although the possibilityfor a delayed response has not beenexcluded. The reports have largelyinvolved use of multiple-dose vials.However, there have been several casesin which products from multiple, single-dose vials have been combined to admin-ister a bolus dose.

Heparin sodium is an anticoagulant usedin patients undergoing kidney dialysis,certain types of cardiac surgery, andtreatment or prevention of other seriousmedical conditions, including deepvenous thrombosis and pulmonaryemboli.

References

1. FDA Public Health Update Recall ofHeparin Sodium Injection and Heparin LockFlush Solution (Baxter) 28 February 2008.http://www.fda.gov/medwatch/report/hcp

2. March 07, 2008 - Updated Questions andAnswers - FDA; February 28, 2008 - PublicHealth Update - FDA; February 28, 2008 -Press Release - Baxter; February 11, 2008 -Public Health Advisory - FDA Updated 02/28/2008 ; February 11, 2008 - Questions andAnswers - FDA; February 11, 2008 - NewsRelease - FDA. http://www.fda.gov/medwatch/report/hcp.htm

Contaminated heparinproducts recalledCanada Health Canada testing ofheparin products marketed in Canadahas identified a contaminant in productsfrom manufacturer B. Braun Medical Inc.The contaminant, oversulphated condroi-tin sulphate, has also been found inheparin products in the United States andAustralia.

On 11 March 2008, Health Canadarequested that all suppliers of heparin forsale in Canada test their heparin productsusing the same methodology that uncov-ered the contamination in the UnitedStates. Health Canada is continuing itstesting of heparin products from allCanadian companies and will continue toupdate Canadians as needed.

Health professionals should only useheparin where it is medically essentialafter careful weighing of the risks andbenefits for each individual patient.Patients should be monitored during andimmediately following heparin administra-tion for signs of allergy or anaphylacticreaction.

Reference: Advisory 2008-49, dated 20 March2008. http://www.hc-sc.gc.ca

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WHO Drug Information Vol 22, No. 1, 2008 Safety and Efficacy Issues

Dacart developmentterminated and LapdaprecalledData from two Phase III clinical trialsassessing use of the artemisinin-basedcombination therapy Dacart, a fixed-dose combination of chlorproguanil,dapsone and artesunate, currently inclinical development have shown disap-pointing results.

The first trial was primarily designed toestablish the efficacy of Dacart versusCoartem (artemetherlumefantrine),currently the first-line antimalarial therapyin many endemic countries. The study,carried out in 1372 patients showedstatistical non-inferiority with 94% efficacyat 28 days for Dacart and 97% forCoartem. However, although theefficacy of Dacart was in line withexpectations, the reduction of haemo-globin observed in patients with glucose-6-phosphate dehydrogenase (G6PD)deficiency taking Dacart, was greaterthan that of Coartem.

A reduction in haemoglobin can lead toanaemia which, in some severeincidences, may require treatment withblood transfusions. G6PD deficiency is ahereditary enzyme disorder which isestimated to impact 1025% of thepopulation in sub-Saharan Africa. TheG6PD enzyme is important for the normalfunctioning of red blood cells and defi-ciency of the enzyme in certain individu-als can only be detected using a bloodtest which is often not a practical option.

The second trial, in 892 patients, wasdesigned to establish the efficacy ofDacart versus Lapdap (chlorpro-guanil and dapsone), another anti-malarial product Glaxo SmithKline devel-oped in partnership with the Medicines forMalaria Venture (MMV). Significantreductions in haemoglobin levels ofpatients with G6PD deficiency wereobserved for both products in this trial.

On the basis of these data, it has beendecided to terminate further developmentof Dacart. A product recall process hascommenced at pharmacy level in Kenya,for Lapdap, this being the only marketwith recent sales of the product.

References

1. Press Release. Update on GSKs malariatreatments: Dacart and Lapdap 29February 2008 at http://www.gsk.com.

2. Medicines for Malaria Venture. http://www.mmv.org

3. Review of the safety of chlorproguanil-dapsone in the treatment of uncomplicatedfalciparum malaria in Africa. WHO/HTM/MAL/2005.1106 at http://www.who.int/malaria/docs/LapDap.pdf

Varenicline and suicideattemptsEuropean Union The EuropeanMedicines Agency (EMEA) has concludedthat updated warnings to doctors andpatients are needed to increase aware-ness of cases of suicidal ideation andsuicide attempts reported in patientsusing varenicline (Champix), a medicineindicated for smoking cessation in adults.

At its December 2007 meeting, theCommittee for Medicinal Products forHuman Use (CHMP) concluded that thereis a need to update the product informa-tion for Champix to warn doctors andpatients that depression has been re-ported. The symptoms of this depressionmay include suicidal ideation and suicideattempt.

The CHMP has requested that the mar-keting authorization holder submit avariation to the marketing authorizationbefore 19 December 2007 to implementthese changes to the product information.The EMEA will continue to keep this issueunder close scrutiny and take appropriateactions if further concerns arise.

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WHO Drug Information Vol 22, No. 1, 2008Safety and Efficacy Issues

Reference: Press Release, Doc. Ref. EMEA/595516/2007. 14 December 2007 www.emea.europa.eu

Norelgestromin-ethinylestradiol: infarction &thromboembolismCanada Evra is a transdermalhormonal contraceptive system contain-ing 6 mg of norelgestromin and 0.6 mg ofethinyl estradiol per patch. Since itsintroduction on the Canadian market inearly 2004, 16 cases of thromboembolismand 1 of myocardial infarction suspectedof being associated with the product havebeen reported to Health Canada. Two ofthe 17 patients died.

Hormonal contraception is a known riskfactor for venous thromboembolism(VTE). Others include prolonged immobil-ity, major surgery, family history of VTE,increasing age, smoking and obesity (15). The risks may be cumulative if morethan one risk factor is present (1). Anassociation between being overweightand thrombosis has also been observedamong women using oral contraceptives(6) and the combined effect was greaterthan the expected risks based on theirindividual effects (6). The risk of VTE isalso reported to be higher during the first3 postpartum months than during preg-nancy (7). The product monograph statesthat women should be encouraged to usea nonhormonal form of contraception inthe 3 months following delivery (5).

Extracted from Canadian Adverse Reac-tion Newsletter, Volume 18(1), January2008 at http://www.hc-sc.gc.ca

References

1. Hirsh J. Guidelines for antithrombotictherapy. 5th ed. Hamilton (ON): BC DeckerInc.; 2005. p. 64.

2. Grimes DA, Shields WC. Family planningfor obese women: challenges and opportuni-ties. Contraception 2005;72:1-4.

3. Sidney S, Petitti DB, Soff GA, et al. Venousthromboembolic disease in users of low-estrogen combined estrogen-progestin oralcontraceptives. Contraception 2004;70:3-10.

4. Stein PD, Beemath A, Olson RE. Obesity asa risk factor in venous thromboembolism. AmJ Med 2005;118:978-80. [PubMed]

5. Evra (ethynilestradiol, norelgestromin)[product monograph]. Toronto: Janssen-OrthoInc; 2007.

6. Abdollahi M, Cushman M, Rosendaal FR.Obesity: risk of venous thrombosis and theinteraction with coagulation factor levels andoral contraceptive use. Thromb Haemost2003;89:493-8.

7. Heit JA, Kobbervig CE, James AH, et al.Trends in the incidence of venous thromboem-bolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med2005;143:697-706.

Emerging cardiovascularconcerns with rosiglitazone

Australia The Australian Adverse DrugReactions Advisory Committee (ADRAC)has drawn the attention of prescribers toan emerging concern about the cardio-vascular safety of the thiazolidinedione(TZD) drug rosiglitazone.

TZD drugs (rosiglitazone, pioglitazone)improve glycaemic control and areapproved for the treatment of Type 2diabetes mellitus. Whether they have longterm benefits in reducing the chroniccomplications of Type 2 diabetes remainsan open question. It is well establishedthat TZDs cause fluid retention and canexacerbate or precipitate cardiac failure.

Recently, three separate meta-analysesof data derived from pooled clinical trialsof rosiglitazone have reported an in-creased risk of cardiac ischaemia (13),The product information for rosiglitazone(Avandia/Avandamet) has been

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amended to reflect these emergingresults and the Therapeutic GoodsAdministration has now required thefollowing boxed warning: The use ofAvandia/Avandamet is not recom-mended in patients with known ischaemicheart disease, particularly in those takingnitrates. Avandia/Avandamet has beenshown to be associated with an increasedrisk of myocardial ischaemia (angina,infarction) in pooled short-term clinicalstudies, particularly in those who neededseveral antidiabetic drugs or nitrates.

The TGA has commissioned an additionalreview of the information. Pending theoutcome of this review, prescribersshould include this potential additionalrisk in their consideration of appropriatedrug therapy for Type 2 diabetes, takinginto account that rosiglitazone should notbe prescribed for patients with knownischaemic heart disease or those consid-ered to be at high risk for ischaemic heartdisease.

Extracted from Australian Adverse DrugReactions Bulletin, Volume 26, Number 6,December 2007. http://www.tga.gov.au

Reference

1. Nissen SE & Wolski K. Effect of rosiglita-zone on the risk of myocardial infarction anddeath from cardiovascular causes. NEJM2007; 356: 2457-2471 (correction published involume 357, p 100).

2. FDA Briefing Document (pdf,6.15Mb)*. Division of Metabolism and EndocrineProducts and Office of Surveillance andEpidemiology. July 30, 2007

3. GlaxoSmithKline Clinical Trial Register.Rosiglitazone studies. Study No.: ZM2005/00181/01 and Study No.: HM2006/00497/00 /WEUSRTP866 .

4. Home PD et al for the RECORD studyGroup. Rosiglitazone evaluated for cardiovas-cular outcomes - An interim analysis. NEJM2007; 357: 28-38.

Disclosure oftransdermal patchesAustralia The Therapeutic GoodsAdministration has received a report of aninadvertent overdose of opioid medicinescaused when subcutaneous morphinewas administered pre-operatively to apatient who was wearing a Norspantransdermal patch, delivering buprenor-phine 20 g/hour. Despite a thoroughmedical history, the patient omitted to tellthe anaesthetist and other medical staffthat she was using Norspan patches, andshe had applied a fresh patch on the dayof surgery. Medical staff discovered thepatch when the patient became comatosewith significant respiratory depressionafter the conventional dose of morphinewas given.

Doctors are advised to remind theirpatients to disclose use of all medica-tions, including those administered bynon-conventional routes such astransdermal patches and subcutaneousimplants. Physical examinations shouldinclude a check for topically applied orsuperficially implanted medicines.


Statement on safetyof HPV vaccineEuropean Union The EuropeanMedicines Agency (EMEA) has receivedreports of deaths in women who hadpreviously received the HPV vaccine,Gardasil, including two reports concern-ing the sudden and unexpected deaths oftwo young women in the European Union

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(EU). Gardasil is a vaccine approved forthe prevention of cervical cancer andother diseases caused by human papillo-mavirus (HPV) types 6, 11, 16 and 18.

The two European cases were reportedas part of the continuous monitoring ofthe safety of medicines. One of the casesoccurred in Austria and the other inGermany. In both cases, the cause ofdeath could not be identified.

Reference: Press Release, Doc. Ref. EMEA/37479/2008, 24 January 2008 at: http://www.emea.europa.eu

IVIG: myocardial infarction,stroke and thrombosisCanada Use of intravenous immuneglobulin (IVIG) is reported to have in-creased by approximately 115% over thepast 78 years, making Canada one ofthe highest per capita users of IVIG in theworld (1). In this context of increasinguse, it is important that health profession-als recognize the serious adverse reac-tions (ARs) suspected of being associ-ated with the use of these products.

IVIG consists mostly of concentrated IgGmanufactured from large pools of humanplasma. Health Canada has authorizedthe use of a number of commercialbrands for such indications as replace-ment therapy for primary or secondaryimmunodeficiency syndromes and treat-ment of idiopathic thrombocytopenicpurpura. In addition, IVIG is often usedoff-label either as a passive immunizingagent or as an immunomodulator for thetreatment of a growing number of condi-tions (2).

From October 1997 to July 2007, 10reports of stroke, 6 reports of thrombosis ,4 reports of myocardial infarction (MI), 2reports of pulmonary embolus and 1report of transient ischemic attack weresuspected of being associated with IVIG.

Two patients received IVIG for commonvariable immune deficiency, and 17 wereprescribed it off-label. Strokes resulted inthe most serious outcomes (1 death, 4cases of persistent sequelae).

Serum viscosity has been shown toincrease following IVIG administration (3).Although several possible mechanismshave been proposed (4), some authorshave postulated that the change in serumviscosity during IVIG administrationtogether with mild dehydration and otherrisk factors (e.g., age, atherosclerosis)contribute to the development of athreshold facilitating the production ofthrombotic ARs (4). Five reports noted theconcomitant use of diuretics, which mayhave contributed to a rise in serumviscosity.

Health care professionals are encouragedto report ARs suspected of being associ-ated with the use of IVIG and to includeany available information that could helpcharacterize potential risk factors.

Extracted from Canadian Adverse Reac-tion Newsletter, Volume 18(1), January2008 at http://www.hc-sc.gc.ca

References

1. Hume HA, Anderson DR. Guidelines for theuse of intravenous immune globulin forhematologic and neurologic conditions.Transfus Med Rev 2007;21:S1-2.

2. Constantine MM, Thomas W, Whitman L, etal. Intravenous immunoglobulin utilization inthe Canadian Atlantic provinces: a report ofthe Atlantic Collaborative Intravenous ImmuneGlobulin Utilization Working Group. Transfu-sion 2007;47(11):2072-80.

3. Steinberger BA, Ford SM, Coleman TA.Intravenous immunoglobulin therapy results inpost-infusional hyperproteinemia, increasedserum viscosity and pseudohyponatremia. AmJ Hematol 2003;73(2):97-100.

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4. Alexandrescu DT, Dutcher JP, Hughes JT,et al. Strokes after intravenous gammaglobulin: Thrombotic phenomenon in patientswith risk factors or just coincidence? Am JHematol 2005;78(3):216-20.

Erythropoietins: lowerhaemoglobin levelsAustralia Dosage instructions for theuse of erythropoiesis-stimulating agents(erythropoietins) in patients with chronickidney disease have been updated in linewith evidence that higher haemoglobinlevels may be associated with an in-creased risk of morbidity and mortality.

Erythropoietins currently available inAustralia are erythropoietin alfa, erythro-poietin beta, and darbepoetin alfa, ap-proved for the treatment of anaemiaassociated with chronic renal failure andwith the treatment of certain malignan-cies.

Recent studies and a meta-analysis havecompared outcomes in patients withchronic kidney disease treated with anerythropoietin (13). The larger of the tworandomized studies showed a lowerincidence of adverse cardiovascularoutcomes in the subnormal (113 g/L)compared to the normal (135 g/L) targethaemoglobin group (1). The second studyshowed no difference in cardiovascularoutcomes between the two groups, (2)and the meta-analysis of nine randomizedtrials showed a lower all-cause mortalityand lower incidence of arteriovenousaccess thrombosis in patients in the lowertarget haemoglobin groups (3).

Product information documents for thethree erythropoietins have been amendedto indicate a target haemoglobin notexceeding 120 g/L in patients with anae-mia due to chronic kidney failure.


References

1. Singh AK, Szczech L, Tang KL, Barnhart H,Sapp S, Wolfson M, Reddan. Correction ofanemia with epoetin alfa in chronic kidneydisease. NEJM 2006; 355: 2085-2098

2. Drueke TB, Locatelli F, Clyne N, EckardtKU, Macdougall IC, Tsakiris D, Burger HU,Scherhag A. Normalization of hemoglobinlevel in patients with chronic kidney diseaseand anemia. NEJM 2006; 355: 2071-2084.

3. Phrommintikul A, Haas SJ, Elsik M, KrumH. Mortality and target haemoglobin concen-trations in anaemic patients with chronickidney disease treated with erythropoietin: ameta-analysis. Lancet 2007; 369: 381-388.

Erythropoiesis-stimulatingagentsUnited States of America On 8November 2007, the Food and DrugAdministration (FDA) strengthened thewarning sections for Epogen/Procrit andAranesp following results of six studiesshowing decreased survival and/ortumour progression in patients withcancer receiving an erythropoiesis-stimulating agent (ESA).

Findings from two additional clinicalstudies (PREPARE and GOG-191) nowshow an increase in mortality and shortertime to tumour progression in patientswith cancer receiving an ESA. This newinfor-mation further underscores thesafety concerns regarding use of ESAs inpatients with cancer.

On 30 November 2007, the manufacturerof epoetin alfa (Epogen and Procrit)and darbepoetin alfa (Aranesp) notifiedFDA of findings from the PREPARE(Preoperative Epirubicin PaclitaxelAranesp) study in patients with primarybreast cancer receiving chemotherapyprior to surgery and randomly assigned toa group that was to receive Aranesp orno Aranesp.

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On 4 December 2007, the manufacturernotified FDA of the findings of GOG-191(National Cancer Institute GynecologicOncology Group), a study in which 109 ofa planned 460 patients with cervicalcancer treated with chemotherapy andradiation were randomly assigned to agroup that was either to receive an ESAor transfusions. The GOG-191 studystopped enrolling patients because of ahigher rate of potentially life-threateningblood clots occurring in the patients whoreceived an ESA.

Both the PREPARE study in breastcancer and the GOG-191 study in cervi-cal cancer showed higher rates of deathand or tumour progression in patientswho received an ESA compared topatients who did not receive an ESA.

FDA is currently reviewing this informa-tion and will take additional actions asappropriate. FDA will hold another publicadvisory committee meeting in early 2008to reevaluate the risk and benefit balanceof ESAs for the treatment of patients withchemotherapy-induced anemia. In theinterim, healthcare professionals shouldconsider the risks of tumour progressionand decreased survival observed whenESAs are used as supportive care inpatients with cancer. These risks shouldbe carefully weighed against the need forand potential risks of red cell bloodtransfusions.

Reference: FDA Medwatch. 3 January 2008http://www.fda.gov/medwatch/

Pregabalin: hypersensitivityreactionsAustralia Pregabalin (Lyrica) isapproved for use in the treatment ofneuropathic pain in adults and as adjunc-tive therapy in adults with partial seizureswith or without secondary generalisation.Post-marketing reports of hypersensitivityreactions to pregabalin comprise 13% ofall the pregabalin adverse reaction

reports in The Australian Adverse DrugReactions Advisory Committee (ADRAC)database, with a range of symptomsreported in 22 individuals (14F:8M).Presentations have included anaphylaxisand 7 reports of allergic skin rash. Theothers were angioedema of eyelids,tongue, mouth, face, lips or upper airway,with breathing difficulty when severe andwidespread.

Of the 22 cases, 6 women developedsymptoms within hours of their first doseof pregabalin. In 14 of the cases,pregabalin was the sole suspected drug.Four patients required emergency treat-ment, including adrenaline and/orparenteral steroids and IM or oral antihis-tamine. Three of the cases of skin reac-tion were confirmed by a positivedechallenge and subsequent rechallenge.There is insufficient information about thepatients histories of atopy or otherallergies to comment on the predictivevalue of such a history.

The pregabalin Product Informationincludes a contraindication for patientswho have demonstrated hypersensitivityto pregabalin or to any of the excipients.Pregabalin prescribers should be alert tothe fact that acute allergic reactions maypresent early after its introduction andafter any dose increases, and counselpatients accordingly.


Cefepime: increasedmortality?United States of America An article ina recent issue of The Lancet InfectiousDiseases has raised the question aboutincreased mortality with the use ofcefepime. The Food and Drug Adminis-tration (FDA) is currently reviewing safetydata and has requested additional data to

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further evaluate the risk of death inpatients treated with cefepime. Cefepimeis a broad spectrum cephalosporinantibiotic currently approved for thetreatment of a variety of infections due tosusceptible strains of microorganisms.

FDA is working with the manufacturer ofcefepime, to further evaluate the findingof increased mortality in patients whoreceived cefepime. Until the evaluation iscompleted, healthcare providers who areconsidering the use of cefepime shouldbe aware of the risks and benefits de-scribed in the prescribing information andthe new information from this meta-analysis.

References

1. Yahav D, Paul M, Fraser A et al. Efficacyand safety of cefepime: a systematic reviewand meta-analysis. Lancet Infect Dis 2007; 7:33848)

2. FDA Medwatch, 14 November 2007. http:/www.fda.gov/medwatch

Mycophenolic acid:pregnancy loss andcongenital malformationUnited States of America The manu-facturer has informed prescribers that useof mycophenolic acid (MPA) (Myfortic)during pregnancy is associated withincreased risks of pregnancy loss andcongenital malformations. This newimportant safety information involves:Increased risk of first trimester pregnancyloss and increased risk of congenitalmalformations, especially external earand facial abnormalities including cleft lipand palate, and anomalies of the distallimbs, heart, oesophagus, and kidney.

This change is a result of postmarketingdata from the United States NationalTransplantation Pregnancy Registry(NTPR) and additional postmarketingdata collected in women exposed to

systemic mycophenolate mofetil (MMF)during pregnancy. MMF is convertedto MPA, the active ingredient in Myfortic,following oral or IV administration. Theprescribing information revisions are inresponse to a Food and Drug Administra-tion (FDA) request sent to all marketedMMF and MPA products.

Reference: Communication from FDA at http:/www.fda.gov/medwatch.

Carbamazepine andskin reactionsUnited States of America The Foodand Drug Administration (FDA) hasinformed patients that dangerous or evenfatal skin reactions (Stevens Johnsonsyndrome and toxic epidermal necroly-sis), that can be caused by carbama-zepine therapy, are significantly morecommon in patients with a particularhuman leukocyte antigen (HLA) allele,HLA-B*1502.

This allele occurs almost exclusively inpatients with ancestry across broad areasof Asia, including South Asian Indians.Genetic tests for HLA-B*1502 are alreadyavailable. Patients with ancestry fromareas in which HLA-B*1502 is presentshould be screened for the HLA-B*1502allele before starting treatment withcarbamazepine. If they test positive,carbamazepine should not be startedunless the expected benefit clearlyoutweighs the increased risk of seriousskin reactions. Patients who have beentaking carbamazepine for more than afew months without developing skinreactions are at low risk of these eventsever developing from carbamazepine.This is true for patients of any ethnicity orgenotype, including patients positive forHLA-B*1502. This new safety informationwill be reflected in updated productlabelling.

Reference: FDA Alert, 12 December 2007 athttp://www.fda.gov/medwatch/report/

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Canada Vigilance: a new nameand databaseHealth Canada is pleased to announceCanada Vigilance as the new name forthe Canadian Adverse Drug ReactionMonitoring Program. The Program is alsoimplementing a new database that willprovide an enhanced capacity for thepostmarketing surveillance of adversereactions (ARs). The Canada Vigilancedatabase will contribute to the ongoingassessment and communication of healthproduct safety information. HealthCanada, through the Canada VigilanceProgram, is responsible for the collectionand assessment of AR reports that havebeen submitted by health professionals orconsumers, either directly or throughMarket Authorization Holders. Since1965, Health Canada has been gatheringinformation on suspected ARs to healthproducts (pharmaceuticals, biologics[e.g., fractionated blood products, andtherapeutic and diagnostic vaccines],natural health products and radiopharma-ceuticals).

Reference: Canadian Adverse ReactionNewsletter, Volume 18(1), January 2008 athttp://www.hc-sc.gc.ca

Desmopressin andhyponatraemiaUnited States of America The Foodand Drug Administration (FDA) hasrequested that prescribing information fordesmopressin includes important newinformation about severe hyponatraemiaand seizures.

Certain patients taking desmopressin areat risk for developing severe hypo-natraemia that can result in seizures anddeath. Children treated with desmo-pressin intranasal formulations for pri-mary nocturnal enuresis (PNE) areparticularly susceptible to severehyponatremia and seizures. As such,desmopressin intranasal formulations areno longer indicated for the treatment ofprimary nocturnal enuresis and shouldnot be used in hyponatraemic patients orpatients with a history of hyponatremia.PNE treatment with desmopressin tabletsshould be interrupted during acute ill-nesses that may lead to fluid and/orelectrolyte imbalance. All desmopressinformulations should be used cautiously inpatients at risk for water intoxication withhyponatremia.

Reference: FDA Alert, 4 December 2007 athttp://www.fda.gov/medwatch/report

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.

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Regulatory Action and News

Influenza virus vaccine:northern hemisphere winterWorld Health Organzation It isrecommended that vaccines for use in the2008-2009 influenza season (northernhemisphere winter) contain thefollowing:

an A/Brisbane/59/2007 (H1N1)-likevirus.

an A/Brisbane/10/2007 (H3N2)-likevirus. (A/Brisbane/10/2007 is a currentsouthern hemisphere vaccine virus).

a B/Florida/4/2006-like virus. (B/Florida/4/2006 and B/Brisbane/3/2007 arecurrent southern hemisphere vaccineviruses).

Reference: Weekly Epidemiological Record,No. 9, 2008, 83, 7788. http://www.who.int/wer

Lumiracoxib-containingmedicines: withdrawalEuropean Union The EuropeanMedicines Agency (EMEA) has recom-mended withdrawal of the marketingauthorizations for all lumiracoxib-contain-ing medicines, because of the risk ofserious side effects affecting the liver.

Lumiracoxib is a nonsteroidal anti-inflammatory drug (NSAID) that belongsto the group COX-2 inhibitors. It is usedfor symptomatic relief in the treatment ofosteoarthritis of the hip and knee.

The liver safety of lumiracoxib has beenmonitored continuously since its launch in2005. In August 2007, the product was

contraindicated for patients with potentialliver problems and advice to doctors thatthey should frequently monitor patientstreated with lumiracoxib for liver reac-tions. More spontaneous reports ofserious liver problems have been re-ceived since then, which have increasedthe concerns regarding hepatic safety forlumiracoxib.

The CHMPs opinion will now be for-warded to the European Commission forthe adoption of a decision.

Reference: Press Release. EMEA/CHMP/579301/2007 13 December 2007www.emea.europa.eu

Thalidomide approved formultiple myelomaEuropean Union The EuropeanMedicines Agency (EMEA) has recom-mended the approval of thalidomide(Thalidomide Pharmion) for the treat-ment of multiple myeloma, a rare cancerof the bone marrow.

The Committee for Medicinal Products forHuman Use (CHMP) concluded that thebenefits of Thalidomide Pharmion incombination with melphalan and pred-nisone outweigh its risks for the first-linetreatment of multiple myeloma for pa-tients over 65 years of age or those whocannot be treated with high-dose chemo-therapy.

Clinical studies have shown that addingThalidomide Pharmion to melphalanand prednisone can prolong survival timeby about 18 months in newly-diagnosedmultiple myeloma patients over 65 yearsof age, as compared to patients whoreceived conventional chemotherapy.

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WHO Drug Information Vol 22, No. 1, 2008Regulatory Action and News

Thalidomide is teratogenic. Because ofthis, the CHMP consulted representativesof thalidomide victims and myelomapatient groups from across the EuropeanUnion to develop measures that caneffectively minimize the risk of foetalexposure to thalidomide and has ap-proved a risk management plan.

Subject to the granting of a marketingauthorization by the European Commis-sion, Thalidomide Pharmion will only beavailable by prescription, and treatmentwill be initiated and monitored by a doctorwho has experience in the treatment ofmultiple myeloma.

Reference: Press Release. Doc. Ref. EMEA/33024/2008, 24 January 2008. http://www.emea.europa.eu

New genetic testfor breast cancerUnited States of America The Foodand Drug Administration has approved atest that helps in assessing the risk oftumour recurrence and long-term survivalfor patients with relatively high-risk breastcancer. The TOP2A FISH pharmDx isthe first approved device to test for theTOP2A (topoisomerase 2 alpha) gene incancer patients.

The TOP2A gene plays a role in DNAreplication. The TOP2A FISH pharmDxtest uses fluorescently labelled DNAprobes to detect or confirm gene orchromosome abnormalities, a technologyknown as fluorescent in situ hybridization(FISH).

The recurrence of cancer depends partlyon certain genes whose activity may bealtered by changes in the number of genecopies in the tumor. Changes in theTOP2A gene in breast cancer cells meanthere is an increased likelihood that thetumor will recur or that long-term survivalwill be decreased.

The test is suitable for breast cancerpatients who are premenopausal or forwhom tumor characteristics, such astumor size or lymph node involvement,suggest a higher likelihood of tumourrecurrence or decreased survival.

Reference: FDA News, 14 January 2008,http://www.fda.gov

Natalizumab for moderate-to-severe Crohn diseaseUnited States of America The Foodand Drug Administration has approvednatalizumab (Tysabri), currently ap-proved for use in treating some forms ofmultiple sclerosis, for the treatment ofmoderate-to-severe Crohn disease inpatients with evidence of inflammationwho have had an inadequate responseto, or are unable to tolerate, conventionalCrohn disease therapies. Crohn diseasepatients using the drug must be enrolledin a special restricted distribution pro-gram.

Natalizumab carries a boxed warning forprogressive multifocal leukoencephalo-pathy (PML), an opportunistic viralinfection that affects the brain and canlead to death or severe disability.

Other serious adverse events that haveoccurred in patients include hypersensi-tivity reactions, such as anaphylaxis andliver injury. Serious opportunistic andother atypical infections have beenobserved in patients receiving immuno-suppressants while on Tysabri. Seriousherpes infections have also been ob-served. Common side effects includeheadache, fatigue, infusion reactions,urinary tract infections, joint and limbpain, and rash.

Reference: FDA News, 14 January 2008,http://www.fda.gov

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First test to detect and identify12 respiratory virusesUnited States of America The Foodand Drug Administration has approved atest that simultaneously detects andidentifies 12 specific respiratory viruses.

The test, called the xTAG RespiratoryViral Panel, is the first test for thedetection and differentiation of influenza Asubtypes H1 and H3. Influenza A is themost severe form of influenza for hu-mans, and has been the cause of majorepidemics. The new panel is also the firsttest for human metapneumovirus (hMPV),newly identified in 2001.

The panel amplifies viral genetic materialfound in secretions taken from the back ofthe throat in patients with possible respi-ratory tract infections. In the test, specificbeads, or microspheres, bind to theamplified viral genetic material. Thebeads are then sorted so that the specificvirus can be identified. Other virusesidentified by the panel:

influenza B - one of three types ofhuman influenza, less severe thaninfluenza A

respiratory syncytial virus subtype A andB (both are leading causes of infantpneumonia and bronchiolitis and oftencontribute to the development of long-term pulmonary disease)

parainfluenza 1, 2 and 3 (all are leadingfactors in croup and the common cold)

rhinovirus (the most common viralinfective agent in humans and a causeof the common cold)

adenovirus (a cause of respiratory tractinfections often similar to strep throat ortonsilitis).

While the test is faster than conventionaltests, it is specific to the dozen viruseslisted and should be used with otherdiagnostics such as patient data, bacterialor viral cultures and X-rays. Positiveresults do not rule out other infection orco-infection and the virus detected maynot be the specific cause of the diseaseor patient symptoms.

Reference: FDA News, 3 January 2008 http://www.fda.gov

Miglustat: withdrawal bymanufacturerEuropean Union The EuropeanMedicines Agency (EMEA) has beenformally notified of the decision to with-draw an application for an extension ofindication for the centrally authorizedmedicine miglustat (Zavesca).

Miglustat was expected to be used for thetreatment of neurological manifestationsin patients with Niemann Pick type Cdisease, a rare inherited neurodegene-rative disease of childhood and adoles-cence. Zavesca is an orphan medicinalproduct.

Zavesca is currently authorized for theoral treatment of mild to moderate type 1Gaucher disease and may be used onlyin the treatment of patients for whomenzyme replacement therapy is unsuit-able.

The Committee for Medicinal Products forHuman Use (CHMP) had given a nega-tive opinion recommending the refusal ofthe type II variation to extend the indica-tion on 18 October 2007. The companyhas stated it will resubmit for this indica-tion in the near future with additionaldata.

Reference: Press Release. Doc. Ref. EMEA/95140/2008, 25 February 2008. http:/www.emea.europa.eu


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Voluntary withdrawal ofclobutinol cough syrup

Singapore Clobutinol (Silomat) waslicenced in Singapore in 1999. It is anorally active non-opioid antitussive agent,and is indicated for the treatment ofirritable, non-productive cough andinflammatory disorders of the airways.

In September 2007, the manufacturervoluntarily withdrew Silomat from theSingapore market as a precautionarymeasure due to concerns of a potentialincreased risk of cardiac arrhythmias thatcould be associated with the activeingredient. Published experimental datahave indicated the potential of clobutinolaffecting the hERG (human ether-a-go-gorelated gene) potassium channels.

Preliminary findings from a recent clinicaltrial with clobutinol in adult healthyvolunteers have shown a prolongation ofthe QTc interval in the ECG. As clobutinolis indicated for a non-serious diseasecondition and in view of the potentiallylife-threatening adverse effects, HSAagreed with the actions of the manufac-turer to withdraw clobutinol from theworldwide market.

A Dear Healthcare Professional Letter(DHCPL) was issued by the company toalert healthcare professionals to thefindings and the decision to recall andsuspend the sales of Silomat.

Reference: Adverse Drug Reaction News,December 2007, Vol.9 No.3, at http://www.hpp.moh.gov.sg.


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Current Topics

Proposed harmonizedrequirements: licensingvaccines in the AmericasA Vaccines Working Group of the Pan-American Network on Drug RegulatoryHarmonization (PANDRH) was estab-lished in March 2005 to develop harmo-nized documents and approaches to thelicensing of vaccines in the Americas.

At its first meeting, held in Panama, theWorking Group, made up of nationalregulatory authorities of seven countries(Argentina, Brazil, Canada, Chile, Cuba,Mexico and Venezuela), proposed thedevelopment of harmonized registrationrequirements for vaccines for human use.Information derived from a survey con-ducted by the Pan-American HealthOrganization (PAHO) of licensing require-ments for vaccines in 16 countries of theregion was reviewed in detail.

A second meeting of the Working Group,held in December 2005 in Venezuela,proceeded to identify and agree upon thebasic requirements and data which needto be submitted by a manufacturer to aNational Regulatory Authority in supportof an application for licensing. At theGroups third meeting, held in Canada,the first draft of a document on harmo-nized requirements for the licensing ofvaccines in the region was reviewed anddeveloped further, as was an accompany-ing guideline on the preparation of appli-cations.

The two draft documents are: ProposedHarmonized Requirements for Licensingof Vaccines in the Americas, and anaccompanying attachment entitledGuidelines for Preparation of Applica-tions. They are available in Spanish, as

well as in English and French versions.The information required is structuredusing the International Conference onHarmonization (ICH) Common TechnicalDocument (CTD), specifically adapted tothe market authorization of vaccines, andcomplemented by Recommendations forvaccines published in the World HealthOrganizations Technical Report Series.Because of their special characteristics,vaccines should always be considered asnew products for the purpose of marketauthorization.

The purpose of these documents is toachieve greater harmonization in theinformation submitted in the applicationfor market authorization of vaccines forhuman use. They apply to all vaccines tobe registered, regardless of whether theyare manufactured in the country of originor not. Since the same information shouldbe submitted to all countries in theAmericas, the licensing process andultimately the availability of vaccinesshould be facilitated. It is expected thathaving a common document will alsobenefit the region by making more effi-cient use of technical and financialresources, as well as facilitating mutualrecognition processes where appropriate.

These draft documents are posted on thePAHO (http://www.paho.org) as well asthe Health Canada (http://www/hc-sc.gc.ca) websites for the purpose ofinviting comments and suggestions onthe proposals . Comments proposingmodifications to the texts should beaddressed to Dra Maria de los AngelesCortes, Regional Advisor on Vaccinesand Biologicals, THR/EV, Pan AmericanHealth Organization, 525 23rd St. NW.Washington DC. 20037-2895 [email protected]

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Sixteen types of counterfeitartesunate circulating inSouth-east AsiaIn the late 1990s counterfeits of artesu-nate, a vital life-saving antimalarial drug,were discovered circulating in South-eastAsia. Surveys have suggested that 38% 53% of shop-bought artesunate in main-land South-east Asia are fake and havebeen reported from Cambodia, thePeoples Republic of China, Lao PDR,Myanmar, Thai/Myanmar border, andVietnam. The diversity of different typesof fake hologram have increased and now16 are recognized.

An article has recently been published inPLoS Medicine which includes an up-dated warning sheet describing theseholograms and stickers Greater action bygovernments and international organiza-tions is strongly urged to combat thisunder-recognized and serious publichealth problem.

Reports of counterfeit artemisinin deriva-tives and ACTs in Africa are also ex-tremely alarming and could underminethe effectiveness of these medicines formalaria control in Africa.

References

1. A Collaborative Epidemiological Investiga-tion into the Criminal Fake Artesunate Trade inSouth East Asia. PLoS Medicine e32doi:10.1371/journal.pmed.0050032. http://medicine.plosjournals.org or: http://www.tropicalmedicine.ox.ac.uk

3. The Pharmacy and Poisons Board, Repub-lic of Kenya Ministry of Health. 2007. Availableat: http://www.pharmacyboardkenya.org.

4. Fake antimalarials in Southeast Asia are amajor impediment to malaria control: multina-tional cross-sectional survey on the preva-lence of fake antimalarials. Trop Med IntHlth, 2004 9:12411246

5. Fake artesunate in southeast Asia. Lancet,2001 357:19481950.

6. USP (2005) Fake antimalarials found inYunnan Province, China, 2004. Available at:http://www.uspdqi.org/pubs

7. AED-SATELLIFE. Center for Health Infor-mation and Technology. http://www.healthnet.org

Eastern MediterraneanMinisters tackle highmedicines pricesMedicines prices, availability, affordabilityand other component issues were re-cently discussed by delegates at ameeting of the Regional Committee forWHOs Eastern Mediterranean Region,held in Cairo 2023 October 2007.

Results were presented from 11 surveysundertaken in the region using the WHO/HAI medicine price measurement meth-odology.

Key findings showed:

Substantial differences in governmentprocurement prices across countries inthe region.

Government purchasing of expensiveoriginator brands, as well as cheapergenerics, in all but 3 countries. Onaverage, originator brands were about 3times more expensive than generics.Prices of generics were often high.

Availability in public sector facilities wasvery poor e.g. 16 of the 35 surveyedmedicines were not found in any outletsurveyed in Yemen, and 23 of 29medicines were not found in over 50%of the outlets in Pakistan.

Excessive prices in the private sector fororiginator brands and lowest pricedgenerics, e.g. Sudanese patients werepaying 18 times international referenceprices for originator brands. Lowestpriced generics were over 5 times thereference prices in most countries.

Current Topics

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Most treatments purchased in theprivate sector were unaffordable (basedon the salary of the lowest paid un-skilled government worker).

Some countries were applying taxes toessential medicines.

A lengthy discussion followed with com-ments from delegates of 16 countries.They acknowledged the many problemsrelated to medicines prices in both thepublic and private sectors. Many alsonoted that the TRIPS Agreement hadcontributed to rising prices and dimin-ished access to medicines, especially indeveloping countries.

Various policy and programme optionswere mentioned including the increaseduse of quality generics to improve afford-ability, regressive mark-ups to encouragethe dispensing of lower priced generics,pooled procurement, greater transpar-ency and the sharing of price information.A number of options were proposed forcountries to consider to reduce prices.Countries were urged to develop, imple-ment and enforce sound evidence-basedpolicies and programmes and monitortheir impact, and to ensure medicines areaffordable and available to all.

A resolution was passed that featured theestablishment of a web-based medicinesprices hub in the region to share informa-tion on medicine prices and pricingstructures, as well as best practices inmedicine management. This innovativeapproach is welcomed as it will improveprice transparency and empower govern-ments to negotiate for more favourableprices. The resolution also urged govern-ments to strengthen pricing policies(including public procurement of generics,and enhanced competition amongstsuppliers) and rationalize supply chaincosts in the private sector. WHO EMROresolved to support Members States inthis work including the development ofguidelines on pricing policies and sharinginformation on best practices from otherregions.

References

1. The resolution and the technical paperMedicine prices and access to medicines inthe Eastern Mediterranean region is availableon WHO EMROs website at http://www.emro.who.int/rc54/

2. Survey data is available on HAIs website:http://www.haiweb.org/medicineprices

Current Topics

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The following anatomical therapeutic chemical (ATC) classifications and defineddaily doses (DDDs) were agreed by the WHO International Working Group for DrugStatistics Methodology in 24-25 October 2007. Comments or objections to the de-cisions from the meeting should be forwarded to the WHO Collaborating Centre forDrug Statistics Methodology at [email protected]. If no objections are received, thenew ATC codes and DDDs will be considered final and included in the January2009 issue of the ATC index.The inclusion of a substance in the lists does not implyany recommendation of use in medicine or pharmacy.

ATC/DDD Classification

ATC/DDD Classification (temporary)

ATC level INN/Common name ATC code

New ATC level codes (other than 5th levels):Other cephalosporins J01DIOther diuretics C03XVasopressin antagonists C03XA

New ATC 5th level codes:Alitretinoin D11AX19Azacitidine L01BC07Calcium acetate and mmagnesium carbonate V03AE04Ceftobiprole medocaril J01DI01Clevudine J05AF12Combinations G03GA30Conivaptan C03XA02Eszopiclone N05CF04Etravirine J05AG04Fluorodopa (18F) V09IX05Glycyrrhizic acid A05BA08Hyaluronic acid R01AX09Influenza, live attenuated J07BB03Lubiprostone A06AX03Metformin and vildagliptin A10BD08Nicotinic acid, combinations C10AD52Olmesartan medoxomil and amlodipine C09DB02Paclitaxel poliglumex L01CD03Pramlintide A10BX05Rivaroxaban B01AX06Romidepsin L01XX39Satraplatin L01XA04

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Sugammadex V03AB35Temsirolimus L01XE09Terguride G02CB06Tolvaptan C03XA01Vorinostat L01XX38

INN/common name Previous ATC New ATC

ATC code changes:Benfluorex C10AX04 A10BX06Bupropion N07BA02 N06AX12Methoxyflurane N01AB03 N02BG09Tedisamil C01EB12 C01BD06

New DDDs:

INN/common name DDD Unit Adm.R ATC code

Alfa1 antitrypsin 0.6 g P B02AB02Aliskiren 0.15 g O C09XA02Ambrisentan 7.5 mg O C02KX02Apomorphine 20 mg P N04BC07Aripiprazole 15 mg P N05AX12Betaine 6 g O A16AA06Darunavir 1.2 g O J05AE10Fesoterodine 4 mg O G04BD11Maraviroc 0.6 g O J05AX09Melatonin 2 mg O N05CH01Methoxy polyethyleneglycol-epoetin beta 4 mcg P B03XA03Paliperidone 6 mg O N05AX13Paricalcitol 2 mcg O A11CC07Prulifloxacin 0.6 g O J01MA17Rufinamide 1.4 g O N03AF03Sitagliptin 0.1 g O A10BH01Stiripentol 1 g O N03AX17Telbivudine 0.6 g O J05AF11


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The following anatomical therapeutic chemical (ATC) classifications and defineddaily doses (DDDs) were agreed by the WHO International Working Group for DrugStatistics Methodology in March 2007. They will be included in the January 2008issue of the ATC index. The inclusion of a substance in the lists does not imply anyrecommendation of use in medicine or pharmacy. The WHO Collaborating Centrefor Drug Statistics Methodology can be contacted at [email protected]


ATC/DDD Classification (final)


New ATC level codes (other than 5th levels):Melatonin receptor agonists N05CH

New ATC 5th level codes:Aliskiren and hydrochloro thiazide C09XA52Azithromycin S01AA26Diphtheria-hemophilus influ- enzae B-pertussis-tetanus- hepatitis B-meningococcus A CJ07CA13Lacosamide N03AX18Maraviroc J05AX09Nitazoxamide P01AX11Raltegravir J05AX08Ramelteon N05CH02Risedronic acid, calcium and colecalciferol, sequential M05BB04Sitimagene ceradenovec L01XX37Tafluprost S01EE05

Change of ATC codes:

INN/common name Previous ATC New ATC

Melatonin N05CM17 N05CH01

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New DDDs:

INN/common name DDD Unit Adm.R ATC code

Argatroban 0.2 g P B01AE03Carbetocin 0.1 mg P H01BB03Dexrazoxane 1.5 g P V03AF02Exenatide 15 mcg P A10BX04Levetiracetam 1.5 g P N03AX14Lumiracoxib 0.1 g O M01AH06Nitazoxanide 1 g O P01AX11Phentolamine 1 mg P G04BE05Risedronic acid, calcium and colecalciferol, sequential 5 mg1 O M05BB04Sitaxentan 0.1 g O C02KX03Sodium phenyl- butyrate 20 g O A16AX03

1 refers to risedronic acid


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Consultation Document

The International Pharmacopoeia

CYCLOSERINUMCYCLOSERINE

Draft proposal for the International Pharmocopoeia (November 2007).Please address any comments to Quality Assurance and Safety: Medi-cines, PSM, World Health Organization, 1211 Geneva 27, Switzerand.Fax +4122 791 4730 or e-mail to [email protected]

C3H6N2O2

Relative molecular mass. 102.1

Chemical name. (R)-(+)-4-Amino-3-isoxazolidinone; (R)-4-aminoisoxazolidin-3-one;CAS Reg. No. 68-41-7.

Other name. Orientomycin, PA-94, 106-7, Closina, Farmiserina, Micosetina,Oxamycin, Seromycin.

Description. A white or pale yellow, crystalline powder.

Solubility. Freely soluble in water; slightly soluble in methanol R and propylene glycolR; very slightly soluble in ethanol (~750 g/l) TS; practically insoluble in chloroform Rand in ether R.

Category. Antibacterial drug.

Storage. Cycloserine should be kept at a temperature between 2 and 8 C in atightly closed container.

ONH

NH2H

O

31

WHO Drug Information Vol 22, No. 1, 2008 Consultation Document

Additional informationCycloserine is slightly hygroscopic and deteriorates upon absorbing water. Its solutionis dextrorotatory.

REQUIREMENTS

Definition. Cycloserine is an analogue of the amino acid D-alanine with broad-spectrum antibiotic and glycinergic activities produced by Streptomyces garyphalusand S. orchidaceus or obtained by synthesis.

Cycloserine contains not less than 98.0% and not more than 100.5% of C3H6N2O2,calculated with reference to the dried substance.

Identity tests

Either test A, or tests B and C may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infra-red region. The infrared absorption spectrum is concordant with the spectrum ob-tained from cycloserine RS or with the reference spectrum of cycloserine.

B. Dissolve about 1 mg in 10 ml of sodium hydroxide (0.1 mol/l) VS. To 1 ml of result-ing solution add 3 ml of acetic acid (~60 g/l) TS and 1 ml of recently prepared mixtureof equal volumes of a 40 mg/ml solution of sodium nitroprusside R and sodium hy-droxide (~200 g/l) TS; a blue colour is developed gradually.

C. The absorption spectrum of a 25 g/ml solution in hydrochloric acid (0.1mol/l) VS,when observed between 215 nm and 360 nm, exhibits a maximum at about 219 nm;the specific absorbance (A

1cm 1%) is between 327 and 361.

Specific optical rotation. Use a 50 mg/ml solution in sodium hydroxide (~80 g/l) TSand calculate with reference to the dried substance; []D 20 C = +108 to +114.

Heavy metals. Use 2.0 g for the preparation of the test solution as described under2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals contentaccording to Method A; not more than 10 g/g.

Sulfated ash. Not more than 5.0 mg/g.

Loss on drying. Dry at 60 C under reduced pressure (not exceeding 0.6 kPa orabout 5mm of mercury) for 3 hours; it loses not more than 10 mg/g.

pH value. pH of a 100 mg/ml solution in carbon-dioxide-free water R, 5.5-6.5.

Related substancesCarry out the test as described under 1.14.4 High performance liquid chromatography,using a stainless steel column (25 cm x 4.6 mm) packed with base-deactivatedoctadecylsilyl silica gel for chromatography R (5 m).

Mobile phase A: 4 volumes of acetonitrile R, 70 volumes of 0.02 mol/l sodiumoctanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 16 volumes ofpurified water.

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WHO Drug Information Vol 22, No. 1, 2008Consultation Document

Mobile phase B: 17 volumes of acetonitrile R, 70 volumes of 0.02 mol/l sodiumoctanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 3 volumes ofpurified water.

Prepare the sodium octanesulfonate solution by dissolving 4.7 g of sodiumoctanesulfonate R in 1000 ml of purified water.

Prepare the phosphate buffer pH 2.8 by dissolving 27.2 g of potassium dihydrogenphosphate R in 800 ml of purified water, adjust the pH to 2.8 by adding phosphoricacid (~20 g/l) TS and dilute to 1000 ml with purified water.

Use the following conditions for gradient elution:

Time Mobile phase A Mobile phase B Comments(min) (% v/v) (% v/v)

0 16 100 0 Isocratic16 18 100 to 0 0 to 100 Linear gradient18 22 0 100 Isocratic22 24 0 to 100 100 to 0 Return to initial conditions24 30 100 0 Isocratic re-equilibration

Prepare the following solutions using mobile phase A as diluent. For solution (1) use0.5 mg of the test substance per ml. For solution (2) dilute a suitable volume of solu-tion (1) to obtain a concentration equivalent to 0.5 g of cycloserine per ml.

For the system suitability test: prepare solution (3) by diluting a suitable volume ofsolution (1) to obtain a concentration equivalent to 25 g of cycloserine per ml, heatcarefully in a boiling water-bath for 30 minutes.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectro-photometer set at a wavelength of 219 nm.

Maintain the column temperature at 45 C.

Inject 50 l of resolution solution. The test is not valid unless the resolution betweenthe principal peak and the large degradation peak with a relative retention of about 3.2is not less than 35. If necessary adjust the amount of acetonitrile in mobile phase A.

Inject alternatively 50 l each of solutions (1) and (2).

In the chromatogram obtained with solution (1), the area of any peak, other than theprincipal peak, is not greater than twice the area of the principal peak obtained withsolution (2) (0.2%). The sum of the areas of all peaks, other than the principal peak, isnot greater than five times the area of the principal peak obtained with solution (2)(0.5%). Disregard any peak with an area less than 0.5 times the area of the principalpeak in the chromatogram obtained with solution (2) (0.05%).

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AssayDissolve about 0.1 g, accurately weighed, in 5 ml of water. Add 75 ml of 2-propanol Rand titrate with carbonate-free sodium hydroxide (0.1 mol/l) VS using thymolphthalein/ethanol TS as indicator. Perform a blanc determination and make any necessarycorrection.

Each ml of sodium hydroxide (0.1 mol/l) VS is equivalent to 10.21 mg of C3H6N2O2.

CYCLOSERINI CAPSULAECYCLOSERINE CAPSULES

Draft proposal for the International Pharmocopoeia (November 2007).Please address any comments to Quality Assurance and Safety: Medi-cines, PSM, World Health Organization, 1211 Geneva 27, Switzerand.Fax +4122 791 4730 or e-mail to [email protected]

Category. Antibacterial drug.

Storage. Cycloserine capsules should be kept in a tightly closed container and storedat a temperature between 2 to 8C.

Additional information. Strength in the current WHO Model list of essential medi-cines: 250 mg.

REQUIREMENTS

Comply with the monograph for Capsules.

Definition. Cycloserine capsules contain Cycloserine. They contain not less than90.0% and not more than 110.0% of the amount of C

3H

6N

2O

2.stated on the label.

Manufacture. The manufacturing process and the product packaging are designedand controlled so as to minimize the moisture content of the capsules. They ensurethat, if tested, the contents of the capsules would comply with a loss on drying limit ofnot more than 20 mg/g when determined by drying a quantity of the capsules contain-ing 0.1 g of cycloserine for 3 hours under reduced pressure (not exceeding 0.6 kPa orabout 5 mm of mercury) at 60 C.

Identity tests

Either tests A or tests B and C may be applied.

A. Examine the chromatograms obtained in the assay. The principal peak in thechromatogram obtained with the test solution is similar in retention time to the principalpeak in the chromatogram obtained with the reference solution.

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WHO Drug Information Vol 22, No. 1, 2008Consultation Document

B. Shake a quantity of the contents of the capsules equivalent to 10 mg of cycloserinewith 100 ml of sodium hydroxide (~40 g/l) TS and filter. To 1 ml of the filtrate add 3 mlof acetic acid (~60 g/l) TS and 1 ml of recently prepared mixture of equal volumes of a40 mg/ml solution of sodium nitroprusside R and sodium hydroxide (~200 g/l) TS; ablue colour is developed gradually.

C. The absorption spectrum of the solution obtained in the assay, when observedbetween 215 nm and 360 nm, exhibits a maximum at about 219 nm.

Related substancesCarry out the test as described under 1.14.4 High performance liquid chromatography,using a stainless steel column (25 cm x 4.6 mm) packed with base-deactivatedoctadecylsilyl silica gel for chromatography R (5 m).

Mobile phase A: 4 volumes of acetonitrile R, 70 volumes of 0.02 mol/l sodiumoctanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 16 volumes ofpurified water.

Mobile phase B: 17 volumes of acetonitrile R, 70 volumes of 0.02 mol/l sodiumoctanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 3 volumes ofpurified water.

Prepare the sodium octanesulfonate solution by dissolving 4.7 g of sodiumoctanesulfonate R in 1000 ml of purified water.

Prepare the phosphate buffer pH 2.8 by dissolving 27.2 g of potassium dihydrogenphosphate R in 800 ml of purified water, adjust the pH to 2.8 by adding phosphoricacid (~20 g/l) TS and dilute to 1000 ml with purified water.

Use the following conditions for gradient elution:

Time Mobile phase A Mobile phase B Comments(min) (% v/v) (% v/v)

0 16 100 0 Isocratic16 18 100 to 0 0 to 100 Linear gradient18 22 0 100 Isocratic22 24 0 to 100 100 to 0 Return to the initial conditions24 30 100 0 Isocratic re-equilibration

Prepare the following solutions using mobile phase A as diluent. For solution (1) mixthe contents of 20 capsules and transfer a quantity equivalent to about 50 mg ofcycloserine, dissolve, dilute to 100 ml and filter. For solution (2) dilute a suitablevolume of solution (1) to obtain a concentration equivalent to 0.5 g of cycloserine perml.

For the system suitability test: prepare solution (3) by diluting a suitable volume ofsolution (1) to obtain a concentration equivalent to 25 g of cycloserine per ml, heatcarefully in a boiling water-bath for 30 minutes.

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Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectro-photometer set at a wavelength of 219 nm.

Maintain the column temperature at 45 C.

Inject 50 l of solution (3). The test is not valid unless the resolution between theprincipal peak and the large degradation peak with a relative retention of about 3.2 isnot less than 35. If necessary adjust the amount of acetonitrile in mobile phase A.


In the chromatogram obtained with solution (1), the area of any peak, other than theprincipal peak, is not greater than four times the area of the principal peak obtainedwith solution (2) (0.4%). The sum of the areas of all peaks, other than the principalpeak, is not greater than ten times the area of the principal peak obtained with solution(2) (1.0%). Disregard any peak with an area less than 0.5 times the area of the princi-pal peak in the chromatogram obtained with solution (2) (0.05%).

AssayEither method A or method B may be applied.

A. Determine by High performance liquid chromatography as described in the test forrelated substances with the following modifications.

Prepare solutions as follows. For solution (1) mix the contents of 20 capsules andtransfer a quantity equivalent to about 10 mg of cycloserine, dissolve, dilute to 100 mland filter. For solution (2) dissolve cycloserine RS in mobile phase A to obtain aconcentration of 0.1 mg/ml.


Calculate the content of cycloserine (C3H

6N

2O

2) from the declared content of

C3H

6N

2O

2in cycloserine RS.

B. To a quantity of the mixed contents of 20 capsules equivalent to 0.250 g of

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