77 WHO Drug Information Vol 22, No. 2, 2008 WHO Drug Information Contents World Health Organization Access to Medicines WHO prequalification: progress in 2007 79 Safety and Efficacy Issues Update on safety of heparin 84 Nicorandil-associated ulceration 85 Topiramate and other drugs causing glaucoma 86 Varenicline: serious psychiatric reactions 86 Montelukast : safety review 88 Neurocognitive effects of chemotherapy 89 New MMRV vaccine recommendations 89 Oseltamivir label updated with neuro- psychiatric warning 90 Ketoconazole tablets: risk of hepato- toxicity 90 Alemtuzumab: infection-related deaths 91 Mycophenolate mofetil: progressive multifocal leukoencephalopathy 91 Modafinil: serious rash and psychiatric symptoms 92 Moxifloxacin: serious hepatic and skin reactions 92 Rimonabant: depression; psychiatric reactions 93 Exenatide: risk of acute pancreatitis 94 Zanamivir: neuropsychiatric events 94 Inosine ponophosphate dehydrogenase inhibitors: congenital anomalies 94 Strontium ranelate : life-threatening allergic reactions 95 Lapatinib and hepatoxicity 96 Telbivudine and peripheral neuropathy 96 International Nonproprietary Names International Nonproprietary Names for monoclonal antibodies: IFPMA proposal 97 Regulatory Action and News Dydrogesterone withdrawn for commercial reasons 108 Enoxaparin contamination: batches recalled 109 Recombinant antihemophilic factor approved 110 Rotavirus vaccine approved 111 New version of genetically engineered Factor VIIa approved 111 International Pharmacopoeia Role of The International Pharmacopoeia in quality assurance 113 Proposed International Nonproprietary Names: List 99 121
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WHO Drug InformationContents
World Health Organization
Access to MedicinesWHO prequalification: progress
in 2007 79
Safety and Efficacy IssuesUpdate on safety of heparin 84Nicorandil-associated ulceration 85Topiramate and other drugs causing
WHO prequalification:progress in 2007The Prequalification Programme formedicinal products is a service providedby the World Health Organization (WHO)to facilitate access to medicines that meetinternational unified standards of quality,safety and efficacy for HIV/AIDS, malaria,tuberculosis and reproductive health.Work is carried out through:
• stringent assessment of pharmaceuticalproduct dossiers;
• inspection of pharmaceutical manufac-turing sites (both for finished dosageforms and active pharmaceutical ingre-dients) and contract research organiza-tions (CROs);
• prequalification of pharmaceuticalquality control laboratories (QCLs); and
• advocacy for medicines of assuredquality.
The Programme also provides high-leveltraining, capacity building and technicalassistance to stakeholders from both theprivate and public sectors. The Bill &Melinda Gates Foundation as well asUNITAID are currently the principlefinancial supporters of the WHO Prequali-fication Programme.
New prequalified productsTwenty-one products were added to the listof prequalified medicines in 2007 – all butone being generics. The number of pre-qualified medicines now stands at 156.A major achievement in 2007 was theprequalification of five new products totreat tuberculosis and three antimalaria
products. This offers a considerableincrease in the choice of prequalifiedmedicines for these diseases.The total number of prequalified productsin 2007 was the lowest since 2001. Themain reasons for this are:
• decreasing number of new submissions;• submitted dossiers did not include
sufficient evidence to prove quality,safety and efficacy of products; and
• little additional substantive evidencewas provided in support of dossierspreviously submitted.
Certain product groups are urgently inneed of expansion to increase availabletreatment options, i.e., second-line anti-tuberculosis and paediatric antiretroviralcombination products. In 2007, only oneantituberculosis treatment submissionand two new submissions for paediatricantiretrovirals were presented for WHOPrequalification.
In the past year, the number and qualityof product dossiers submitted for assess-ment was very uneven. Conversely, aconsiderable number of new applicantsapproached WHO. However, most of thenewcomers have limited or no experiencein production to international standardsand are not yet capable of generating therequired evidence. The manufacturingconditions and quality specificationspresented for reproductive health andantimalarial products were particularlypoor.
Efforts needed to reachprequalification statusThe products prequalified in 2007 were,on average, under assessment and
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adjustment for two years before attainingcompliance with international standards.During this period, eight to nine assess-ment sessions and five inspections wererequired before the ultimate positiveconclusions were reached. Thus, consid-erable time and resources are neededfrom applicants, as well as dedication toimplementing the necessary correctiveaction, to meet international qualitystandards.All involved stakeholders agree andunderstand that expansion of the list ofprequalified medicines can only berealized if capacity building and technicalassistance activities increase in resource-limited countries. Therefore, such actionshave become one of the core objectivesof the Prequalification Programme.
Maintaining the listof prequalified medicinesInclusion in the list does not mean thatthe prequalified status of a product lastsforever. All prequalified medicines haveto be checked regularly in order to ensurethat any changes undertaken by manu-facturers do not undermine the quality,safety and efficacy of the products.
In order to reach this objective, WHOassesses variations in manufacture andcarries out random quality control tests ofprequalified medicines, as well as re-inspections of manufacturing sites. As theprequalified products list is constantlygrowing, maintaining and updating theinformation becomes increasingly impor-tant in order to ensure the quality andsafety of the medicines.
The WHO Prequalification Programme:
• Prequalified a total of 21 medicinal products, including 5 anti-tuberculosis and 3anti-malarial medicines
• Intensified and widened the scope of prequalification of quality control laborato-ries
• Doubled the number of training workshops for capacity building in resource-limited countries
• Organized 10 technical assistance missions for manufacturers to support im-provements in the quality of their products
• Planned and implemented a comprehensive sampling and testing programme• Developed guidelines and standards to facilitate global quality assurance activi-
ties, including pharmacopoeial monographs and chemical reference substances• Undertook special efforts to facilitate development of paediatric formulations• Recruited additional full-time staff to maintain sustainability and improve perform-
ances of prequalification process• Streamlined the process between receiving a complete dossier and the first
assessment or inspection of manufacturing sites• Developed tools to increase transparency and allow monitoring of the prequalifi-
cation process
Summary of activities in 2007
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Capacty buildingfor regulatory authoritiesRecognizing the importance of capacitybuilding through training and hands-onpractice, the WHO Prequalificationprogramme organized nine trainingcourses in 2007 and co-organized fourtraining activities together with otherpartners in nine different countries.These exercises offered tuition on gen-eral or specific technical issues for larger
groups, including staff from regulatoryagencies and quality control laboratories,and for manufacturers. Such trainingincludes group sessions as well ascommunication between involved parties,such as manufacturers and the present-ers, who are themselves part of theassessment or inspection teams workingwith the Prequalification Programme.In 2007, four national regulatory expertsfrom Ethiopia, Tanzania, Uganda and
Training Workshops organized in 2007
Date Location Content of training
16–20 April Cape Town, Pharmaceutical development with aSouth Africa focus on paediatric medicines
6–7 June Cairo, Egypt WHO Prequalification Programme – introduction for EMRO countries
25–27 June Kiev, Ukraine Dissolution, pharmaceutical productinter-changeability and biopharma-ceuticals classification system
10–14 September Dar Es Sallam, Assessment of dossiers based onTanzania WHO Prequalification guidelines for
staff of East Africa Communitynational medicine regulatory authorities
15–19 October Tallinn, Estonia Pharmaceutical development with afocus on paediatric medicines
5–9 November Jiaxing, China Pharmaceutical quality, Good Manufacturing Practice and bioequivalence witha focus on anti-tuberculosis products
26–29 November Rabat, Morocco Quality assurance, Prequalificationand quality control in quality controllaboratories
10–14 December Dakar, Senegal Good Manufacturing Practice trainingcourse for countries of francophoneAfrica
5–7 December Dar Es Sallam, Quality assurance, Prequalification andTanzania development of standards in quality
control laboratories
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Zimbabwe were offered a full-time posi-tion at WHO for three months. Theobjective was to create a rotationalnetwork between WHO and resource-limited countries, increase capacitybuilding of national regulatory authoritiesand enhance information exchangebetween all parties.
Technical assistanceto manufacturersSince 2006, the WHO Prequalificationprogramme has provided coordinatedtechnical assistance aimed at resolvingspecific practical problems encounteredby manufacturers or quality controllaboratories. Assistance is given by aqualified professional in the form of anaudit and training in technical or regula-tory areas.In 2007 alone, the WHO Prequalificationprogramme provided a total number of 13technical assistance sessions in ninedifferent countries, compared to six infour countries in 2006.To avoid conflict of interest, WHO uses apool of specialists working either fornonprofit organizations or acting asindividual technical consultants unrelatedto prequalification activities. Theseexperts are not involved in assessmentsand inspections.
Dossier assessmentsand expert adviceIn 2007, six assessment sessions wereorganized at the UNICEF Supply Divisionin Copenhagen where the product dossi-ers are received and stored. In total, 39external assessors from both well andless resourced regulatory authoritiesparticipated in the assessment sessions.It is worth noting that regulators from theWHO Africa Region have been especiallyactive in the process.In addition to regular assessment acti-vities, considerable increase in expertscientific advice provided to applicantswas observed in 2007 – a total of 16bioequivalence study protocols werereviewed, with more than 80 bioequiva-lence queries answered, and 35 separatequality issues handled by the respectiveexpert panels.
InspectionsA total of 45 inspections were carried outin seven different countries in 2007, with35 taking place in India. As in the previ-ous year, considerable assistance withinspections was received from nationalinspectorates belonging to The Pharma-ceutical Inspections Convention andPharmaceutical Inspection CooperationScheme (jointly referred to as PIC/S). Asin 2006, France, was the leading countryin terms of providing inspection support.
Date Location Content of technical assistance6–9 February Ukraine Stability studies and GMP5–10 March China GMP of manufacture under aseptic conditions26 March – 2 April Cambodia GMP of packaging combination products1–5 May Zimbabwe GMP of antiretroviral products20–26 May India Manufacturing process validation and GMP17–29 July Cambodia GMP of packaging combination products23–29 August Bangladesh Pharmaceutical engineering and GMP04–09 November Zimbabwe GMP of antiretroviral products17–21 December India Manufacturing process validation and GMP17–22 December China GMP of manufacture under aseptic conditions
Technical assistance organized by WHO Prequalification Programme in 2007
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Prequalification of qualitycontrol laboratoriesOne laboratory was prequalified in 2007,while 12 laboratories expressed interestin prequalification but only seven submit-ted the required information file. TheProgramme carried out six pre-audit visitsand inspectors concluded that all appli-cants needed training and technicalassistance.
Strengthening andtransparency of activitiesIn January 2007, there were five full-timeprofessional staff members working forthe WHO Prequalification Programme —a number that increased to 12 by the endof the year. A database to log and trackdossier assessment and inspections wasdeveloped and became operational in2007.
Developments to the website at http://www.who.int/prequal include:
• creation of a public tool to monitordossier status of products currentlyunder evaluation;
• more and better guidance for applicants;• new invitations to manufacturers of HIV,
antimalaria, antituberculosis and repro-ductive health products;
• publication of the annual report in sixlanguages;
• creation of a section in Chinese toaccommodate the translated documentson prequalification; and
• creation of a searchable and custom-ized registry of prequalified medicines.
Dossier AssessmentAssessment sessions in Copenhagen 6Total number of assessment days 42Total number of assessment reports 463Assessment reports on HIV/AIDS products 298Assessment reports on TB products 100Assessment reports on malaria products 54Assessment reports on reproductive health products 11
InspectionsManufacturing sites of finished product manufacturers 26Manufacturing sites of active pharmaceutical ingredients 6Contract research organizations 13National pharmaceutical quality control laboratories 1
Prequalification assessment and inspection statistics: 2007
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Safety and Efficacy IssuesUpdate on safety of heparinWorld Health Organization — On 17January 2008, Baxter Healthcare Corpo-ration began voluntary recall of nine lotsof heparin sodium in the USA. The ad-verse events are described as acuteallergic-type reactions and have beendocumented by the US Centers forDisease Control (CDC) (1). The numberof recent adverse reactions associatedwith the Baxter heparin preparations isover 700, including 19 deaths. The USFood and Drug Administration (FDA) andBaxter are conducting an investigationinto these clusters of adverse reactionreports.The active pharmaceutical ingredient(API) for the batches of heparin associ-ated with adverse reactions originatedfrom the Scientific Protein Laboratories(SPL) Changzhou facility in China. TheFDA investigation included inspections ofthe manufacturing plants in China and theUSA. The FDA’s report of its inspection ofthe Changzhou SPL manufacturing plantwas critical of several aspects of itsprocesses.
The US FDA has found that heparinbatches associated with adverse reac-tions contain 5–20% by weight of a“heparin-like compound which is notheparin” contaminant. The contaminanthas been identified as an oversulfatedchondroitin sulfate (2). The FDA haspublished two screening methods whichcan identify the presence of the heparin-like contaminant oversulfated chondroitinsulfate; one of them involves protonnuclear magnetic resonance (NMR)spectroscopy, and the other involvescapillary electrophoresis (CE). These
tests are now mandatory for batch re-lease of all heparin API preparations inthe USA (3).
In Germany, 80 or more recent cases ofsimilar adverse events (no deaths)relating to specific batches of heparinproducts manufactured by RotexmedicaGmbH have also been reported.Rotexmedia initiated a recall on severalbatches of heparin injection in earlyMarch 2008 (4). The origin of the heparinin these products is the ChangzhouQuianhong Bio Pharma Co. Ltd., China,and the Yantai Dongcheng BiochemicalsCo., China.Further recalls of heparin products fromother suppliers have followed morerecently, in the USA and elsewhere.Heparin is on the WHO Model List ofEssential Medicines, and WHO distrib-utes the 5th International StandardHeparin for measurement of the potencyof unfractionated heparin preparationsaccording to methods outlined in theInternational Pharmacopoeia. OtherWHO International Standards for heparinare the low molecular weight heparinstandards for both biological activity andfor molecular weight calibration. All theWHO International Standards for heparinhave been found to be free of contamina-tion according to criteria defined in themost recent version of the FDA’s “Impu-rity evaluation of Heparin Sodium byNMR Spectroscopy” (5).
Adverse reactions to heparin productsshould be reported to the appropriateNational Regulatory Authority. WHO hasa programme on International DrugMonitoring, co-ordinated by the UppsalaMonitoring Centre, Uppsala, Sweden (6).
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WHO can offer advice and help to na-tional regulatory authorities in countrieswith limited resources for the characteri-zation of suspect batches of heparin API,including testing by NMR and CE asrecommended by the FDA, through theWHO Collaborating Centre for BiologicalStandards.
The WHO Expert Committee on Specifi-cations for Pharmaceutical Preparations,which oversees the activities related toThe International Pharmacopoeia, to-gether with the WHO Expert Committeeon Biological Standardization, will reviewthe above information as well as appropri-ate validated tests for impurity evaluationof unfractionated heparin.
7. World Health Organization. http://www.who.int/medicines and http://www.who.int/biologicals
Nicorandil-associatedulcerationAustralia — Nicorandil (Ikorel®) is asynthetic nicotine derivative, whichcauses arterial and venous dilatation.It is indicated for the treatment of chronicstable angina pectoris at a dose of10–20 mg daily.Nicorandil-associated ulceration wasinitially reported in oral mucosa (1).
Subsequently, ulceration has beenreported at other sites, including anal,perianal, vulvar, perivulvar, gastrointesti-nal and parastomal tissues, and variouscutaneous sites, including the loweranterior leg, natal cleft, umbilicus andareas affected by flexural psoriasis;ulcers may occur at multiple sites (2, 3).The reaction occurs rarely, appears to bedose-related and the time to ulcer onsetmay be up to months after startingnicorandil. The ulcers are persistent,deep and ‘punched out’ in appearance,with non-specific inflammatory histology.Their pathogenesis remains unclear.
Unless nicorandil is recognized as apotential cause and the drug withdrawn,the ulcers are likely to persist despiteother treatment. Conservative ulcermanagement is ineffective and surgerymay exacerbate the tissue damage.Typically any discomfort resolves quicklyafter nicorandil is withdrawn, althoughhealing may take considerably longer.
Seven of 51 reports received by theTherapeutic Goods Administration (TGA)for nicorandil describe ulceration. Six ofthe seven reports described tongue ormouth ulcers. Failure to recognizenicorandil-induced ulceration can lead tosubstantial morbidity, inappropriateinvestigation and treatment, and unnec-essary surgery.Extracted from Australian Adverse DrugReactions Bulletin, Volume 27, Number 2,April 2008
References
1. Reichert S et al. Major aphthous stomatitisinduced by nicorandil. Eur J Dermatol 1997; 7:132–3.
2. Watson A et al. Nicorandil induced analulceration. Lancet 2002; 360: 546–7.
3. McKenna DJ et al. Nicorandil-induced legulceration. Br J Dermatol 2007; 156: 394–6.
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Topiramate and other drugscausing glaucomaAustralia —Topiramate is an antiepilepticindicated for either monotherapy or add-on therapy in adults and in children agedtwo years and over; and for the prophy-laxis of migraine in adults. It has anauthority required Pharmaceutical Ben-efits Schedule (PBS) listing for thetreatment of epilepsy, and was recentlyPBS-listed as a third-line agent for theprophylaxis of migraine.
Topiramate has been rarely associatedwith the development of angle-closureglaucoma. To date, the TherapeuticGoods Administration (TGA) has received11 reports of glaucoma associated withthe use of topiramate out of 175 totalreports for the drug, Five patients hadrecovered at the time of reporting, threehad not yet recovered, and recoverystatus was unknown in the other three.
Although all of these cases have involvedadults, a literature report has describedbilateral angle-closure glaucoma present-ing as headache, nausea, and fatigue ina five year old girl 10 days after startingtopiramate (1).A published review of reports of ocularreactions to topiramate included 86 casesof acute glaucoma, 83 of which werebilateral (2). In this series, time to onsetwas one to 49 days after startingtopiramate, with 85% of cases occurringin the first two weeks of treatment.Permanent vision loss was described inseven reports. Topiramate was alsoassociated with a number of other ocularadverse effects, including acute myopia,suprachoroidal effusions, periorbitaloedema, and scleritis (2).
Management of topiramate-inducedglaucoma involves immediate cessationof topiramate and urgent medical treat-ment of the glaucoma as required. Anumber of mechanisms have been
proposed for this reaction, but becausepupillary block is not involved, pilocarpineand iridotomy are generally ineffective.Permanent vision loss can occur if thecondition is not managed appropriately(3). Of note is that migraine itself maycause eye pain and it is important thatnon-migraine causes should be consid-ered in patients treated with topiramatefor migraine, who present with eye pain.
Extracted from Australian Adverse DrugReactions Bulletin, Volume 27, Number 2,April 2008
References
1. Lin J, Fosnot J and Edmond J. Bilateralangle closure glaucoma in a child receivingoral topiramate. Journal of American Associa-tion for Pediatric Ophthalmology and Strabis-mus [JAAPOS] 2003; 7: 66-68.
3. Levy et al. Topiramate-induced bilateralangle-closure glaucoma. Can J Ophthalmol2006; 41: 221-225.
Varenicline: seriouspsychiatric reactionsCanada — Varenicline tartrate(Champix®) has been marketed inCanada since April 2007 and is indicatedfor smoking-cessation treatment in adultsin conjunction with smoking-cessationcounselling (1). The efficacy ofvarenicline in smoking cessation isbelieved to be a result of the drug’s partialagonist activity at the nicotinic acetylcho-line receptor. By binding to thesereceptors, varenicline induces 2 results(2). First, it signals the release ofdopamine and creates similar reinforcingeffects, but not to the full extent thatnicotine does because of its partialbinding of the receptor (2). Second, it actsas a physical antagonist by binding to the
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Case/Patient History of Adverse reaction(s)† Time to Outcome afterage/sex psychiatric onset of discontinuation
* These data cannot be used to determine the incidence of adverse reactions (ARs) be-cause ARs are underreported and neither patient exposure nor the amount of time the drugwas on the market has been taken into consideration.† Terms are listed according to the World Health Organization Adverse Reaction Terminol-ogy (WHOART).‡ Estimated from the beginning of treatment.§ At the time of reporting, the patient was still taking varenicline and had not yet recovered.¶ The onset of depression was after the discontinuation of the drug.** Family history of depression was reported.
Table 1: Summary of reports of aggression, depression and suicidal tendencysuspected of being associated with varenicline submitted to Health Canadafrom 1 April 2007 to 23 Noveber 2007*
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nicotine receptor and by blocking theeffects of nicotine or a nicotine-replace-ment agent (2).Smoking cessation with or without treat-ment is associated with various symp-toms such as depressed mood, insomnia,irritability, frustration or anger, and anxiety(1). From 1 April to 23 November 2007,Health Canada received 107 reports ofadverse reactions (ARs) suspected ofbeing associated with varenicline. Ofthese reports, 46 described psychiatricARs of which 14 reported cases ofaggression, depression or suicidal idea-tion (table 1). The remaining cases ofpsychiatric disorders included ARs suchas amnesia, abnormal dreams, anxiety,insomnia, abnormal thinking and somno-lence.
The impact of a smoking-cessation pro-duct with partial nicotinic-receptor agonistproperties in patients with underlyingpsychiatric illness is unknown, and careshould be taken with these patients (1).Two case reports recently described theexacerbation of schizophrenia in onepatient (3) and a manic episode in apatient with bipolar disorder taking vare-nicline (4).
The Canadian Product Monograph forvarenicline was recently revised toindicate that there have been postmarketreports of depressed mood, agitation,changes in behaviour, suicidal ideationand suicide (1). The product monographstates that not all patients had known pre-existing psychiatric illness and not all hadcompletely discontinued smoking (1).
Extracted from Canadian Adverse Reac-tion Newsletter, Volume 18, Issue 2, April2008
2. Stack NM. Smoking cessation: an overviewof treatment options with a focus on vareni-cline. Pharmacotherapy 2007;27(11): 1550–7.
3. Freedman R. Exacerbation of schizophreniaby varenicline. Am J Psychiatry 2007;164(8):1269.
4. Kohen I, Kremen N. Varenicline-inducedmanic episode in a patient with bipolardisorders. Am J Psychiatry 2007; 164(8):1269–70.
Montelukast : safety reviewUnited States of America — The Foodand Drug Administration (FDA) is investi-gating a possible association between theuse of montelukast (Singulair®) andbehavior/mood changes, suicidality andsuicide. Montelukast is a leukotrienereceptor antagonist used to treat asthmaand symptoms of allergic rhinitis, and toprevent exercise-induced asthma.
Over the past year, the manufacturer hasupdated the prescribing and patientinformation to include the following post-marketing adverse events: tremor (March2007), depression (April 2007), suicidality(October 2007), and anxiousness (Febru-ary 2008).
FDA is working with the manufacturer tofurther evaluate a possible link betweenthe use of Singulair® and behavior/moodchanges, suicidality and suicide. Untilfurther information is available, healthcareprofessionals and caregivers shouldmonitor patients for suicidality or changesin behavior and mood.
Other leukotriene modifying medicationsinclude zafirlukast (Accolate®), which isalso a leukotriene receptor antagonistand zileuton (Zyflo® and Zyflo CR®),which is a leukotriene synthesis inhibitor.FDA is reviewing postmarketing reports ithas received of behavior/mood changes,suicidality and suicide and will assesswhether further investigation is warranted.
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Reference: Information from FDA dated 27March 2008 at http://www.fda.gov/medwatch
Neurocognitive effects ofchemotherapyAustralia —There is growing evidencethat some patients who survive cancercan suffer neurocognitive impairmentafter chemotherapy.
Although the symptoms are generallysubtle and improve after ceasing chemo-therapy, for some survivors the symptomsare sustained and can impact significantlyon their quality of life. Some studies havereported that 15–50% of patients havecognitive impairment after chemotherapyfor solid tumours. Areas most affected areusually attention, concentration, verbaland visual memory and processingspeed.
Studies published in the past few yearsreport that up to 30% of patients withsolid tumours may have cognitive impair-ment before receiving chemotherapy.It is likely that the regimen, dose andduration of chemotherapy influence theincidence and severity of cognitiveimpairment. Studies have found higherrates of cognitive dysfunction in patientsreceiving high doses of chemotherapycompared to those on standard doses.There are no proven interventions toprevent impairment and the mainstay oftherapy is to treat any depression andanxiety.Reference: Australian Prescriber MediaRelease, 4 February 2008 at http://www.tga.gov.au
New MMRV vaccinerecommendationsUnited States of America — On 27February 2008, new information waspresented to the Advisory Committee onImmunization Practices (ACIP) regarding
the risk for febrile seizures among chil-dren aged 12—23 months after adminis-tration of the combination measles,mumps, rubella, and varicella (MMRV)vaccine (ProQuad®). ACIP updatedrecommendations remove ACIP’s previ-ous preference for administering combi-nation MMRV vaccine over separateinjections of equivalent componentvaccines (i.e., measles, mumps, andrubella [MMR] vaccine and varicellavaccine).
The combination tetravalent MMRVvaccine was licensed by the Food andDrug Administration (FDA) on 6 Septem-ber 2005, for use in children aged 12months–12 years (1). MMRV vaccine canbe used in place of trivalent MMR vaccineand monovalent varicella vaccine toimplement the recommended 2-dosevaccine policies for prevention of mea-sles, mumps, rubella, and varicella (1, 2).The first vaccine dose is recommended atage 12–15 months and the second at age4–6 years.
In MMRV vaccine prelicensure studies,an increased rate of fever was observed5–12 and 0–42 days after the first vaccinedose, compared with administration ofMMR vaccine and varicella vaccine at thesame visit (3, 4). Because of the knownassociation between fever and febrileseizures (5), CDC and Merck initiatedpostlicensure studies to better understandthe risk for febrile seizures that might beassociated with MMRV vaccination.
ACIP also recommended establishing awork group to conduct in-depth evaluationof the findings regarding the increasedrisk for febrile seizures after the first doseof MMRV vaccine to present for consid-eration of future policy options. CDC,FDA, and ACIP will communicate updatesand implement further necessary actionsbased on these evaluations (6).
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References
1. CDC. Licensure of a combined live attenu-ated measles, mumps, rubella, and varicellavaccine. MMWR 2005;54:1212—3.
2. CDC. Prevention of varicella: recommenda-tions of the Advisory Committee on Immuniza-tion Practices (ACIP). MMWR 2007;56(No.RR-4).
3. Shinefield H, Black S, Digilio L, et al.Evaluation of a quadrivalent measles, mumps,rubella and varicella vaccine in healthychildren. Pediatr Infect Dis J 2005;24:665—9.
5. Seizures in childhood. In: Kliegman RM,Behrman RE, Jenson HB, Stanton BF, eds.Nelson textbook of pediatrics. 18th ed.Philadelphia, PA: Saunders; 2007:2457—75.
6. Update: Recommendations from theAdvisory Committee on Immunization Prac-tices (ACIP) Regarding Administration ofCombination MMRV Vaccine. MMWR Morbid-ity & Mortality Weekly Report. March 14,2008. 57(10);258-260
Oseltamivir label updated withneuropsychiatric warningUnited States of America —The productlabel for oseltamivir phosphate (Tamiflu®)has been revised to include a warningabout possible neuropsychiatric events.The updated label is based on recom-mendations from the agency’s PediatricAdvisory Committee meeting in Novem-ber 2007.Postmarketing reports indicate that somepatients with influenza who were receiv-ing oseltamivir had delirium and abnormalbehavior, leading to injury and evendeath. Most of the cases occurred inchildren and in Japan. The label nowcautions clinicians to monitor their pa-tients for abnormal behavior when takingthe drug.
Reference: Physician’s First Watch, 5 March2008.
Ketoconazole tablets:risk of hepatotoxicityUnited Kingdom — Following a system-atic review of all available data, themanufacturer of ketoconazole (Nizoral ®)tablets has released information on achange to the Summary of ProductCharacteristics (SmPC) because of a riskof serious hepatotoxicity and the availabil-ity of other effective antifungal treatments.Nizoral® tablets are now indicated for:
• Treatment of dermatophytosis andMalassezia (previously calledPityrosporum) folliculitis that cannot betreated topically because of the site,extent of the lesion or deep infection ofthe skin, in patients resistant to, orintolerant of, fluconazole, terbinafineand itraconazole.
• Treatment of chronic mucocutaneouscandidiasis, cutaneous candidiasis, andoropharyngeal candidiasis that cannotbe treated topically because of the site,extent of the lesion or deep infection ofthe skin, in patients resistant to orintolerant of both fluconazole anditraconazole.
In addition to the existing drug interac-tions and contraindications, several otherdrugs have been added to the list ofcontraindicated drugs, including: diso-pyramide; sertindole; nisoldipine; eplere-none; and ergot alkaloids such as di-hydroergotamine, ergometrine (ergono-vine), ergotamine and methylergometrine(methylergonovine)
Very rare cases of serious hepatic toxic-ity, including cases with a fatal outcomeor requiring liver transplantation, haveoccurred with the use of oral ketocona-zole. Some patients had no obvious riskfactors for liver disease.
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The risk of serious hepatic toxicity in-creases with longer duration of treatment;courses of greater than 10 days shouldonly be given after full consideration ofthe extent of treatment response and therisk benefit of continuing treatment. Liverfunction must be monitored in all patientsreceiving treatment with Nizoral® tablets.
The following Postmarketing adversedrug reactions have been added: anaphy-lactoid and anaphylactic reactions;angioneurotic oedema; adrenocorticalinsufficiency; cirrhosis, the reporting ratebeing very rare.Reference: Communication from Janssen-Cilag Ltd January 2008 \\mhralonfs01\home$\tilstonec\Website\Feb 2008\Nizoral DDL.docon the Medicines and Healthcare productsRegulatory Agency (MHRA) website at http://www.mhra.gov.uk/Safetyinformation
Alemtuzumab: infection-related deathsUnited Kingdom — Bayer ScheringPharma AG and Genzyme Europe BVhave informed physicians of six infection-related deaths, reported from a trial(CALGB10101) in which previouslyuntreated, symptomatic B-cell chroniclymphocytic leukemia (CLL) patients weretreated with fludarabine and rituximabfollowed by alemtuzumab for remissionconsolidation.
Alemtuzumab (MabCampath®) is ap-proved for the treatment of patients withB-cell chronic lymphocytic leukaemia (B-CLL) for whom fludarabine combinationchemotherapy is not appropriate andshould not be used as consolidationtherapy following induction withfludarabine + rituximab outside of aclinical trial.
Fludarabine, rituximab and alemtuzumaball have known immunosuppressiveproperties, and it is possible that the fatalinfectious complications which occurred
in this trial are the result of a prolongedperiod of immunosuppression resultingfrom the sequencing of these drugswithout sufficient time for recovery, aswell as other factors specific to this trial.
The five fatal infections were reported as:viral meningitis, Listeria meningitis,Legionella pneumonia, cytomegalovirusinfection and Pneumocystis jirovecipneumonia, all in patients who achieveda complete response after inductiontherapy.
References:
1. Communication from Bayer ScheringPharma AG and Genzyme Europe BV at http://www.mhra.gov.uk
2. Lin TS, Donohue KA, Lucas MS, Byrd JC,Bengtson EM, Peterson BL, Larson RA(Cancer and Leukemia Group B USA).Consolidation therapy with subcutaneous (SC)alemtuzumab results in severe infectionstoxicity in previously untreated CLL patientswho achieve a complete response (CR) afterfludarabine and rituximab (FR) inductiontherapy: Interim Satefy Analysis of the CALGBStudy 10101. Blood 2007 Nov;110(11): 232a–233a, [Abstract 755]
3. CALGB10101 abstract available online athttp://www.hematology.org.
Mycophenolate mofetil:progressive multifocalleukoencephalopathyEuropean Union — In agreement withthe European Medicines Agency (EMEA),the manufacturer of mycophenolatemofetil (CellCept®) has advised physi-cians of new safety information.CellCept® has been on the market forover 10 years, as an immunosuppressiveagent indicated in combination withciclosporin and corticosteroids.
Isolated cases of progressive multifocalleukoencephalopathy (PML) have beenreported in patients receiving CellCept®.
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The case reports have been associatedwith confounding factors in particular thenature of the underlying disease, con-comitant immunosuppression and thelatency between the use of CellCept®and the onset of PML. However, basedon the temporal relationship observed insome cases, the contributory role ofCellCept® cannot be excluded.
Leukoencephalopathy (PML) is a rare,progressive, demyelinating disease of thecentral nervous system (CNS) thatusually leads to death or severe disability.PML is caused by the reactivation of theJC virus, a polyomavirus that resides inlatent form in 70 – 90% of the adultpopulation worldwide. JC virus usuallyremains latent, typically only causing PMLin immunocompromised patients. Thefactors leading to activation of the latentinfection are not fully understood al-though abnormalities in T-cells have beendescribed as important for reactivation ofJC virus and PML. Patients usuallypresent with focal CNS abnormalities andradiographic evidence of white matterdisease without mass effect.
Reference: Communication from Roche,P212828, 18th February 2008 at http://www.mhra.gov.uk
Modafinil: serious rash andpsychiatric symptomsUnited Kingdom —The manufacturer ofmodafinil (Provigil®) has informed physi-cians of new warnings and safety infor-mation regarding:
• Serious skin rash and psychiatricsymptoms. The safety concern involvesserious skin rashes requiring hospitali-zation and discontinuation of treatmentin adults and children occurring within 1to 5 weeks after treatment initiation[isolated cases have been reported afterprolonged treatment (e.g. 3 months)].
Modafinil should be discontinued at thefirst sign of rash and not restartedunless the rash is clearly not drug-related.
• Psychiatric adverse experiences (psy-chosis, mania, delusion, hallucinations,suicidal ideation and aggression) havebeen reported in patients treated withmodafinil. If psychiatric symptomsoccur, modafinil should be discontinuedand not restarted.
Caution should be exercised whenadministering modafinil to patients witha history of psychosis, depression ormania given the possible emergence orexacerbation of psychiatric symptoms.
Modafinil is not approved for use inchildren for any indication.
Modafinil is indicated for the symptomaticrelief of excessive sleepiness associatedwith narcolepsy, Obstructive SleepApnoea/Hypopnoea Syndrome (OSAHS)or moderate to severe chronic Shift WorkSleep Disorder (SWSD) in adult patients.
Reference: Communication from Cephalondated 14/02/2008 at http://www.mhra.gov.ukproduct information available on the electronicmedicines compendium site http://emc.medicines.org.uk
Moxifloxacin: serious hepaticand skin reactionsUnited Kingdom/European Union — Inagreement with EU regulatory authorities,including the Medicines and HealthcareProducts Regulatory Agency (MHRA), themanufacturer of moxifloxacin (Avelox®)has released important safety informa-tion. A recent assessment of adversereactions associated with the use ofmoxifloxacin resulted in the followinginformation and recommendations:
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• Treatment with moxifloxacin is associ-ated with a risk of developing fulminanthepatitis potentially leading to lifethreatening liver failure and risk ofpotentially life threatening bullous skinreactions like Stevens-Johnson-Syn-drome (SJS) or toxic epidermal necroly-sis (TEN).
• Due to limited clinical data, moxifloxacinis contraindicated in patients withimpaired liver function (Child Pugh C)and in patients with transaminasesincreased > 5 fold the upper limit ofnormal.
• Patients should be advised to stoptreatment and to contact their physicianif early signs and symptoms of thesereactions occur.
Liver injuries possibly related to moxi-floxacin were more frequently of choles-tatic or mixed hepatocellular-cholestatictype than of hepatocellular type. Eightreports of fatal hepatic injuries wereconsidered as possibly related to moxi-floxacin therapy. Cases of positive re-challenge gave further evidence of acausal relationship. However, the majorityof patients experiencing serious liverinjuries where the outcome was reportedimproved or recovered.
TEN was reported in several cases wherea causal relationship was consideredpossible; this included two cases withfatal outcome. Additionally, a total of 35individual cases of SJS were reported,including three cases where there was afatal outcome and seven cases whichwere considered life-threatening. In these10 cases of severe SJS, a progression toTEN was documented in three patients.Based on the large patient exposure, theincidence of both life threatening liverinjuries and TEN is very low, although adefinite frequency cannot be calculatedfrom these reports.As a consequence of this review, themanufacturer has revised the product
information for moxifloxacin across theEuropean Union.
Reference: Communication from BayerSchering Pharma, Bayer plc February 2008, atMedicines and Healthcare products Regula-tory Agency (MHRA) http://www.mhra.gov.uk
Rimonabant: depression;psychiatric reactionsUnited Kingdom — Rimonabant(Acomplia®) is contraindicated in patientswith ongoing major depression or thosetaking antidepressants. Prescribers areencouraged to take a detailed historyfrom patients before prescribing. How-ever, depressive reactions may occur inpatients who have no obvious risk factors,apart from obesity itself.
Up to the end of January 2008, 673 ADRreports (reporting 1971 individualreactions) had been received withrimonabant in the UK, 423 of which wereserious. Four reports had a fatal outcome.The most common reported ADRs, whichare labelled in the Summary ofProduct Characteristics, were:
• General disorders (fatigue, asthenia)• Skin and subcutaneous disorders
(pruritus, sweating)
876 psychiatric reactions were reported(44% of all 1971 reported reactions).The most common psychiatric reactionswere depression and related disordersof mood and associated symptoms. 52reactions involved suicidal and
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self-harming thoughts or behaviours,most of which were suicidal ideations(42 reports).
Many patients who receive rimonabantare diabetic. There have been sevenreports of hypoglycaemia/decreasedblood glucose. This type of reaction maybe due to inadequate monitoring of blood-glucose control in patients whohave managed to reduce calorie intakewithout appropriate adjustment of oralantidiabetics (and possibly insulin).
Reference: Drug Safety Update. Volume 1,Issue 10, May 2008
Exenatide: risk of acutepancreatitisUnited Kingdom — Exenatide (Byetta®),the first-in-class incretin mimetic, is aglucagon-like-peptide-1 analogue thatstimulates insulin release from pancreaticcells in a glucose dependent manner.Exenatide is indicated for treatment oftype 2 diabetes mellitus in combinationwith metformin, with or withoutsulphonylureas in patients who have notachieved adequate glycaemic control onmaximally tolerated doses of these oraltherapies. Exenatide was first marketed inthe European Union in November 2006.
Several reports of acute pancreatitis havebeen received in association withexenatide use worldwide. Up to 30September 2007, 89 reports of pancreati-tis had been received: 87 from the USAand two from Germany. One case had afatal outcome. A UK report of acute andchronic pancreatitis was received inNovember 2007.
If pancreatitis is suspected, exenatideand other potentially suspectmedicines should be discontinued.
Reference: Drug Safety Update. Volume 1,Issue 10, May 2008
Zanamivir: neuropsychiatriceventsUnited Kingdom — The manufacturer ofzanamivir (Relenza®) Inhalation Powderhas updated the package insert as aresult of postmarketing reports (mostlyfrom Japan) of delirium and abnormalbehaviour leading to injury in patients withinfluenza who were receiving neuramini-dase inhibitors, including zanamivir .
Therefore, patients should be observedfor signs of unusual behaviour and ahealthcare professional should be con-tacted immediately if the patient showsany signs of unusual behaviour.
Zanamivir is indicated for treatment ofuncomplicated acute illness due toinfluenza A and B virus in adults andpaediatric patients 7 years of age andolder who have been symptomatic for nomore than 2 days.
Reference: Communication from GSK atwww.gsk.com posted at http://www.fda.gov/medwatch
United States of America —The Foodand Drug Administration (FDA) is awareof reports of infants born with seriouscongenital anomalies, including microtiaand cleft lip and palate, following expo-sure to mycophenolate mofetil (MMF)during pregnancy. MMF, the active drugsubstance in CellCept®, is an ester of theactive metabolite mycophenolic acid(MPA), the active drug substance inMyfortic®. In most cases, the motherswere taking MMF following an organtransplant to prevent organ rejection.However, some mothers taking MMFwere being treated for immune-mediatedconditions such as systemic lupus ery-
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thematosus (SLE) and erythema multi-forme. Treatment began before theirpregnancies and continued into the firsttrimester or until the pregnancy wasdetected. MMF is approved in the US foruse in the prophylaxis of organ rejectionin patients receiving allogeneic renal,cardiac or hepatic transplants and MPA isapproved in the US for use in the prophy-laxis of organ rejection in patients receiv-ing allogeneic renal transplants. Inpatients who are transplant recipients,these drugs are almost always used incombination with other immunosuppres-sant drugs.MMF and MPA increase the risk ofspontaneous abortion in the first trimesterand can cause congenital malformationsin the offspring of women who are treatedduring pregnancy. The labelling for bothMMF and MPA was revised in November2007 to change the Pregnancy Categoryto “D” (positive evidence of human fetalrisk, but potential benefits may warrantuse of the drug in pregnant womendespite the potential risk) and to addthese findings about the risk of earlypregnancy loss and congenital malforma-tions to the boxed warning.Reference: FDA Alert, 16 May 2008 athttp://www.fda.gov/medwatch
Strontium ranelate : life-threatening allergic reactionsSingapore — Strontium ranelate(Protos®, Servier) has been registeredsince July 2006 for the treatment of post-menopausal osteoporosis to reduce therisk of vertebral and hip fractures. Sinceits launch in Europe in 2004, Protos® hasbeen registered in 64 countries and has atotal of about 570 000 patient-years ofexposure.
In November 2007, the European Medi-cines Agency’s (EMEA) Committee forMedicinal Products for Human Use(CHMP) was alerted to an increasing
number of reports of drug rash witheosinophilia and systemic symptoms(DRESS) associated with the use ofProtos®. DRESS is a rare but seriousand life-threatening type of allergicreaction to a drug. The condition startswith a skin rash, accompanied by a fever,swollen glands, eosinophilia, adenopathyand systemic involvement which mayinclude hepatic, renal and pulmonaryimpairment. In most cases, the symptomsresolved upon discontinuation of Protos®and with the initiation of corticosteroidtherapy. However, it has been reportedthat recovery can be slow and there is arisk of symptoms returning during therecovery period.
As of November 2007, 16 cases ofDRESS were reported to the CHMP. Inlight of these reports , the CHMP con-cluded that the use of Protos® is linked toan increased risk of DRESS and recom-mended that warnings on severe hyper-sensitivity syndromes, including DRESSand Stevens Johnson syndrome beincluded in the product and patientinformation
To date, the Health Sciences Agency(HSA) has not received any ADR reportsassociated with Protos® and DRESS.There is one case of a patient whodeveloped Stevens Johnson syndromeafter taking both Protos® and Arcoxia®(etoricoxib) simultaneously for about onemonth.
In view of this emerging safety concern,prescribers are reminded to alert theirpatients of the risk of severe allergicreactions and to inform them to stopProtos® immediately should a rash occurand to seek medical advice. For patientswho have stopped treatment due tohypersensitivity reactions, Protos®should not be re-introduced.
Reference: Strontium (Protos®) - A safetyupdate. 25 Mar 2008: at http://www.hsa.sg
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Lapatinib and hepatoxicitySingapore — In consultation with HSA,the manufacturer of lapatinib (Tykerb®)has informed healthcare professionals ofnew safety information on hepatotoxicity.
From the manufacturer’s worldwidesafety database, 39 cases of hepatotoxic-ity were identified, of which 38.5% ofsubjects were receiving lapatinib mono-therapy while 53.8% were receivinglapatinib in combination with otherchemotherapies, such as capecitabine.
Majority of the key cases were fromclinical trials, which yielded a crudeincidence of 0.4% for hepatobiliary eventsin the entire lapatinib clinical programwhile 7 cases of hepatotoxicity were fromspontaneous sources. There have been13 incidences of death with reported liver-related events.
Healthcare professionals are advised tomonitor their patients’ liver functionsbefore initiating treatment and at approxi-mately monthly intervals thereafter or asclinically indicated. Tykerb® should bediscontinued and not restarted in patientswith severe changes in liver function.
Reference: Tykerb® (lapatinib) and newsafety information on hepatotoxicity, 1 April2008 at http://www.hsa.sg
Telbivudine and peripheralneuropathySingapore — Telbivudine (Sebivo®) isindicated for the treatment of HBeAg-positive and HBeAg-negative chronichepatitis B in patients who have compen-sated liver disease, evidence of viralreplication and active liver inflammation,and who are nucleoside analogue naive.
In a pilot clinical trial, 8 cases of periph-eral neuropathy were reported out of the48 patients treated with telbivudine and astandard dose of pegylated interferonalfa-2a. The time to onset for the eventwas approximately 2 to 6 months. Incontrast, the rate of peripheral neuropa-thy in the 2-year pivotal study with telbivu-dine monotherapy was uncommon.
As the risk of developing peripheralneuropathy appears to be increased inthe telbivudine and pegylated-interferonalfa-2a combination, the manufacturer isworking with the Health Sciences Agency(HSA) to update the product information.
Reference: Peripheral neuropathy seen withthe combination treatment of Sebivo® (telbivu-dine) with pegylated interferon alfa-2a, 17March 2008 at http://www.hsa.sg
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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International Nonproprietary Namesfor monoclonal antibodies: IFPMA proposal
International NonproprietaryNames
* The article was prepared by Anna-Maija Autere, Nicole Wagner and Georg-Burkhard Kressefrom Roche on behalf of International Federation of Pharmaceutical Manufacturers & Associa-tions (IFPMA) Biotech Working Group: http://www.ifpma.org/Issues/Biologicals/. Correspond-ence: Ryoko Krause, IFPMA at [email protected]
This summary represents the IFPMA proposal presented to the 46th Consultation onInternational Nonproprietary Names (INNs) for Pharmaceutical Substances held atthe World Health Organization in Geneva in April 2008. The proposal was developedby the IFPMA (International Federation of Pharmaceutical Manufacturers & Associa-tions) Biotech Working Group, which includes twenty companies, two regional andthree national associations located in Europe, Japan and USA.The pioneering work of Kohler and Milstein (1) in the 1970s provided the means toproduce monoclonal antibodies (MAbs) derived from a single clone of cells whichbind to a single antigenic determinant with predefined specificity. This paved the wayto use this class of biomolecules as diagnostic tools as well as therapeutic drug sub-stances for treatment of cancer, auto-immune, and other diseases. Technologicaladvances in the generation of antibodies with reduced immunogenicity permitted thedevelopment of MAb-based therapies as a major strategy in biomedicine (2). Today,more than 20 MAb-based medicines have been approved for marketing, and a fur-ther 160 MAbs were in development in 2006 (3).The appearance of the first MAb-based drugs in the late 1980s created the impetusfor the WHO INN programme to establish a naming system for monoclonal antibod-ies in 1990/91. By 2006, more than 140 INNs had been selected for MAbs. The sys-tem was gradually expanded but the general policy for naming of MAbs remainedunchanged [reviewed in (4)]. The nomenclature rules for monoclonal antibodies arecomplex. Furthermore, current developments in the use of different antibody typeswith different functions, antibody fragments and antibody glycoengineering add tothis complexity. Therefore, it was decided (5) that consideration should be given toestablishing a small expert group to review these developments and to make specificrecommendations on INN policy for monoclonal antibodies.In order to support this process, the IFPMA has developed Proposals for principlesfor INNs of new monoclonal antibodies (6). This summary is intended to give a shortoverview on MAbs, their molecular structure and aspects relevant to their use aspharmaceutical drug substances, and to communicate and explain the IFPMA nam-ing proposal. It should be emphasized that the additional explanations given in thispaper do not necessarily represent a harmonized IFPMA position but reflect the per-sonal views of the authors.*
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Molecular structure of antibodies –the immunoglobulin moleculeAntibodies, also called immunoglobulins,are a large group of closely related glyco-proteins with a molecular weight of up to150 kDa. Each immunoglobulin moleculeis composed of two identical heavychains and two identical light chains,linked together by disulfide bonds (Fig.1).The amino acid sequences of the amino-terminal regions, referred to as VH and VL,are highly variable and are involved inantigen binding. The constant part of thelight chain is called CL, and the constantpart of the heavy chain is sub-divided intothree domains CH1, CH2, and CH3. Twoheavy and two light chains form a “Y-shaped” hetero-tetrameric superstructure.It consists of three structurally independ-ent moieties connected by a flexible hingeregion, which are termed Fab (the antigen-
binding fragments comprising one lightchain and the VH and CH1 parts of oneheavy chain), responsible for antigenspecificity and binding, and Fc (“fragmentcrystallizable”, comprising the CH2 andCH3 parts of two heavy chains).Based on the amino acid sequence dif-ferences in the constant part of the heavychains, immunoglobulins are classed byisotypes (e.g. human IgA, IgG, IgM, IgD,and IgE). All licensed therapeutic antibod-ies belong to the IgG isotype. HumanIgG–Fc contains carbohydrate residuesbound to residue Asn297 in each of theCH2 domains, thus characterizing IgG asa glycoprotein. In addition, 15–20% ofhuman IgG molecules have N-linkedoligosaccharides within the Fab region (7).The oligosaccharides provide importantrecognition sites mediating a variety ofinteractions (see 8) and play specificstructural roles.
Figure 1. Structure of an IgG Molecule
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Within the IgG isotype, there are fourdifferent sub-classes (IgG1, IgG2, IgG3,and IgG4) differing in their amino acidsequence, hinge length, binding to Fcreceptors and complement, and biologicalfunction. In development of therapeuticmonoclonal antibodies, scientists havefocused on the IgG1, IgG2, and IgG4subclasses (9).
Immune effector functions andglycoengineeringAntibodies specifically bind to theirantigens via their Fab fragment regions. Ingeneral, they thereby can prevent patho-gens from entering or damaging cells,interfere with signal transduction medi-ated by interactions of ligands with cellsurface receptors, and induce cell-deathmechanisms through apoptosis or byblocking the action of survival pathways.
Furthermore, by virtue of interaction siteslocated in the Fc part of IgG, antibodiescan also stimulate removal of a pathogenor tumour cell by macrophages and othercells of the immune system. This ismediated by interaction with Fc-gammareceptors (FcgRs) present on the immunecells and eliciting antibody-dependentcellular cytotoxicity (ADCC). Antibodiescan also trigger direct pathogen or celldestruction by stimulating other immuneresponses such as the complementpathway (complement-dependent cyto-toxicity, CDC). These effects have beentermed “immune effector functions” ofantibodies.
It has been shown (10,11) that the pres-ence and structure of the Fc-boundcarbohydrate moieties of the IgG mol-ecule are essential for binding to a certainsubtype of FcgRs (FcgRIIIa) and promo-tion of effector functions: IgG moleculeswith an ungycosylated Fc portion retainlittle ability in activating complement andbinding to FcgRs. On the other hand, thelack of a fucose residue in human IgG1enhances the binding to FcgRIIIa and
thereby increases in-vitro ADCC morethan 50-fold. The presence or absence ofgalactose and sialic acid residues alsoinfluences ADCC (12) and CDC.Several studies (e.g. 13,14) have high-lighted the importance of FcgR-mediatedkilling of target cells for the efficacy ofantibody treatment in cancer therapies,which represents an essential mechanismfor efficacy. Modulation of IgGglycosylation (“glycoengineering”) whichresults in removal of part or all of thefucose residues in order to enhancepotency is considered a promising tech-nology to enhance the efficacy of thera-peutic MAbs (15), as already demon-strated in murine xenograft models (16).MAb-based medicines containingglycoengineered antibodies have enteredclinical development.In contrast to the importance of Fc inter-actions in cancer, in some disease areas(e.g. for treatment of inflammatory dis-eases) Fc-mediated effects can lead tosafety issues and it may be desirable tominimize or even eliminate Fc-mediatedinteractions. Thus, glycosylation ofantibodies can be crucial for their clinicalprofile, including aspects of safety andefficacy, and the consistency of glyco-sylation has to be carefully controlled.
Monoclonal antibody productionand heterogeneityAccording to the original Kohler-Milsteintechnology, monoclonal antibodies areobtained from hybridoma cells. Today,therapeutic MAbs are usually producedusing recombinant DNA technology. Dueto the requirement for glycosylation, allantibody therapeutics that are currentlylicensed are manufactured from mamma-lian cell culture, using e.g. Chinesehamster ovary (CHO) and mouse mye-loma (NS0 or Sp2/0) cells. Other systemsbased on transgenic animals, yeast,plants, etc. are under development.Unglycosylated Fab fragments can beproduced from prokaryotic systems.
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Manufacturing of recombinant MAbs,which is a complex multi-step process,requires the same high standards inprocess development, validation andcontrol as for other recombinant thera-peutic proteins. Sound product andprocess knowledge (preferentially basedon “quality by design” concepts) is indis-pensable in order to ensure and maintainproduct quality. The safety and efficacy ofantibody therapeutics, including theirstability and immunogenic potential, arecritically dependent on post-translationalmodifications such as, but not limited to,glycosylation which are highly dependingon the manufacturing and control charac-teristics of the process.
In this context, it should be emphasizedthat even highly purified recombinantproteins, due to the complexity of boththeir molecular structure and their manu-facturing process, are never single anduniform molecular entities, but families ofclosely related molecular variants (18,19).These variations will be introduced by themanufacturing cell itself, as well as by theproduction process. For an IgG antibody,it has been estimated that, even consider-ing only a limited number of glycoformvariants (17), up to 108 variants aretheoretically possible; in fact, variabilitymay be even greater since there may bemany more glycoforms than considered inthis analysis (7). In contrast to the situa-tion with small, chemically synthesizedmolecules, current protein-analyticalmethods are not able to characterizecomplex proteins completely, and thefunctional impact is known only forparticular attributes (or defined combina-tions of some attributes). Therefore, forrecombinant proteins including mono-clonal antibodies manufactured bydifferent, independently developedprocesses, differences in microhetero-geneity have to be expected whoseimpact on clinically relevant propertiesusually cannot be predicted.
Lowering the immunogenicityMonoclonal antibodies obtained by theoriginal Kohler-Milstein procedure, andthe first MAb which was licensed in 1986for use in therapy (muromonab-CD3),were murine proteins. However, rodentMAbs can elicit an immunogenic re-sponse referred to as human anti-mouseantibodies (HAMA). Furthermore, thera-peutic efficacy may be reduced by rela-tively faster clearance (as compared tohuman antibodies) and weak effectorfunctions in humans (19). Therefore,efforts were made to make MAbs more“human-like” by genetically fusing rodentvariable domains to human constantdomains (resulting in “chimeric” antibod-ies which still contain about 35% rodentsequences). “Humanized” antibodies withonly approximately 10% rodent se-quences have also been produced bygrafting only the six loops, termedcomplementarity determining regions(CDRs), of the antibody sequence whichcan potentially interact with the targetmolecule to a human antibody framework,combined with some additional sequenceoptimization. These chimeric or human-ized antibodies indeed exhibit lessimmunogenicity, and most of the mono-clonal antibody products presently li-censed contain either chimeric or human-ized antibodies.More recently, methods have becomeavailable to obtain MAbs with “fullyhuman” sequence (20), either by usingphage display selection techniques, or bygenerating the antibodies in mice trans-genic for the human immunoglobulingenes. Currently, two therapeutic “fullyhuman” MAbs (adalimumab, panitumu-mab) are licensed, with many more beingin clinical development. Alternatively,efforts are ongoing to reduce the immu-nogenicity of chimeric MAbs by “de-immunization” based on in-silico identifi-cation of potential linear T-cell epitopeswhich then are removed by altering thesequence. Several of these MAbs which
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strictly cannot be designated as “chi-meric” nor “humanized” or “human” haveentered clinical development.
However, even “fully human” MAbs havea significant immunogenic potential inpatients. The formation of antibodies maybe due to the presence of foreign se-quences or epitopes, but also to productquality issues (e.g., presence of aggre-gates) and/or patient- and disease-relatedfactors. Thus, even small differences intherapeutic protein products may lead tounexpected immunogenicity.
Bi-specific antibodies, antibodyfragments, antibody conjugatesWhereas unmodified, intact antibodiesrepresented the first wave of licensedimmunotherapeutic reagents, it soonbecame clear that it is often desirable toimprove clinically relevant properties,such as pharmacokinetics, potency,avidity, or half-life. Among the approachesto address these topics is the construc-tion of bi-specific antibodies (containingtwo different binding specificities con-nected together) which in some casesare even designated as “trifunctional” dueto immune effector functions mediated bythe Fc part (e.g. catumaxomab).
It is possible to minimize Fc-mediatedeffects in therapeutic MAbs by selectingIgG subclasses with low effector func-tions, such as IgG2, IgG4, or IgG1 mu-tants. Another option to eliminate un-wanted Fc functionalities is the use ofantibody fragments obtained by proteoly-sis of intact antibodies or by recombinantexpression of monovalent fragments(such as Fab, Fv, or single-chain Fv frag-ments) which are devoid of the Fc part ofthe IgG molecule (21). Due to theirsmaller size, these antibody fragmentsmay exhibit better pharmakokinetics fortissue (e.g., tumour) penetration. If multi-valent binding is desired to increaseretention times on the target, such frag-ments can be engineered into di- or
oligomeric conjugates. Several Fab frag-ments have already been licensed for useas drugs (e.g., abxicimab, ranibizumab,99mTc-sulesomab). As a result of theirsmaller size, antibody fragments usuallyexhibit shorter in-vivo half-life than intactantibodies. However, their in-vivo half lifecan be increased by conjugation withpoly(ethylene glycol)(PEG).
Due to their exquisite antigen bindingspecificity, antibodies (or their Fab frag-ments) can be used for targeting cytotoxicdrugs, cytokines, toxins, or radio-isotopesto the desired location, e.g. tumour cells(22). Licensed products following thisprinciple include e.g. ibritumomab tiux-etan, gemtuzumab ozogamicin, or(131I)tositumomab.
The Fc part of the IgG molecule, whenfused genetically to otherwise short-livedprotein sequences, can serve to extendthe in-vivo half-life considerably. Severalfusion proteins relying on this concepthave been licensed (e.g., etanercept,rilonacept, alefacept).
The present policy of MAb namingInternational Nonproprietary Names(INNs) are unique names which areglobally recognized. They are assigned toallow the clear and unambiguous identifi-cation, safe prescription and dispensingof active pharmaceutical ingredientsbased on molecular characteristics andpharmacological class (23). Since initia-tion of the INN system in 1950, INNshave become essential for health profes-sionals as a tool for correct prescriptionand are used by drug manufacturers,regulatory authorities, authorities involvedin reimbursement and some other inter-ested parties. They play a key role incommunication, prescription, interchange-ability and reimbursement of medicinesas well as pharmacovigilance.
The concept of INNs was initially devel-oped for small chemical entities that can
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be fully characterized by physicochemicalmeans. Due to the progress in biomedicaland biotechnological research, medicinalproducts containing significantly morecomplex substances of biological originhave been and will continue to be devel-oped. As a consequence, INNs need tobe assigned for these complex products.The challenge is that these active phar-maceutical ingredients (APIs) are oftenvery large macromolecules which cannotbe fully characterized analytically. More-over, these APIs are not single specificingredients but mixtures of molecularspecies which are differently glyco-sylated, or otherwise modified post-translationally.A systematic scheme for INNs of MAbswas implemented in the early 1990s. Thecommon stem is ‘-mab’, sub-stemsindicate the source of the product (e.g. -o-for mouse, -u- for human, -xi- for chi-meric, -zu- for humanized), and furthersub-stems indicate the disease or targetclass (e.g. -li- for immunomodulators, -vi(r)- for viral) or tumour type (e.g. -co- forcolon, -ma(r)- for mammary, -me(l)- formelanoma, -tu(m)- for miscellaneous).The prefix is chosen randomly, but shouldcontribute to a euphonious and distinctivename. If necessary, a second word isadded, indicating radiolabelling or conju-gations, e.g. to toxins. In this case, theinfix -toxa- can be inserted. Severalfurther rules and restrictions apply (i.e.,avoid conflicts with trademarks and brandnames). To accommodate new technicaldevelopments the system has becomeincreasingly complex. Due to the increas-ing number of INNs selected for MAbs,difficulties have arisen especially in thoseMAb groups which attract the biggestresearch interest, e.g. cancer andautoimmune diseases. As a conse-quence, new INNs tend to becomelonger, more complicated, and there isthe potential for confusion.Therefore, it was decided at the 44thConsultation on International Nonpro-
prietary Names (INNs) for PharmaceuticalSubstances held at WHO Headquarterson 22–24 May 2007 (5) that considerationshould be given to review these develop-ments and to make specific recommenda-tions on a revised INN policy for mono-clonal antibodies.
IFPMA proposals for principleson INNs for new MAbsWith the intention of supporting thisprocess, IFPMA has developed thefollowing ideas for principles which, fromthe industry view, should preferably befollowed in the naming of new MAbs (6).The following proposals should serve tofocus attention on a number of importantaspects. Proposals approved by theIFPMA Biotech Working Group areprinted in bold italic.
1. The naming convention for mono-clonal antibodies should follow thesame policy as established for all(glyco)proteins. Thus, protein drugsubstances (including MAbs) withdifferences in amino acid sequenceshould always have different INNs.
Monoclonal antibodies are glycoproteins,and there is good reason to use the samegeneral policy as for naming of otherglycosylated proteins where the INNsystem is well established and proved tobe useful for all stakeholders.
2. IFPMA proposes to continue the useof the common stem –mab for mono-clonal antibodies. For antibody frag-ments (such as Fab fragments), the useof –fab instead of –mab might beconsidered.
We propose to differentiate betweencomplete (intact) antibodies and antibodyfragments which presently are alsonamed using the same stem –mab (e.g.,abxicimab, ranibizumab). Differentiationwould be helpful for the INN users.However, it is open for discussion
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whether other distinct stems should bedefined for products based on otherimmunoglobulin fragments such as Fv,scFv, or other fragments (see 21), orwhether a general stem (such as –fab)might be used to indicate that the productis derived from a Mab type structure.
3. An invented part of the INN is stillconsidered necessary. IFPMA pro-poses that WHO makes efforts toprovide related names for MAbsdirected against the same moleculartarget (although these MAbs neverthe-less may differ in amino acid se-quence, epitope specificity, immuneeffector functions, binding constants,etc.).The specificity of a MAb for its antigen(which represents the molecular target) isthe most important element of informationcharacterizing a monoclonal antibody asa drug substance. Presently, antigenspecificity is not apparent from the INNsselected for MAbs. Since the number ofclinically validated MAb targets is limited,it can be expected that there will beseveral MAbs entering clinical studies orobtaining marketing approval which aredirected against the same antigen – infact, this is already reality (e.g., cetuxi-mab and panitumumab both adress theepidermal growth factor (EGF) receptoralthough this is not evident from therespective INNs). It would help the usersof INNs if related, although different, INNswould be provided for MAbs addressingthe same antigen. However, it is notsuggested that the INN system shoulddevelop systematic naming principles forall potential antigens, which clearly is notpossible.
4. Consistent with the naming conven-tions for other glycoproteins, it ismandatory that differences in post-translational modifications (for exam-ple, but not limited to, theglycosylation pattern) are indicated inthe INN of MAbs. This might be done
using designators (e.g., Greek letters,details to be decided by WHO) as forother glycosylated proteins. This require-ment is justified scientifically since it hasclearly been shown that differences inglycosylation (e.g., fucosylation, galacto-sylation, sialylation) influence immuneeffector functions and thus may have animpact on clinically relevant properties.Consequently, MAbs with an identicalamino acid sequence but a differentglycosylation pattern have to be consid-ered different drug substances andtherefore should have different INNs.In accordance with the naming policy forglycosylated proteins, MAbs with adifferent glycosylation pattern (or otherdifferences in post-translational modifica-tions) should have distinct INNs even iftheir amino acid sequence is the same.This is important because cases areexpected where MAbs with the sameamino acid sequence, but proven orpotential differences in glycosylation aredeveloped which may possess differentclinical properties. Such differences mayeither be intended, e.g. in glycoengineer-ed antibodies, or unintended but inevita-ble due to the use of different, independ-ent manufacturing processes, e.g. insubsequent-entry (stand-alone follower orbiosimilar) products.
5. At the time of INN application it maynot yet be clear whether modification(e.g., glycosylation) is identical ordifferent. Therefore, monoclonalantibodies made independently (i.e.,by different manufacturers usingdifferent processes) should generallyobtain distinct INNs. These distinctINNs should have the same stem butinclude different designators or identifiers.
It should be noted that this policy inpractice will only be efficient if WHO andthe drug regulatory authorities agree tomake it mandatory for the second manu-facturers to present their substances toWHO and apply for a distinct INN.
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Manufacturers usually apply for INNsduring early clinical development whenthe final manufacturing process may stillbe under development and the qualityprofile, including the modification (e.g.glycosylation) pattern of the product to becommercialized, has not yet been finallyestablished. So, as a matter of precau-tion, distinct INNs should be given at thattime to MAbs made by different manufac-turers using different, independent proc-esses. Even if it turns out later on that theglycosylation pattern of two products isthe same, the issue of having two prod-ucts with identical properties but distinctINNs can be considered minor comparedto the risk of having two products with thesame INN but different clinical propertiesbecause in this latter case, “clear identifi-cation, safe prescription and dispensing”as requested by WHO (23) based on theINN would be impossible.This concept does not contradict the factthat there may be some batch-to-batchvariability of the glycosylation pattern, aswell as slight glycosylation differencesafter manufacturing changes in a givenproduct. In these cases, the range ofvariability is validated by the results ofclinical development and by the compara-bility exercise to be performed by themanufacturer according to the ICH Q5Eguideline (24) in case of processchanges. Thereby it is ensured that withinthe design space defined by these data,there is no adverse impact on the quality,safety or efficacy of the drug product. Sothere is no need to select a distinct INNafter manufacturing changes providedthat pre- and post-change comparabilityis demonstrated.
6. Generally, the INNs contain informa-tion on the “pharmacological class” ofthe substance. Until now, this hasbeen done for MAbs by including asub-stem for the “disease or target”class. However, targeted therapies suchas monoclonal antibodies often addressbiological mechanisms (and molecular
targets) which may be involved in morethan one indication or disease. Therefore,it is likely (and already reality in somecases) that MAb drug substances will beused in more than one disease (e.g.,cancer and inflammatory diseases). Whileit is recognized that information on thedisease is useful for the physician, IFPMAbelieves that WHO should discusswhether it is appropriate to includeinformation on the disease, or rather onthe molecular target (e.g., CD20, HER-2,etc.) in the INN.
In cases where the same MAb is used intherapy for more than one disease (e.g.,rituximab in non-Hodgkin lymphoma aswell as rheumatoid arthritis), it is confus-ing when the INN includes informationrelating to only one of these diseasesonly. Although this can also be the casewith chemically synthesized, low-molecu-lar weight drug substances, it is morelikely to occur with monoclonal antibody-based medicines because biopharma-ceuticals discovery and development isbased on interfering with complexsignaling pathways, which may be in-volved in multiple diseases, rather thansolely on organ pathology. Therefore, itshould be considered to include informa-tion on the antigen/molecular target (cf.proposal 3 above) rather than on thedisease in the name.
7. IFPMA does not believe that moredetailed information on the mecha-nism of action (e.g., inhibitory, stimu-latory, etc.) has to be part of the INN toavoid too much complexity of thenames. This information should rather bepart of the substance description. How-ever, this should be left to WHO’s discre-tion.8. Specific information for which subtypeof disease (e.g., kind of tumour) anantibody drug substance is used (e.g.,colon, testis, ovary, etc.) is not usefulbecause many MAbs in oncology may beused for several tumour types. Naming
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according to the first indication (whichoften will turn out not to be the mostimportant) would be misleading. IFPMAproposes to remove this information fromthe INN.9. In order to simplify the INNs forMAbs, IFPMA also considers INNdifferentiation dependent on the“source of product” (human, mouse,chimeric, humanized, etc.) no longernecessary. This distinction is scientifi-cally questionable due to the fact thatthere are emerging approaches to designMAb sequences in silico, in order toreduce immunogenicity, for removal of T-cell epitopes. The resulting MAbs canneither be classified “murine” or“chimerized”, “humanized”, or “human”.The same principle applies to MAbsgenerated by, for example, phage display.This type of information should be part ofthe description of the substance ratherthan the INN.Proposals 8 and 9 are intended to sup-port simplification of the MAb INNs. Thiscan only be done if some of the abovementioned informative parts — whichaccording to the present policy areincluded in the names — will be removed.Information on the “kind of tumour” aswell as on the “source of product” bothare scientifically questionable and caneven be misleading for the user, andtherefore need not necessarily be part ofthe name itself. However since thisinformation certainly is helpful in somesituations, it should be retrievable withinthe substance description which isassociated with the INN.
10. Distinct names should be assignedto derivatives of antibodies includinge.g. bispecific antibodies, antibody-peptide or antibody-toxin conjugates,and radio-labelled antibodies. INNs forconjugates might be composed (e.g. astwo separate words) from the namesassigned to the individual components. Inaccordance with the naming policy for
other pegylated proteins, pegylated MAbsand Fabs should obtain the prefix “peg-”.Differences in conjugation (e.g., site ofmodification, conjugate chemistry, linkerchemistry, chain length of polymer, etc.)would require differentiation as for othertypes of modification. As far as possible,the naming of antibody conjugates shouldfollow the naming convention applied tonon-antibody conjugates.
11. Fusion constructs containing partsof an immunoglobulin molecule ge-netically fused to another sequencehave to be treated as a new proteinand should obtain individual INNs.WHO should discuss whether it is moreappropriate to follow the policy for MAbnaming, or for non-antibody proteins inthese cases.In the present INN policy (4), fusionconstructs containing the immunoglobulinFc part connected to a receptor molecule(or part of a receptor molecule) havebeen designated with the stem –cept(e.g., alefacept, abatacept, rilonacept).From these names, it is not apparent thatthe products contain part of an immu-noglobulin sequence. In future, there maybe fusion products which contain e.g. Fcsequences fused to other peptide (but notnecessarily receptor) sequences. While itis evident that each of these products willneed a distinct INN, it is proposed toconsider whether the presence of anti-body (Fc) sequences should be indicatedin the INN.
ConclusionDue to technological progress and theincreasing number of MAb-based drugsunder development and on the market, arevision of the present policy for INNs ofMAbs should be performed. With theproposals described in this paper, IFPMAwould like to support this process andcontribute to the establishment of a MAbnaming system that is able to accommo-date the recent and emerging technicaldevelopments in the field of monoclonal
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antibodies, while at the same time beingas clear and simple as possible.
References
1. Kohler, G., Milstein, C. Continuous culturesof fused cells secreting antibody of predefinedspecificity. Nature 1975; 256:495–497.
2. Brekke, O.H., Sandlie, I. Therapeuticantibodies for human diseases at the dawn ofthe twenty-first century. Nature Revs. DrugDiscovery 2003; 2:52–62.
3. PhRMA (Pharmaceuticals Research andManufacturers of America). Medicines indevelopment: Biotechnology. 2006. http://www.phrma.org/files/Biotech%202006.pdf.
4. WHO Programme on International Nonpro-prietary Names. International NonproprietaryNames (INN) for biological and biotechnologi-cal substances (a review). INN WorkingDocument 05.179. 2007.
5. WHO Programme on International Nonpro-prietary Names. 44th Consultation on Interna-tional Nonproprietary Names (INNs) forPharmaceutical Substances, ExecutiveSummary. 2007. http://www.who.int/medi-cines/services/inn/FinalConsolidatedExecSum44INN.pdf [cited 2008 Apr 24].
6. IFPMA. Proposal to the WHO INN ExpertGroup: Principles for naming of new mono-clonal antibodies. 2008. http://www.ifpma.org/fileadmin/templates/ifpmaissues/pdfs/2008_03_21_IFPMA_Proposal_for_naming_of_new_monoclonals.pdf [cited 2008 Apr 24].
7. Jefferis, R. Glycosylation of recombinantantibody therapeutics. Biotechnol. Prog. 2005;21:11–16.
8. Arnold, J.N., Wormald, M.R., Sim, R.B.,Rudd, P.M., Dwek, R.A. The impact ofglycosylation of the biological function andstructure of human immunoglobulins. Annu.Revs. Immunol. 2007; 25:21–50.
9. Salfeld, J.G. Isotype selection in antibodyengineering. Nature Biotechnol. 2007;25:1369–1372.
10. Tao, M.H., Morrison, S.L. Studies ofaglycosylated chimeric mouse-human IgG.Role of carbohydrate in the structure andeffector functions mediated by the human IgGconstant region. J. Immunol. 1989; 143:2595–2601.
11. Mimura, M., Sondermann, P., Ghirlando,R., Lund, J., Young, S.P., Goodall, M., Jefferis,R. Role of oligosaccharide residues of IgG1-Fc in FcgRIIb binding. J. Biol. Chem. 2001;276:45539-45547.
12. Scallon, B.J., Tam, S.H., McCarthy, S.,Cai, A.N., Raju, T.S. Higher levels of sialylatedFc glycans in immunoglobulin G moleculescan adversely impact functionality. Mol.Immunol. 2007; 44:1524–1534.
13. Cartron, G., Dacheux, L., Salles, G., Solal-Celigny, P., Bardos, P., Colombat, P., Watier,H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphismin IgG Fc receptor FcgRIIIa gene. Blood 2002;99:754–758.
14. Clynes, R.A., Towers, T.L., Presta, L.G.,Ravetch, J.V. Inhibitory Fc receptors modulatein vivo cytotoxicity against tumor targets.Nature Med. 2000; 6:443–446.
15. Umana, P., Jean-Mairet, J., Moudry, R.,Amstutz, H., Bailey, J. Engineered glycoformsof an antineuroblastoma IgG1 with optimizedantibody-dependent cellular cytotoxicity.Nature Biotechnol. 1999; 17:176–180.
16. Friess, T., Gerdes, C., Nopora, A., Patre,M., Preiss, S., van Puijenbroek, E., Schuell,C., Bauer, S., Umana, P., Klein, C. GA101, anovel humanized type II CD20 antibody withglycoengineered Fc and enhanced cell deathinduction, mediates superior efficacy in avariety of NHL xenograft models in compari-son to rituximab. Blood. 2007; 110:2338.
17. Kozlowski, S., Swann, P. Current andfuture issues in the manufacturing anddevelopment of monoclonal antibodies. Adv.Drug Delivery Revs. 2006; 58:707–722.
18. ICH Q6B Guideline: Specifications: testprocedures and acceptance criteria forbiotechnological products, 1999, http://www.ich.org/LOB/media/MEDIA432.pdf [cited2008 Apr 16].
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19. Walsh, G., Jefferis, R. Post-translationalmodifications in the context of therapeuticproteins. Nature Biotechnol. 2006; 24:1241-1252.
20. Presta, L.G. Engineering of therapeuticantibodies to minimize immunogenicity andoptimize function. Adv. Drug Delivery Revs.2006; 58:640-646.
21. Hudson, P.J., Souriau, C. Engineeredantibodies. Nature Med. 2003; 9:129-134.
22. Schrama, D., Reisfeld, R.A., Becker, J.C.Antibody targeted drugs as cancer therapeu-tics. Nature Revs. Oncology 2006; 5:147-159.
23. World Health Organization. Guidelines onthe use of International Nonproprietary Names(INNs) for pharmaceutical substances, WHO/PHARM S/NOM 1570, 1997.
24. ICH Q5E Guideline: Comparability ofbiotechnological/biological products subject tochanges in their manufacturing rocess, 2005,http://www.ich.org/LOB/media/MEDIA1196.pdf[cited 2008 Apr 24].
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Regulatory Action and NewsDydrogesterone withdrawnfor commercial reasonsUnited Kingdom — Dydrogesterone(Duphaston ®) is to be withdrawn fromthe market from March 2008 for commer-cial reasons. Dydrogesterone was li-censed for use in several indications,including threatened or recurrent miscar-riage, dysfunctional uterine bleeding, andhormone replacement therapy.
A Public Assessment Report has re-viewed evidence for the efficacy ofprogesterone and dydrogesterone in themaintenance of pregnancy in women withthreatened miscarriage or recurrentmiscarriage.
For several decades, progesterone andprogestogens (such as dydrogesterone)have been used to maintain early preg-nancy. However, this practice seems tohave been based on theoretical consid-erations rather than robust evidence ofefficacy. Although the methodological andethical difficulties associated with con-ducting efficacy trials in these indicationsneed to be considered, the quality ofmuch of the evidence is generally poorrelative to today’s standards.Reference: Medicines and Healthcareproducts Regulatory Agency (MHRA) informa-tion release. http://www.mhra.gov.uk/Safetyinformation
Withdrawal of lumiracoxibAustralia — Lumiracoxib is a selectiveCOX-2 inhibitor, which was registered inAustralia in 2004 for the symptomaticrelief of osteoarthritis (at 200 mg daily)and for the treatment of acute pain andpain due to primary dysmenorrhoea (400
mg daily for up to five days). Lumiracoxibwas not widely used in Australia until itwas included on the PharmaceuticalBenefits Schedule (PBS) in July 2006.
Following the evaluation of trial datashowing that the efficacy of a 100 mgdaily dose was comparable to that of the200 mg dose, a 100 mg tablet wasregistered for use in Australia in June2007 for the relief of symptoms of osteo-arthritis. In the 12 month period up to theend of July 2007, 567,903 prescriptionsfor lumiracoxib were dispensed in Aus-tralia.
In March 2007, the first Australian reportof serious hepatotoxicity associated withthe use of lumiracoxib was received.Concerns about this case stimulated apriority review of the general safety profileof lumiracoxib, with a focus on hepato-toxicity.
By the time of the Australian AdverseReactions Advisory Committee (ADRAC)meeting on 10 August, the TherapeuticGoods Administration (TGA) had receivedeight reports of serious liver injury associ-ated with the use of lumiracoxib. Therewere also three reports of minor in-creases in liver enzymes. There were fivereports of hepatic failure, including twofatalities and two liver transplants, and anadditional three reports of severe jaun-dice or acute hepatitis without liver failure.
ADRAC was informed of a further threeoverseas reports of hepatic failure withlumiracoxib, all from South America.ADRAC also reviewed data provided bythe sponsor of lumiracoxib regarding liverabnormalities seen in the clinical trialprogramme.
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At the August meeting, it was known thata 100 mg dose of lumiracoxib had beenregistered recently in Australia. However,the Committee was concerned there wasinsufficient evidence for an adequatemargin of safety with the 100 mg dailydose because of the possibility that thehepatotoxicity of lumiracoxib may beidiosyncratic; that lower doses may behepatotoxic in specific populations suchas the elderly, low-weight individuals, orthose with other underlying disease; orthat the 100 mg daily dose may beexceeded by patients seeking more painrelief. ADRAC also considered that theapparent rate of severe liver injury withlumiracoxib appeared greater than forother marketed nonsteroidal anti-inflam-matory drugs.After the above review and advice fromADRAC that the risks of lumiracoxiboutweighed its benefits, the TGA actedimmediately to cancel the registration ofall forms of lumiracoxib in Australia, onthe grounds that failure to cancel theregistration would create an imminent riskof death, serious illness or serious injury.Following the cancellation, the TGAadvised that all patients should stoptaking lumiracoxib immediately, andshould be assessed by their doctor forany evidence of liver damage (see TGAwebsite at www.tga.gov.au/alerts/prexige.htm)
Extracted from Australian Adverse DrugReactions Bulletin, Volume 27, Number 2,April 2008
Enoxaparin contamination:batches recalled
Australia —The Therapeutic GoodsAdministration (TGA) has recalled fivebatches of the anticoagulant medicineenoxaparin (Clexane®) due to the detec-tion of an impurity in the affected batches.
The TGA has required testing of allheparin containing products in Australiasince March 2008, following the identifica-tion of a contaminant known as "over-sulphated chondroitin sulphate (OSCS)"implicated in several severe allergicreactions in the USA and Europe.
As a result of this testing contaminationwith OSCS has been detected in fivebatches of the low molecular weightheparin product Clexane®. Thesebatches have been quarantined pendingfurther assessment.
To date, there have been no reports ofadverse events in Australia of the typereported in the United States associatedwith heparin products. Nevertheless, theTGA has decided to quarantine theaffected batches so no patients are put atundue risk at this time.
Responses from regulatory agenciesaround the world have varied, with someagencies initiating recalls and otherscontinuing to allow contaminated productto remain in the market, based on theview that in many clinical settings thebenefits of continued use of these bloodthinning agents outweigh the possiblerisks from contamination.
Reference: Therapeutic Goods AdministrationAlert, 22 April 2008. http://www.tga.gov.au/alerts/medicines/clexane.htm
Sweden — On 23 April 2008, the MedicalProducts Agency decided to recall thecontaminated batches of enoxaparin(Klexane®) found on the Swedish market.The level of contamination is low and therecall was made as a precautionarymeasure.
During January and February 2008Baxter recalled almost all of their heparinproducts from the US market after reportson serious adverse events. At the begin-
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ning of March 2008, the US Food andDrug administration (FDA) announcedthat the adverse events were associatedwith the presence of an unknown heparin-like impurity that could only be detectedwith new analytical methods presented onthe FDA website.
The Medical Products Agency decidedthat all Companies supplying heparinproducts for the Swedish market shouldtest their products for this specific con-tamination. A few batches of the lowmolecular weight heparin, Klexane®,were found to be contaminated with lowlevels of the same impurity as in theunfractionated heparin detected in theUSA, i.e. oversulphated chondroitinsulphate (OSCS). Therefore, the MedicalProducts Agency decided to recall thesecontaminated batches as a precautionarymeasure.
No reports of similar severe adversereactions as seen in the USA have beenreported to the MPA. The batches ofKlexane® that have not been withdrawncan be used according to the approvedindications. They do not contain anyimpurity.
Reference: Medical Products Agency, 29 April2008. http://www.lakemedelsverket.se/Tpl/NewsPage____7312.aspx
Recombinant antihemophilicfactor approvedUnited States of America — The Foodand Drug Administration (FDA) haslicensed a treatment for hemophilia A, arare, hereditary blood-clotting disorderthat affects approximately 15 000 indi-viduals, almost exclusively males, in theUnited States.The new treatment, called Xyntha®Antihemophilic Factor (Recombinant)Plasma/Albumin Free, is a geneticallyengineered version of factor VIII
Xyntha® is licensed for the control andprevention of bleeding, which can occurspontaneously or after an accident orinjury in patients diagnosed withhemophilia A. This recombinant FactorVIII is produced without additives fromhuman or animal material, which furtherminimizes any risk of infection from theproduct.
In clinical trials, Xyntha® was shown tobe effective at preventing or controllingbleeding, including preventing bleeding insurgery, for hemophilia A patients. Gener-ally, the most frequently reported adversereaction was headache. Most adversereactions reported in either study wereconsidered mild or moderate in severity.In addition, two of 89 individuals whoreceived 50 days of treatment withXyntha®, developed factor VIII inhibitors,which are antibodies that counteracttreatment with factor VIII.
Reference: FDA News, 21 February 2008 athttp://www.fda.gov
Esomeprazole magnesiumapproved for childrenUnited States of America — The Foodand Drug Administration (FDA) hasapproved esomeprazole magnesium(Nexium®) for short-term use in children1–11 years of age for the treatment ofgastroesophageal reflux disease (GERD).The agency approved Nexium® in twoforms, a delayed-release capsule andliquid form, in 10 mg or 20 mg daily forchildren 1–11 years old compared to 20mg or 40 mg recommended for pediatricpatients 12–17 years of age.
Children prescribed this drug should bemonitored by their physicians for anyadverse drug reactions.Esomeprazole magnesium is part of aclass of drugs known as proton pumpinhibitors (PPIs). PPIs decrease the
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in the United States would likely beinfected at least once with rotavirus byage 5. There are many different strains ofrotavirus. The vaccine protects againstrotavirus gastroenteritis caused by theG1, G3, G4, and G9 strains.
The most common adverse reactionsreported during clinical trials were fussi-ness, irritability, cough, runny nose, fever,loss of appetite and vomiting.
To help ensure that Rotarix® does notincrease the risk of intussusception, itsmanufacturer conducted a study of morethan 63 000 infants. In that study, therewas no increase in the risk of intussus-ception in those who received Rotarix®(31 673 infants) compared to those whoreceived placebo (31 552 infants).
Increased rates of convulsion and pneu-monia-related deaths were observed inthe Rotarix® recipients in the intussus-ception study, however these events werenot observed in other studies conductedby the manufacturer. Although the FDAhas concluded that the available data donot establish that these events are relatedto the vaccine, the agency has requestedthe manufacturer to conduct post-market-ing safety studies involving more than40 000 infants to provide additional safetyinformation.
Reference: FDA News, 3 April 2008 at http://www.fda.gov
New version of geneticallyengineered Factor VIIaapprovedUnited States of America — The Foodand Drug Administration (FDA) hasapproved a new formulation of the geneti-cally engineered version of Factor VIIa, aplasma protein essential for the clotting ofblood. The new formulation allows theproduct to be stored at room temperaturefor up to two years.
amount of acid produced in the stomachand help heal erosions in the lining of theesophagus known as erosive esophagitis.
FDA approved the use of esomeprazolemagnesium in patients 1 to 11 years forshort-term treatment of GERD basedupon the extrapolation of data fromprevious study results in adults to thepaediatric population, as well as safetyand pharmacokinetic studies performed inpaediatric patients. In one study, 109patients 1-11 in age, diagnosed withGERD, were treated with esomeprazolemagnesium once-a-day for up to eightweeks to evaluate its safety and tolerabil-ity. Most of these patients demonstratedhealing of their esophageal erosions aftereight weeks of treatment.
The most common adverse reactions inchildren treated with esomeprazolemagnesium were headache, diarrhea,abdominal pain, nausea, gas, constipa-tion, dry mouth and sleepiness. Thesafety and efficacy of Nexium® has notbeen established in children less thanone year of age.Reference: FDA News, 28 February 2008 athttp://www.fda.gov
Rotavirus vaccine approvedUnited States of America — The Foodand Drug Administration (FDA) hasannounced the approval of Rotarix®, thesecond oral US licensed vaccine for theprevention of rotavirus, an infection thatcauses gastroenteritis (vomiting anddiarrhea) in infants and children. Rotarixis a liquid and given in a two-dose seriesto infants from 6–24 weeks of age.Although the disease is usually self-limiting, rotavirus causes about 2.7 millioncases of gastroenteritis in US childreneach year — about 55 000 to 70 000 ofthose require hospitalization; and be-tween 20 and 60 deaths are attributed toit. Without vaccination, nearly every child
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The new formulation of NovoSevenCoagulation Factor VIIa (Recombinant)®—contains sucrose and L-Methionine,which allow for storage at room tempera-ture.
NovoSeven RT uses include treatment ofhemophilia A or B; treatment of bleedingand prevention of surgical bleeding inpatients with congenital Factor VII defi-ciency; and prevention of surgical bleed-ing in patients with acquired hemophilia.
The most commonly observed adversereactions with NovoSeven RT® are fever,bleeding, injection site reaction, jointdiscomfort, headache, elevations or fallsin blood pressure, nausea, vomiting, pain,swelling, and rash. Some elderly patientsexperienced an increased risk of arterialclotting when they were treated withNovoSeven RT® outside of its approvedindications.Reference: FDA News, 9 May 2008 at http://www.fda.gov
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International Pharmacopoeia
Role of The InternationalPharmacopoeia in qualityassuranceIn the pharmaceutical sense, a pharma-copoeia is an official, legally bindingpublication containing recommendedquality specifications for the analysis anddetermination of drug substances, spe-cific dosage forms, excipients and fin-ished drug products. A quality specifica-tion is a set of appropriate tests which willconfirm the identity and adequate purityof the product, ascertain the strength oramount of the active substance and,when needed, performance characteris-tics. General requirements are also givenin the pharmacopoeia on importantsubjects related to drug quality, such asmicrobiological purity, dissolution testing,or stability.
The underlying principles of a pharmaco-poeia are that pharmaceutical substancesand products intended for human useshould be manufactured at sites that areadequately equipped, dispose of appro-priate professional and technical knowl-edge and are operated by qualified staff.General rules of appropriate pharmaceu-tical manufacture are contained in thegood manufacturing practices (GMP)guidelines recommended by WHO (1)and/or those laid down by the competentnational or regional authority in thecountry of manufacture.
Protection provided by compendialstandards will depend not only on techni-cal content but also to a great extent onhow they are used in the context of othercontrol measures. When pharmacopoeialstandards are used to establish regula-
tory product compliance, the followingprinciples should be applied:
• the interpretation of a monograph mustbe in accordance with all generalrequirements and testing methods,texts, or notices pertaining to it;
• a product is not of pharmacopoeialquality unless it complies with all therequirements stated.
There is a practical distinction betweenpharmacopoeial standards and manufac-turers’ release specifications, althoughboth comprise sets of tests to which agiven product should conform. Releasespecifications are applied at the time ofmanufacture of a pharmaceutical productto confirm its appropriate quality but theyalso need to have a predictive value, tosupport the notion that the manufactureris responsible for the product during itsentire shelf-life. In many cases, pharma-copoeial monographs are based on thespecifications developed by the manufac-turers of innovator products.
Therefore, pharmacopoeial specificationsare not used to launch innovator productsbecause the manufacturer’s qualityspecifications will be evaluated by thecompetent regulatory authorities usingrigorous scientific assessment in conjunc-tion with pre-clinical and clinical safetyand efficacy data. It is important to notethat the regulatory focus has been shiftingfrom finished dosage form quality controlto the control of the whole complex ofprocesses and procedures involved in themanufacture of both active pharmaceuti-cal ingredients (APIs) and finished dos-age forms. The objective of a regulatoryapproval nowadays is to ensure that the
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manufacturer has built quality into theproduct from A to Z. In the case of amultisource (generic) medicine, wellresourced regulatory authorities requirethat it should contain the same activeingredients as the innovator drug and:• be identical in strength, dosage form,
and route of administration• have the same use indications• be bioequivalent (as a marker for
therapeutic interchangeability)• meet the same batch requirements for
identity, strength, purity and quality• be manufactured under the same strict
standards of GMP required for innovatorproducts.
In the case of multisource (generic)medicines, which are formulated afterpatents and other exclusivity rightsexpire, pharmacopoeial monographs areimportant as they enable manufacturersto develop products to meet the require-ments of pharmacopoeial standards (bothfor APIs and finished dosage forms)rather than elaborate their own specifica-tions. It should be noted that not allpharmacopoeias present monographs(quality standards) for finished dosageforms.
Pharmacopoeial standards should beused in the framework of all regulatorymeasures such as good manufacturingpractice (GMP) inspection of the manu-facture of active pharmaceutical ingredi-ents and finished dosage forms, andscientific assessment of all quality specifi-cations, interchangeability data andlabelling information. Their greatest valueis revealed during post-marketing surveil-lance of the quality of multisource (ge-neric) medicines.
Pharmacopoeial standards have alsocertain limitations. For example, testingusing pharmacopoeial methods will not
necessarily identify all possible danger-ous impurities. Pharmacopoeial methodsare usually designed to catch the impuri-ties that are likely to occur during theroute of synthesis that has been utilizedby the originator. In case of a differentroute of synthesis or accidental contami-nation with other chemicals, it may notnecessarily pick up impurities even if theypose a danger to health. This is why wellresourced regulatory authorities neverbase marketing authorization ofmultisource (generic) products on qualitycontrol testing based on pharmacopoeialmonographs alone. In fact, pre-marketingquality control testing has diminishedconstantly and more accent is put onmarket surveillance after the product isreleased onto the market.
Pharmacopoeial monographs help toverify the quality and, in the case ofmultisource (generic) medicines, theymay indicate pharmaceutical interchange-ability with the originator product.
Beginnings and history ofThe International PharmacopoeiaThe history of The International Pharma-copoeia dates back to 1874 when theneed to standardize terminology and tospecify dosages and composition ofdrugs led to attempts to produce aninternational pharmacopoeial compen-dium. A first conference, called by theBelgian Government and held in Brusselsin 1902, resulted in the Agreement for theUnification of the Formulae of PotentDrugs, which was ratified in 1906 by 19countries. A second agreement, theBrussels Agreement, was drawn up in1925 and ratified in 1929. This 41-articleagreement stipulated that the League ofNations would be responsible for theadministrative work to produce a unifiedpharmacopoeia, and a permanent secre-tariat of an international organizationwould coordinate the work of nationalpharmacopoeial commissions. Generalprinciples for the preparation of galeni-
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cals, maximal doses, nomenclature, andbiological testing of arsenobenzoneswere included in the articles of thisagreement, as was a table of dosagestrengths and descriptions for 77 drugsubstances and preparations.
In response to repeated calls from phar-maceutical experts in various countriesthat the Brussels Agreement be revisedand extended to cover an internationalpharmacopoeia, the Health Organizationof the League of Nations set up a Techni-cal Commission of PharmacopoeialExperts in 1937. This first committeecomprised seven experts from Belgium,Denmark, France, the Netherlands,Switzerland, United Kingdom, and UnitedStates of America.
In 1947 the Interim Commission of WHOtook over the work on pharmacopoeiaspreviously undertaken by the HealthOrganization of the League of Nations,and set up an Expert Committee on theUnification of Pharmacopoeias to con-
tinue the work of the League’s TechnicalCommission. In 1948 the First WorldHealth Assembly approved the establish-ment of the Expert Committee by theInterim Commission. In 1951 this becamethe Expert Committee on the InternationalPharmacopoeia; and subsequently, in1959, the Expert Committee on Specifica-tions for Pharmaceutical Preparations.The panel of experts serving this Commit-tee was named the WHO Expert AdvisoryPanel on the International Pharmaco-poeia and Pharmaceutical Preparations.
Managing The InternationalPharmacopoeiaWork on The International Pharmaco-poeia is carried out in collaboration withmembers of the WHO Expert AdvisoryPanel on the International Pharmaco-poeia and Pharmaceutical Preparationsas well as with specialists from thepharmaceutical industry and other institu-tions. This is followed by consultation withnational and regional pharmacopoeiasand a working procedure based on wide
1874 Discussion on Unification of terminology and composition of drugs
1902 First Conference organized by the Government of Belgium
1906 Agreement on Unification of the Formulae of Potent Drugs ratifiedby 19 states
1925 Brussels agreement (signed 1929)
1937 First meeting - Health Organization of the League of Nations
1947 Interim Commission of WHO takes up health-related work ofLeague of Nations
1948 First World Health Assembly (WHA) establishing the Expert Committee on Unification of Pharmacopoeias
1950 WHA approved publication of Pharmacopoeia Internationalis
2006 Publication of 4th edition of The International Pharmacopoeia (3)
International Pharmacopoeia milestones
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international consultation. The specifica-tions and general methods included inThe International Pharmacopoeia benefitfrom an international worldwide validationprocess, using a global network of exper-tise. This is undertaken with a view toserve all 193 WHO Member States, theglobal market and increasing tradearound the world. This is a major differ-ence with other pharmacopoeias thatprovide control specifications for themedicines sold within their country orregion.
Development of monographs for inclusionin The International Pharmacopoeia
Procedure
Step 1: Identify specific pharmaceuticalproducts for which quality control (QC)specifications need to be developed,obtain confirmation from all WHO partiesconcerned (e.g. Department of MedicinesPolicy and Standards, Prequalificationproject team and specific disease pro-grammes).
Step 2: Provide contact details for manu-facturers of the above products in col-laboration with all parties concerned.
Step 3: Contact manufacturers to requestprovision of QC specifications and sam-ples.Step 4: Identify and contact QC laborato-ries to collaborate in the project (2–3laboratories depending on how manypharmaceutical products have beenidentified in step 1. Contract for laboratorywork.
Step 5: Prepare the contract for draftingthe specifications and undertaking thenecessary laboratory work.
Step 6: Search for information on QCspecifications available in the publicdomain.
Step 7: Conduct laboratory testing,development and validation of QC specifi-cations.
Step 8: Support WHO CollaboratingCentre in the establishment of Interna-tional Chemical Reference Substances.
Step 9: Follow the consultative process:send copies of draft specifications toExpert Advisory Panel and to specialistsfor comments.
Step 10: Discuss comments with contractlaboratories and WHO CollaboratingCentres. Conduct additional laboratorytesting to verify and/or validate specifica-tions.
Step 11: Hold a consultation to discussthe comments and test results receivedas feedback.
Step 14: Present final draft to the WHOExpert Committee on Specifications forPharmaceutical Preparations for possibleformal adoption (for example, see theCommittee report from 2006, reference 6).If not adopted, repeat steps 11–13.
The aim within this process is to keep thenumber of reference standards to aminimum, thus balancing the cost ofanalysis with identification of potentialhealth risks for users.
Advantages of The InternationalPharmacopoeiaUnlike national (and regional) pharma-copoeias The International Pharmaco-poeia has no determined legal status andWHO Member States are free to adoptand incorporate it, either in part or inwhole, into national legislation. Advan-
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tages of The International Pharmaco-poeia are:
• International validation of specificationsthrough an independent scientificprocess.
• Input from WHO Collaborating Centresand national drug quality control labora-tories in the six WHO regions of Africa,the Americas, Eastern Mediterranean,Europe, South-East Asia and WesternPacific.
• Collaboration with manufacturersaround the world, especially for newprojects where no public standardsexist.
• Collaboration with standard-settingorganizations and parties, includingregional and national pharmacopoeias.
• Networking and close collaboration withWHO Member States and drug regula-tory authorities.
• Maintaining minimum cost of analysisthrough use of robust test methods andminimum number of references stand-ards.
• Input and feedback from other WHOactivities, such as the WHO/UNICEF/World Bank Prequalification Project.
• Free for use by all WHO MemberStates.
Published editions ofThe International Pharmacopoeia
First editionThe first edition, published with the aim ofcreating a worldwide, unified pharmaco-poeia, relied on collaboration with na-tional pharmacopoeia commissions for itspreparation. It was published in twovolumes (1951 and 1955) and a supple-ment (1959) in English, French andSpanish, and was also translated intoGerman and Japanese. Altogether, itincluded 344 monographs on drug
substances, 183 monographs on dosageforms (capsules, injections, tablets andtinctures) and 84 tests, methods, andgeneral requirements.A large number of national pharma-copoeias and official lists were examinedand assistance was also obtained fromthe International Pharmaceutical Federa-tion (FIP) to determine the selection ofsubstances and products to be describedin the pharmacopoeia.
Second editionThe second edition was published in1967 as Specifications for the QualityControl of Pharmaceutical Preparations.The selection of monographs and appen-dices was based largely on the availabil-ity, at the time, of specifications intendedfor publication in national pharmaco-poeias and in other volumes of specifica-tions for pharmaceutical quality control.Specifications for 162 pharmaceuticalpreparations not included in the firstedition were introduced in the secondedition, while 114 monographs weredeleted, based on feedback from the firstedition. New analytical methods werealso added.
Third editionIn 1975, The International Pharmaco-poeia was re-focused on the needs ofdeveloping countries and recommendedsimple, classical chemical techniques thathad been demonstrated as sound. Prioritywas given to medicines that were widelyused throughout the world and medicinesimportant to WHO public health pro-grammes, also targeting those sub-stances likely to contain impurities arisingfrom degradation or due to difficulties inmanufacture. Robust analytical testmethods and procedures were preferredwhenever applicable without compromis-ing public health. A flexible approach wasemployed to facilitate accessibility ofcontrol specifications for less wellequipped national quality control labora-tories. Since 1979, the medicines appear-
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ing in The International Pharmacopoeiahave been selected from the WHO ModelList of Essential Medicines.
The five volumes of the third editioncontained 62 general methods of analysisand requirements, quality specificationsfor 255 active pharmaceutical ingredients— the majority of essential drug sub-stances in the WHO Model List of Essen-tial Medicines — 65 quality specificationsfor pharmaceutical excipients, and 67finished dosage forms.
Fourth editionThe fourth edition of The InternationalPharmacopoeia was published in 2006(2). It comprises two volumes: GeneralNotices and monographs for pharmaceu-tical substances (A to O) are to be foundin Volume 1 and the remaining mono-graphs for pharmaceutical substances (P-X), together with those for dosage formsand radiopharmaceutical preparations,methods of analysis and the reagentsections are to be found in Volume 2.
This new edition consolidates the texts ofthe five separate volumes of the thirdedition and includes new monographs forantiretrovirals together with updates andrevisions of the existing, previouslypublished texts. Significant changes andimprovements have been made in thepresentation, cross-referencing to generalmethods.
The new notice on Definition, for exam-ple, serves to define dosage forms asbeing manufactured with active ingredi-ents of pharmacopoeial quality and toclarify the mandatory status of certainstatements in monographs. The newnotice on Manufacture governs theinterpretation of statements includedunder this heading in monographs suchas the general monographs for dosageforms, the monographs for the differentgrades of water and certain other indi-vidual monographs. The need for a notice
on Impurities arose from the inclusion ofinformation at the end of certain newmonographs for antiretroviral substances.Such lists of known and potential impuri-ties that have been shown to be control-led by the tests in a monograph are likelyto be included more widely in future.
Most importantly, a new series of mono-graphs has been added for antiretrovirals.These monographs have been developedas part of the WHO strategy to makequality antiretroviral medicines widelyavailable. Such specifications support thejoint WHO/UNICEF/World Bank Prequali-fication Project managed by WHO (3).These new monographs provide anelement of choice in relation to testmethods used for identification and,where possible, a titration method forassay, in line with established policy.However, in order to provide adequatecontrol of impurities, it has been foundnecessary to place reliance on HPLC.
CD-ROMThe fourth edition was published simulta-neously both in print and on CD-ROM (2).This provides users of The InternationalPharmacopoeia with a choice of formatwith which to consult the publicationdepending on the circumstances and thetype of enquiry. The response from usersof the CD-ROM has demonstrated theusefulness of making the publicationavailable electronically. The simplifiedstructure of the fourth edition and theimproved functionality of the CD-ROM willfacilitate both reading and searching text.
Future role of The InternationalPharmacopoeiaWork is in progress on the preparation ofnew monographs for antiretroviral sub-stances, the associated dosage formsand for a number of fixed-dose combina-tion products for the treatment of HIV/AIDS, malaria and tuberculosis. Specialattention is also being given to paediatricformulations.
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Revision of monographs is also continu-ing to improve specifications, for exam-ple, by providing better means of impuritycontrol or by the addition of a dissolutiontest. Additions and revisions to the fourthedition will be made available at appropri-ate intervals.
Meanwhile, attention is drawn to theWHO Medicines website (htpp://www.who.int/medicines), where texts ofmonographs adopted by the ExpertCommittee on Specifications for Pharma-ceutical Preparations are providedtogether with other detailed information.
International ChemicalReference SubstancesInternational Chemical Reference Sub-stances (ICRS) are primary chemicalreference standards. They are suppliedfor use in physical and chemical tests andassays described in the specifications forquality control of drugs published in TheInternational Pharmacopoeia or proposedin draft monographs. The ICRS may beused to calibrate secondary standards.
Analytical data on ICRS are given incertificates enclosed with the referencesubstances. ICRS may also be used intests and assays not described in TheInternational Pharmacopoeia. The re-sponsibility for assessing the suitability ofthe reference substances then rests withthe user.
For ordering information, please visit thewebsite of the WHO Collaborating Centrefor Chemical Reference Standards: http://www.apl.apoteket.se/who.
Links to other WHO activitiesAn important feature of The InternationalPharmacopoeia is that it forms a basicelement of quality assurance activities.WHO gives advice on the establishmentand management of national qualitycontrol laboratories, prepares guidelineson functioning, publishes guidance and
gives advice on good manufacturingpractices and other regulatory issues,following the underlying principle thatquality must be built into a product fromthe very beginning of the manufacturingprocess.
There is also a close link with the Interna-tional Nonproprietary Names (INN)programme which is responsible fornaming new pharmaceutical entities. Thelists of International NonproprietaryNames are published in a regular manner(3). The whole area of work is overseenby the WHO Expert Committee on Speci-fications for Pharmaceutical Preparations.The WHO Expert Committee on Specifi-cations for Pharmaceutical Preparationsis an advisory body on quality assuranceto WHO and its Member States. Adviceand recommendations provided by thisExpert Committee are intended to supportnational and regional authorities (inparticular drug regulatory authorities),procurement agencies, and internationalbodies and institutions such as the GlobalFund, and international organizationssuch as UNICEF, to combat problems ofcounterfeit and substandard medicinesand underpin important WHO initiatives.
ConclusionThe role of WHO in quality assurance ofmedicines, especially for those countriesthat have no or little means to developtheir own quality control specifications, isimportant. WHO has numerous activitiesto support Member States such ascreating nomenclatures and developingguidance, while also delivering trainingcourses and workshops on various topicsof quality assurance to build nationalcapacity to regulate medicines. TheInternational Pharmacopoeia in conjunc-tion with International Chemical Refer-ence Substances are regarded as essen-tial tools in the overall framework ofquality control and quality assurance ofpharmaceuticals, thus contributing to thesafety and efficacy of drugs.
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References
1. World Health Organization. Quality assur-ance of pharmaceuticals. A compendium ofguidelines and related materials, Volume 2,2nd update. Good manufacturing practicesand inspection. 2007 (388 pages)
2. World Health Organization. The Interna-tional Pharmacopoeia, 4th edition (alsoavailable on CD-ROM). Volume 1: generalnotices; monographs for pharmaceuticalsubstances (A–O). Volume 2: monographs forpharmaceutical substances (P–Z); mono-graphs for dosage forms and radiopharmaceu-tical preparations; methods for analysis;reagents , 2006 (1499 pages)
3. Prequalification Programme. Web site:http://mednet3.who.int/prequal/
4. World Health Organization. Expert Commit-tee on Specifications for PharmaceuticalPreparations. Fortieth report. Technical ReportSeries, No. 937. 2006 (461 pages)
5. World Health Organization. Internationalnonproprietary names (INN) for pharmaceuti-cal substances. CD-ROM, 2007 (web site:http://bookorders.who.int/bookorders/anglais/qsearch1.jsp?sessla
