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Who drug information vol2

  1. 1. WHO Drug Information Vol 23, No. 2, 2009 World Health OrganizationWHO Drug Information ContentsPharmacovigilance Focus Sodium valproate and fetal malformations 113 Abacavir: determining risk of heart attack 114Biosimilar medicines and safety: new Carbamazepine: serious adverse skinchallenges for pharmacovigilance 87 reactions 114 Electronic adverse reaction reporting tool 115Blood and Biomedicines Intensive monitoring of varenicline 116Availability, quality and safety of blood and blood products 95 Regulatory Action and News Influenza virus vaccines: 2009–2010New Regulatory Challenges season 117Contribution of clinical pharmacologists Sale of efalizumab suspended 117 to government: opportunities and Efalizumab: voluntary withdrawal 118 challenges 99 Oseltamivir: extension of shelf life 118 Antiviral medicines in an influenza pandemic 119Safety and Efficacy Issues European Union and Health Canada:Etanercept: histoplasmosis and invasive confidentiality arrangement 119 fungal infections 104 Ixabepilone: withdrawal of applicationZonisamide: metabolic acidosis 104 for marketing authorization 120Progressive multifocal leuko- Peginterferon alfa–2b: withdrawal of encephalopathy 105 application for marketing authorization 120Severe adverse reactions with Levodopa/carbidopa/entacapone: intravenous immunoglobulin 105 withdrawal of application forExanatide: risk of severe pancreatitis extension of indication 120 and renal failure 106Benefits of methylphenidate continue to Medicines Strategy outweigh risks 106Chromic phosphate P32: acute and Policies lymphocytic leukaemia 107 Good Governance for MedicinesWarning for metoclopramide-containing Programme 122 drugs 108Metabolic effects of antipsychotics 108Cefaclor and serum sickness-like Recent Publications, reactions in children 108 Information and EventsToremifene: prolongation of QTc interval 109 ASEAN: mutual recognition arrangementAtomoxetine: risk of psychotic or manic for GMP 127 symptoms 109 Losing artemisinin? 127Lignocaine with chlorhexidrine gel: International drug price indicator guide 128 anaphylaxis 110Moxifloxacin safety update 110Codeine toxicity in breastfed infants 110 Proposed InternationalAtypical antipsychotics: risk of stroke 111Biphosphonates: atypical stress fractures 112 Nonproprietary Names: 129Effects of MRI on implantable drug pumps113 List 101 85
  2. 2. World Health Organization WHO Drug Information Vol 23, No. 2, 2009 WHO Drug Information is also available online at http://www.who.int/druginformation NEW ! WHO Drug Information DIGITAL LIBRARY with search facility at http://www.who.int/druginformation Subscribe to our e-mail service and receive the table of contents of the latest WHO Drug Information (To subscribe: send a message to LISTSER@WHO.INT containing the text: subscribe druginformation)86
  3. 3. WHO Drug Information Vol 23, No. 2, 2009Pharmacovigilance FocusBiosimilar medicines and Biological medicinal products (biopharma- ceuticals) have a successful record insafety: new challenges for treating many life threatening and chronicpharmacovigilance diseases. However, their cost has often been high, thereby limiting their access toRegulatory experience of approving and patients, notably in developing countries.monitoring the safety of biosimilar medi- More recently, the expiration of patentscines varies across the world. Recently, and/or data protection for the first majorthe European Union (EU) took the lead in group of innovative biotherapeutics isestablishing a transparent regulatory stimulating development of productsprocess for approving biosimilars. To “similar” to the original biological productsdate, the EU has approved a number of which rely for their licensing, in part, onbiosimilars such as formulations of data from originator products licensed onsomatotropin, epoietin and, most recently, a full registration dossier.filgrastim. The prevailing view amongregulators is that proteins are much more A variety of terms, such as ‘biosimilars’,complex than small molecule medicines ‘follow-on protein products’ and ‘subse-and it may not be possible to demonstrate quent-entry biologics’ have been used bythe identical nature of two biological different jurisdictions to describe theseproducts originating from different manu- products. The term ‘generic’ medicine isfacturing sources solely based on quality used extensively for chemical, smallinformation. molecule medicinal products that are structurally and therapeutically equivalentThis has led to the view that follow-on to an originator product whose patentbiological products manufactured by and/or data protection period has expired.generic manufacturers after expiry ofpatent and other exclusivity rights cannot Current situationbe approved using the same simplified In many countries, a regulatory pathwayregulatory procedures as applied for for the approval of generic medicines hassmall molecule-based generic drugs. been established. Since biological medici-Generating additional nonclinical and nal products consist of large and highlyclinical data to demonstrate that these complex molecular entities that aremedicines have an equivalent, or similar, difficult to characterize, the approachsafety and efficacy profile to the originator established for small molecule genericproduct is needed. However, several medicines is not fully appropriate forparties have raised concerns that such development, evaluation and licensing ofregulatory procedures may not be enough biosimilars — as they are called in theto ensure the safety and efficacy of these EU. The fine structure of a biotherapeuticproducts. This article gives an overview of medicine is very sensitive to variousregulatory experience as well as the main production parameters and the fullprinciples and issues concerning quality, understanding of all processes involved issafety and efficacy of these products. complicated. Thus, it is unlikely that one* This article does not necessarily reflect the policies and views of the World Health Organiza-tion. 87
  4. 4. Pharmacovigilance Focus WHO Drug Information Vol 23, No. 2, 2009manufacturer will be able to precisely regulation was formally recognized by thereproduce a biotherapeutic medicine World Health Organization (WHO) inmanufactured by another company. 2007. Since then, WHO has been work-Indeed, an increasingly wide range of ing with regulators from many countriesbiosimilars are under development or on a draft document that provides guid-already licensed in many countries. ance for the development and evaluation of biological therapeutic products thatAs stated, the EU has taken the lead in may be subject to abbreviated licensingestablishing a regulatory process for pathways [11]. The document is expectedapproving biosimilars and EU legislation to be finalized later in 2009.now differentiates between “genericmedicinal products” and “similar biological Generic medicines and biosimilars:medicinal products”. It also defines the similarities and differencesregulatory approach for EU marketing Multisource (generic) medicines areauthorization of biosimilar medicinal formulated when patent and other exclu-products. Both general [1–3] and product- sivity rights expire. These medicines havespecific guidelines dealing with recom- an important role to play in public healthbinant erythropoietin [4], granulocyte as they are well known to the medicalcolony stimulating factor (G-CSF) [5], community and usually more affordablehuman somatotropin [6] and human due to competitive availability.insulin [7] have been issued by theCommittee for Medicinal Products for The key requirement for authorization ofHuman Use (CHMP) of the European generic medicines is therapeutic inter-Medicines Agency (EMEA). Draft guide- changeability with the originator product.lines have also been issued for interferon To ensure therapeutic interchangeability,alfa [8] and low molecular weight generic products must contain the sameheparins [9]. All these guidelines have amount of active ingredient and have theone common feature — identifying the same dosage form and be bioequivalentneed for at least some clinical data to to the originator product. Bioequivalencesupport the approval of biosimilar medici- is usually established using comparativenal products. in vivo pharmacokinetic studies with the originator product (or reference product).In the USA, there is currently no set of A detailed description of how this isguidelines comparable to those of the EU carried out is described in respectivefor biosimilars. The Food and Drug WHO and national regulatory guidelinesAdministration (FDA) has approved [12, 13]. Well-resourced regulatoryOmnitrope®, a growth hormone biosimilar, authorities require that a multisourcebut this was done using the abbreviated (generic) medicine must meet certainnew drug application (ANDA) procedure regulatory requirements. In a well estab-which essentially defines biosimilars as lished setting, a generic medicine in“chemical” generic drugs rather than general must:biopharmaceuticals [10]. However, thismethod of approval is rather exceptional • contain the same active ingredients asas specific US regulatory guidelines for the innovator drug;approval of biosimilars do not currentlyexist. Also, in most other countries a • be identical in strength, dosage form,comparative set of guidelines to those of and route of administration;the EU is absent. • have the same use indications;The need for additional global regulatory • be bioequivalent (as a surrogate markerguidelines for evaluation and overall for therapeutic interchangeability).88
  5. 5. WHO Drug Information Vol 23, No. 2, 2009 Pharmacovigilance Focus• meet the same batch requirements for necessarily implies different host cell identity, strength, purity and quality, and impurities as a minimum but the regulator has accepted the product as biosimilar• be manufactured under the same [14]. Differences with other products have standards of good manufacturing been justified as being within the range of practice (GMP) required for innovator natural variants without major clinical products. impact.Traditional generic medicines are small, Originator products can go through aorganic molecules with a well-character- number of variations during productized structure which can be more easily development and the post marketingdefined by their atomic structure than period. However, it is difficult to ascertaintheir manufacturing processes. In the whether major process variations (e.g.case of more complicated generic medi- cloning, selection of a suitable cell line,cines, processes of synthesis are used. fermentation, purification and formulation)For example, biotechnological methods will affect the end product. Thus, a bio-are applied to produce large molecule similar may differ significantly from themedicines such as antibiotics (for exam- originator product. In principle, some ofple, streptomycin). Sometimes, several the variations applied by originators canmethods of synthesis are combined, be more substantial than those applied byincluding the use of genetically engi- generic manufacturers. When assessingneered microorganisms in fermentation. and accepting variations applied to theWhat makes a difference is how well the manufacture of originator products,resulting active pharmaceutical ingredient regulators can acquire valuable informa-(API) can be characterized without risking tion for assessing biosimilars.unidentified impurities and subtle struc-tural changes resulting in different safety At present, lack of consistency betweenand efficacy profiles. originator epoietins and products manu- factured in countries outside well regu-The current challenge facing international lated markets (such as the EU and USA)development of a programme for bio- was demonstrated at the World Congresssimilars is that there is no way of confirm- of Nephrology in 2007 [15, 16]. Someing that the reference product on the products were identified as containingmarket in one region complies with additional basic isoforms — more thanrequirements in other regions. It is true 4% aggregates and bacterial endotoxinthat even identifying a global comparator contamination. These findings may affectfor generic “chemical” medicines is efficacy, immunogenicity and patientsometimes very challenging. Above all, safety, respectively [16, 17]. Finally, somethe essential characteristics of a bio- of these biosimilar products were notsimilar are not yet perfectly defined. For approved under a specific well-definedexample, some consider that only fully and transparent regulatory framework.characterized proteins with no major Biopharmaceutical safety and efficacydifferences in their structure or impurity data are difficult to transcribe into aprofile can be considered biosimilar. discernable format and it is a challengeHowever, EU regulators have accepted a demonstrating that a biosimilar product isdegree of difference provided it can be as safe or effective as the originator. It isjustified. For example, Valtropin® (soma- hoped that rapid advances in science andtotropin) is expressed from yeast whereas knowledge obtained from regulatoryits reference product, Humotrope®, is practice may make this task easier in theexpressed from Escherichia coli. This future. 89
  6. 6. Pharmacovigilance Focus WHO Drug Information Vol 23, No. 2, 2009Safety of biosimilars: specific Another important factor is potentialpoints of concern contamination during manufacturing.The two main issues of concern with Impurities in biopharmaceuticals maybiosimilar agents involve variable po- derive from chemicals or antibiotics usedtency/response and immunogenicity during manufacture or may result fromthought to be due to one of three main microbial or viral contamination. Impuritiesmechanisms: glycosylation, contamina- such as endotoxins or denatured pro-tion or changes to three-dimensional teins, for example, may give a dangerstructure. Immunogenicity is generally the signal to T cells which may then sendprimary safety concern, but variation in activating signals to B cells leading to anpotency can also raise safety issues in immune response.the case of substitution of the originalmolecule with biosimilars, e.g. variability An important lesson was learned in thein haemoglobin values seen with original case of an increasing incidence of anti-epoietin [18] and its possible association body-mediated pure red cell aplasiawith increased mortality in dialysis pa- (PRCA) observed outside the USAtients [19]. The issues of safety and between 2000 and 2002 which revealedefficacy cannot easily be separated as that a small change in the formulation of abinding of an agent by immune system well-established innovator biopharma-molecules will often decrease its clinical ceutical product (epoietin alfa) witheffect and changes to the shape or extensive patient years experience maystructure of a protein can alter binding to have significant clinical consequencesimmune system receptors as well as to its [22]. The sharp increase in incidencephysiological target. Therefore, biosimi- occurred primarily among those onlars could induce immune responses Eprex®/Erypo®, and coincided withwhich may be either clinically irrelevant or replacement of human serum albumin ascould have severe and potentially lethal a stabilizer by glycine and polysorbate 80.consequences. Subsequent withdrawal of the SC formu- lation of epoietin alfa led to a consider-The glycosylation of recombinant proteins able decrease in the incidence of PRCAcan influence degradation, exposure of cases. A number of possible mechanismsantigenic sites and solubility, as well as have been proposed to explain theimmunogenicity. Changes in degradation observed upsurge of PRCA but it is likelycan produce novel antigenic epitopes not the modification in formulation played afound in the parent molecule with poten- major role [23].tially increased immunogenicity andbiological activity and metabolic half-life Alterations to the three-dimensionalalso affected. The degree of glycosylation structure of a protein may also havedepends primarily on the host cell expres- important effects on immunogenicity.sion system. For example, recombinant Major sources of such changes includeG-CSF expressed in Escherichia coli is protein aggregation (which has beennon-glycosylated, whereas that ex- suggested as one possible explanation ofpressed in Chinese hamster ovary cells is the PRCP epidemic described above),glycosylated. Similarly, proteins manufac- oxidation and deamidation. Likely aggre-tured in yeast cells contain high levels of gation is of particular concern as it maymannose sugar groups, rendering them lead to the immune system recognizingmore prone to degradation and thereby the protein as non-self and mounting adecreasing their half-life. [See references response [24]. This is probably because20 and 21 for more details about effects the repeating structure of protein aggre-of immunogenicity.] gates more closely resembles the micro-90
  7. 7. WHO Drug Information Vol 23, No. 2, 2009 Pharmacovigilance Focusbial structures that the immune system is even very small changes in manufactur-primed to act against [25]. The process ing can have major consequences for aby which the body becomes reactive to product’s adverse effects [27]. Pharma-the protein can be very slow: antibodies covigilance is thus likely to be a long-termto products such as interferon and eryth- project for any biosimilar medicine.ropoietin may be detected for more than a Overall, routine pharmacovigilance isyear after treatment cessation [26]. recommended for products where no special concerns have arisen, whereasClinical safety data additional pharmacovigilance activitiesand pharmacovigilance and action plans will be required forThe concerns raised above have been medicinal products with important estab-addressed, as far as possible and in line lished risks, potential risks or missingwith present scientific knowledge, in EU information.regulatory guidance. For example,erythropoietin is a more complex mole- Spontaneous reporting still remains thecule compared to either insulin or growth cornerstone of pharmacovigilance but hashormone. The respective guidelines several weaknesses. Often, only thereflect this complexity and, in order to international nonproprietary name (INN)identify potential immunogenicity, advo- is used as the sole product identifier andcate conducting at least two randomized in the case of several products with thecontrolled trials confirming safety data same INN (originator, plus generics orcollected over a minimum of 12 months biosimilars) it may be difficult to trace thefrom at least 300 patients. Within the EU exact manufacturer of the product. Aauthorization procedure, the applicant much better traceability of products isshould present a risk management needed [28], particularly in the case ofprogramme/pharmacovigilance plan in biosimilars.accordance with current EU legislationand pharmacovigilance guidelines. Recent developments within the Interna- tional Conference on Harmonization ofIn order to further study the safety profile Technical Requirements for Registrationof the biosimilar medicinal product, data of Pharmaceuticals for Human Use (ICH)for rare adverse events should be col- raise hopes that a harmonized set oflected from a cohort of patients represent- product identifiers will become availableing all approved therapeutic indications. soon and could improve future traceabil-Specific reference is made to include ity. Recently, the ICH Steering Committeeassessment of the incidence of PRCA recognized the benefits of continuing towithin the pharmacovigilance plan for work with International Standard Develop-epoietin biosimilars [4]. It is clear that with ment Organizations in developing harmo-300 patients PRCA may not be detected nized electronic messages to transferdue to the relatively small number of regulatory information with a view topatients involved as compared to the developing harmonized formats forrarity of this complication. Consequently, Individual case safety reports (ICSR) andEMEA guidelines for epoietins also identification of medicinal products [29]require immunogenicity testing andpharmacovigilance programmes to Different versions of biopharmaceuticalsmonitor the efficacy and safety of have been available in both India andbiosimilar products during post-approval. China for several years [30]. It is impor- tant to note that both India and China areNonetheless, some adverse effects may considered to have less stringent regula-take more than a year to appear [26] and tory standards than the EU and the USA. 91
  8. 8. Pharmacovigilance Focus WHO Drug Information Vol 23, No. 2, 2009Unfortunately, both countries have under- but patients should not be expected todeveloped pharmacovigilance systems bear the burden of excessive trial-errorand provide only small number of adverse incidents.drug reaction reports to the WHO Interna-tional Programme on Drug Monitoring Referencesdatabase managed by the Uppsala 1. European Medicines Agency. Guideline onMonitoring Centre [31]. Similar Biological Medicinal Products, CPMP/ 437/04, October 2005. www.emea.europa. eu/Conclusions pdfs/human/biosimilar/043704en.The cost of providing effective therapiesin different disease areas increases 2. European Medicines Agency. Guideline onprogressively and biosimilar medicines Similar Biological Medicinal Products Contain- ing Biotechnology-derived Proteins as Drugmay offer considerable advantages to Substance – Non Clinical and Clinical Issues,hard-pressed health-care budgets glo- CHMP/42832/05, February 2006. www.emea.bally. Regulatory decisions to permit europa.eu/pdfs/human/biosimilar 4283205en.clinical use should be based on rigorousand highly competent case by case 3. European Medicines Agency. Similarscientific assessments and presence of Biological Medicinal Products Containingappropriate systems for pharmacovigi- Biotechnology-derived Proteins as Active Substance: Quality Issues, CHMP/49348/05,lance. Clearly this area of rapidly evolving February 2006. www.emea.europa.eu/pdfs/regulatory science would benefit from human/biosimilar/4934805en.better cooperation and informationexchange between different regulators 4. European Medicines Agency. Annexinternationally. Safety has to come first Guideline on Similar Biological Medicinaland effective pre- and post-marketing Products Containing Biotechnology-derivedsafety monitoring remains the key. Proteins as Drug Substance – Non Clinical and Clinical Issues containing Recombinant Human Erythtropoietin, CHMP/94526/05,Sufficient regulatory tools are currently March 2006. www.emea.europa.eu/pdfs/available to ensure safety of biosimilars human/biosimilar/9452605en.but the proper implementation of thesetools may prove challenging, particularly 5. European Medicines Agency. Annexoutside well established and resourced Guideline on Similar Biological Medicinalregulatory settings. Even in the EU, Products Containing Biotechnology-derivedapplying pharmacovigilance programmes Proteins as Drug Substance –Non Clinical andwith uniform excellence across the region Clinical Issues containing Recombinantremains a challenge. Pharmacovigilance Granylocyte Colony-Stimulating Factor, CHMP/313297/05, February 2006. www.is a responsibility that is shared among emea.europa.eu/pdfs/human/biosimilar/actors in the pharmaceutical industry, 313297/05en.physicians and pharmacists, with inputfrom appropriately educated and informed 6. European Medicines Agency. Annexpatients. Much better cooperation be- Guideline on Similar Biological Medicinaltween all stakeholders is needed to Products Containing Biotechnology-derivedensure that everyone involved fully Proteins as Drug Substance – Non Clinicalunderstands the complex scientific and Clinical Issues containing Recombinantarguments and regulatory decisions Human Growth Hormone, CHMP/94528/05,applying to biosimilar products. This February 2006. www.emea.europa.eu/pdfs/ human/biosimilar/9452805en.would hopefully lead to safer use andbetter qualitative and quantitative report- 7. European Medicines Agency. Annexing of suspected adverse reactions. Guideline on Similar Biological MedicinalBiosimilar medicines clearly have a future Products Containing Biotechnology-derived92
  9. 9. WHO Drug Information Vol 23, No. 2, 2009 Pharmacovigilance FocusProteins as Drug Substance – Non Clinical 16. Singh AK. Gaps in the quality and potentialand Clinical Issues. Guidance on Similar safety of Biosimilar epoetins in the developingMedicinal Products Containing Recombinant world: an international survey. Abstract S-PO-Human Insulin CHMP/BMWP/32775/05, 0412. World Congress of Nephrology, AprilFebruary 2006. www.emea.europa.eu/pdfs/ 21–25, 2007, Brazil, Rio de Janeiro. Availablehuman/biosimilar/3277505en. at: http://www.wcn2007.org8. European Medicines Agency. Guideline on 17. Hermeling S, Schellekens SH, CrommelinSimilar Biological Medicinal Products Contain- DJ et al. Micelle-associated protein in epoetining Low-molecular Weight Heparins EMEA/ formulations: a risk factor for immunogenicity?CHMP/BMWP/118264/07. Draft released for Pharm Res 2003, 20:1903–1907.consultation in April 2008. www.emea.europa.eu/pdfs/human/biosimilar/11826407en. 18. Berns JS, Elzein H, Lynn RI et al. Hemoglobin variability in epoetin-treated9. European Medicines Agency. Guideline on hemodialysis patients. Kidney Int 2003Similar Biological Medicinal Products Contain- 64:1514–1521.ing Recombinant Interferone Alpha EMEA/CHMP/BMWP/102046/06. Draft released for 19. Yang W, Israni RK, Brunelli SM, et al.consultation in October 2007. www.emea. Hemoglobin variability and mortality in ESRD.europa.eu/pdfs/human/biosimilar/ J Am Soc Nephrol 2007 18:3164–3170.10204606en.10. Belsey MJ, Harris LM, Das RR et al. 20. Kessler M, Goldsmith D, Schellekens H.Biosimilars: initial excitement gives way to Immunogenicity of biopharmaceuticals.reality. Nat Rev Drug Discov 2006, 5:535–536 Nephrology Dialysis Transplantation 2006 21(5:v9-v12). http://ndt.oxfordjournals.org/cgi/11. World Health Organization. Regulatory content/full/21/suppl_5/v9pathways for biosimilar products. WHO DrugInformation 2008 22(1). www.who.int/ 21. Biosimilars and biopharmaceuticals: whatdruginformation the nephrologists need to know—a position paper by the ERA–EDTA Council. Nephrology12. World Health Organization. Multisource Dialysis Transplantation 2008 23(12):3731–(generic) pharmaceutical products: guidelines 3737 http://ndt.oxfordjournals.org/cgi/content/on registration requirements to establish inter- full/23/12/3731changeability. In: WHO Expert Committee onSpecifications for Pharmaceutical Prepara- 22. Casadevall H, Nataf J, Viron B et al. Puretions. Fortieth Report. Technical Report red-cell aplasia and anti-erythropoietinSeries, 937, Annex 7, 347–390. antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002 346:469–13. European Medicines Agency. Guideline on 475.the Investigation of Bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1. Draft released for 23. Schellekens H. Immunologic mechanismsconsultation in July 2008. www.emea.europa. of EPO-associated pure red cell aplasia. Besteu/pdfs/human/qwp/140198enrev1. Pract Res Clin Haematol 2005 18:473–480.14. European Medicines Agency. Valtropin. 24. Rosenberg AS. Effects of protein aggre-European Public Assessment Report, Revi- gates: an immunologic perspective. AAPSsion 1. www.emea.europa.eu/humandocs/ Journal 2006 8: E501–E507.Humans/EPAR/valtropin/valtropin.htm. 25. Schellekens H. Immunogenicity of thera-15. Park SS, Deechongkit S, Patel SK. peutic proteins: clinical implications and futureAnalytical comparisons of certain erythropoi- prospects. Clin Ther 2002 24:1720–1740.etin products from Asia and Amgen’s epoetinalfa. Abstract M-PO-0592. World Congress of 26. Schellekens H. The first biosimilar epoetin:Nephrology, April 21–25, 2007, Rio de but how similar is it? Clin J Am Soc NephrolJaneiro, Brazil. Available at: http://www.wcn 2008 3:174–178.2007.org 93
  10. 10. Pharmacovigilance Focus WHO Drug Information Vol 23, No. 2, 200927. Schellekens H. Erythropoietic proteins and Brussels, Belgium, Novermber 8–13, 2008,antibody-mediated pure red cell aplasia: a http://www.ich.org/cache/compo/276-254-potential role for micelles. Nephrol Dial 1.htmlTransplant 2004 19:2422. 30. Frost and Sullivan. Biogenerics demand to28. Lamarque V, Merle L. Generics and go up in Asia. Express Pharma Pulse OctoberSubstitution Modalities: Proposed Methods for 7 (2004), Available at: http://www.expressthe Evaluation of Equivalence, Traceability pharmaonline.com/20041007/biogenerics01.and Pharmacovigilance Reporting. Thérapie2008 63:311–319 31. The Uppsala Monitoring Centre. http:// www.who-umc.org/DynPage.aspx29. ICH Steering Committee Press Release.Evolving Science in Drug Safety and Quality,94
  11. 11. WHO Drug Information Vol 23, No. 2, 2009Blood and BiomedicinesAvailability, quality and manufacture of medicinal products and in supply of other blood components suchsafety of blood and blood as platelets and red cells.products Developed countries have implementedBlood has been collected, stored, tested, procedures, policies and methods toand transfused as a therapeutic since the ensure the safety, quality and availabilitybeginning of the Twentieth century. Until of all products derived from blood. Thisthe 1950s, activities concentrated on has facilitated wider access to a compre-improving storage of cells and ensuring hensive range of safe blood products forblood group compatibility. Thereafter, patients with bleeding, immunological ormethods were developed for preparing other severe diseases. Additionally, goodtherapeutic products from human blood manufacturing practices (GMP) haveand plasma, for use in treating life- been introduced into plasma fractionationthreatening diseases, and to support centres and are now also applied in bloodcomplex surgical procedures and trans- establishments. Improvements in healthplantation. and transfusion safety have been docu- mented by haemovigilance and phar-For the past 25 years, efforts have macovigilance programmes. Conversely,focused on improving the safety and comparable levels of availability, qualityefficacy of components derived from and safety do not yet exist in manyblood and plasma, developing and developing countries (1).validating new methods, and seeking newtherapeutic uses. Blood products such as Equitable and universal access to bloodblood clotting factors and human and blood products of assured qualityimmunoglobulins (polyvalent and specific) and efficacy will contribute to achieve-are now included in the World Health ment of the UN Millennium DevelopmentOrganization’s (WHO) Model List of Goals relating to reduction of maternalEssential Medicines. This reflects the and child mortality, as well as to efforts toimportance of blood and blood products prevent HIV, HBV and HCV transmission.in treating congenital, immune-acquiredlife-threatening diseases, and conditions Specific issues requiringsuch as bleeding or trauma. In vitro actiondiagnostic devices for sensitive detectionof infectious disease markers play a role Wastage of blood plasmain successfully screening donor blood and Several reasons account for the lack oftesting plasma pools prior to fractionation, blood products in developing countries.as well as in clinical diagnosis. Plasma collected in developed countries is restricted and the potential for generat-Transmission of infectious diseases by ing surplus products sufficient to meet theblood (notably HIV, hepatitis B (HBV) and needs of developing countries is small.hepatitis C (HCV)) has underscored the Moreover, such products would be tooimportance of quality systems and effec- expensive. Developing countries musttive regulation in the preparation of therefore create their own sustainableplasma as a raw material for use in the supplies of blood products using blood 95
  12. 12. Blood and Biomedicines WHO Drug Information Vol 23, No. 2, 2009plasma collected by their own blood material. Substantial improvement willestablishments from their own popula- prevail through introduction and enforce-tions. Currently, however, a large percent- ment of appropriate independent andage of the plasma collected in developing transparent quality assurance regulationscountries is categorized as a waste and inspection procedures.material and destroyed. This is becauseappropriate technology and enforcement Cross-border threatsof GMP are not available. Fractionation The risks of disease migration are esca-capacity could, however, become avail- lating due to changes in habitat, increas-able if plasma production complied with ing mobility of populations, wars andinternationally-agreed standards. global climate change. Pandemic infec- tions may also affect the supply of bloodRisk of transfusion-transmitted and blood products in different ways.diseases These factors underscore the need toIf rigorous standards for donor selection, introduce and strengthen quality assur-testing and donation are not applied, ance regulations in developing countries.blood products and blood transfusion The trend towards global regulatoryremain potent vectors for transmission of convergence favours sharing of bestinfectious diseases. Unfortunately, current practices and the creation of internation-arrangements for blood plasma collection, ally agreed regulations. Internationalprocessing and testing are inadequate in coordination, notably in areas such as thea vast number of developing countries. In manufacture of blood products, is there-addition, increasing international mobility fore becoming increasingly important.of populations and globalization of theblood industry highlight the need to WHO activitiesintroduce and strengthen quality assur- For more than 50 years, WHO has beenance regulations. closely involved in setting quality and safety standards and training regulatorsThe history of blood transfusion has in the manufacture and quality control ofamply demonstrated the risks. Examples biological and blood products. The overallinclude transmission of HIV, HCV and technical responsibility for these activitiesHBV, bacteria, trypanosoma and malarial lies with the WHO Expert Committee onparasites, as well as emerging and re- Biological Standardization (ECBS).emerging diseases. Although worldwide Guidelines on the manufacture andexpansion of human blood plasma quality control of blood and blood prod-collection and processing of blood prod- ucts have been developed, updated anducts has the capacity to save lives, promoted by WHO (2–4). They representwithout appropriate control and standardi- global consensus on the part of manufac-zation it can also amplify public health turers, regulators, professional interna-risks. tional societies and national blood pro- grammes with respect to production andPoor regulation of blood products in quality assurance procedures for blooddeveloping countries and blood products.Developing countries recognize the needto regulate blood products and assure International biological reference prepara-blood safety. Blood establishments tions (5) to assist in establishing theshould be subject to inspection and audit quality and safety of blood products andby national regulatory authorities and related in vitro diagnostic devices havefractionators should demonstrate effective also been adopted following validation incontrol and traceability of plasma raw global coordinated studies. The value of96
  13. 13. WHO Drug Information Vol 23, No. 2, 2009 Blood and Biomedicinesreliable internationally agreed reference As a first step, up-to-date mechanisms formaterials is that manufacturers, regula- implementing and enforcing qualitytors and blood establishments can standards relating to blood products andcompare results worldwide despite the blood safety-related in vitro diagnosticincreasing diversity of products. devices will need to be introduced in countries. Activities should be supportedPublic health challenges demonstrate the by WHO guidelines for the production ofneed for international collaboration and blood plasma for fractionation, comple-cooperation and the need to create mented with additional guidelines toregulatory networks to support dissemina- promote and support implementation oftion of regulatory actions, knowledge GMP. Work should also be undertaken totransfer and organization of training review existing national regulations forprogrammes. The International Confer- blood products and to support and furtherence on Drug Regulatory Authorities develop technical upgrading of medicines(ICDRA) provides regulatory authorities of regulatory authorities. Furthermore,WHO Member States with a forum to strategies should be sought to share themeet and discuss ways to strengthen expertise and experience already gener-collaboration. In 2005, the WHO Blood ated in developed countries and toRegulators Network was established in develop regional regulatory networks.response to the request by ICDRAparticipants and the ECBS. The Network The dimension and complexity of thewas set up to foster development of situation requires a multifaceted strategyinternational consensus on effective incorporating input from partners atregulatory approaches. national, regional and international levels.Recognizing the importance of the WHO is well placed to secure the supportprovision of safe blood, blood compo- of international and nongovernmentalnents and plasma derivatives, the Fifty- organizations, international professionaleighth World Health Assembly in 2005 associations and other agencies devoted(Resolution 58.13) expressed its support to finding solutions for health problems.for “full implementation of well organized,nationally coordinated and sustainable Creating sustainable blood and plasmablood programmes with appropriate programmes with appropriate regulatoryregulatory systems” and stressed the role systems will ensure both specific andof “voluntary, non-remunerated blood wider public health benefits including:donors from low-risk populations”. • optimal use of donated blood plasma;Improving access to blood • safer blood components;and blood products • sustainable and affordable supply ofIn order to ensure the availability of safe safe essential products for the treatmentblood products in developing countries, of congenital diseases, trauma andMember States should be alerted to the immunologically mediated conditions;risks of inadequate regulation and guid-ance should be provided on establishing • reduction of infectious disease transmis-regulatory oversight of blood systems. sion via blood-borne pathogens, bothEfforts should be made to increase the within countries and across nationaltransfer of validated technology and to borders;build capacity with the overall aim ofimproving access to safe, effective and • improved quality and safety of allaffordable blood products. products from blood establishments 97
  14. 14. Blood and Biomedicines WHO Drug Information Vol 23, No. 2, 2009 through the enforcement of national References (and international) quality assurance regulations; 1. Global Database on Blood Safety. http://www.who.int/bloodsafety/global_• substantial contribution to national/ database/en/ regional public health programmes through, for example, improved popula- 2. World Health Organization. Requirements tion epidemiology for infectious dis- for the collection, processing and quality control of blood, blood components and eases such as HIV, HBV and HCV, plasma derivatives. Technical Report Series, prevention and control of disease No. 840 (1994). transmission, and blood donor health monitoring; 3. World Health Organization. WHO Recom- mendations for the production, control and• potential application of quality systems regulation of human plasma for fractionation. and GMP principles to other medical Technical Report Series, No. 941 (2007). laboratory disciplines, and 4. World Health Organization. Guidelines on• inclusion of developing countries in the viral inactivation and removal procedures international transfusion community and intended to assure the viral safety of human in activities of associated plasma blood plasma products. Technical Report fractionation industries. Series, No. 924 (2004).The strategic goal is to improve public 5. World Health Organization. WHO Interna-health by providing safe and effective tional Biological Standards: http://www.who.medicine to the world’s population. A risk– int/bloodproducts/catalogue/en/index.htmlbenefit analysis must ensure that suffi-cient quantities of the required productsare available at a cost that does not limitaccess.98
  15. 15. WHO Drug Information Vol 23, No. 2, 2009New Regulatory ChallengesContribution of clinical pharmacologists to government:opportunities and challenges . Clinical pharmacology is a scientific discipline that focuses on evaluating the effect of medicines in humans. Within a wider context of promoting safety, maximizing efficacy and minimizing side-effects, the work of the clinical pharmacologist is par- ticularly valuable in clinical trials. Other branches of the discipline involve pharma- covigilance, pharmacokinetics, drug metabolism, pharmacoepidemiology and, more recently, pharmacoeconomics. The clinical pharmacologist collaborates closely with other clinicians, pharmacists, biologists, analytical chemists, statisticians, epidemi- ologists and health economists. The clinical pharmacologist receives training in the evaluation of drug therapy and drug products and this makes the profession valu- able in a number of public activities such as drug approval, post-marketing surveil- lance, drug therapy selection, reimbursement decisions and ethical review of re- search projects. Faced with the task of regulating increasingly complex medicines and biomedicines markets, many regulatory authorities and health departments in developing coun- tries rely for advice on pharmacists who may have a limited medical background and lack the resources to access and assess information on the latest clinical research. On the other hand, clinical pharmacologists have a rigorous medical and scientific training which enables them to evaluate evidence and produce new data through well designed studies and interaction with other healthcare professionals. A clinical pharmacologist can provide the link between government and health care outcomes, serving also as a powerful advocate of evidence-based medicine. They can be in- valuable in addressing current challenges such as assessing new medicines, pro- viding unbiased medicines-related information, contributing to treatment guideline development, identifying preventable adverse drug reactions through promoting ra- tional use of medicines and improving prescribing practices. Politicians are often unaware of the valuable role that clinical pharmacology can play in improving per- formance of regulatory and health systems through closing the gap between current medical practices and latest clinical science.Regulation and clinical tary and provide the means of attainingpharmacology: emerging the health and wellbeing of citizens.alliances In a broad sense, the role of regulatoryAs a function of protecting and promoting agencies is multidimensional. The Worldpublic health, a government must con- Health Organization (WHO) proposes thatsider the ethical, scientific and develop- regulatory goals are achieved throughmental aspects of medicines. Activities in ensuring the safety, efficacy and quality ofthese three dimensions are complimen- medicines, rational use, and providing 99
  16. 16. New Regulatory Challenges WHO Drug Information Vol 23, No. 2, 2009appropriate medicines information to the many essential and interrelated activitiespublic and health professionals (1). which underpin the most important role ofSimilarly, the European Medicines the government in the broader sense: i.e.,Agency (EMEA) coordinates the work of to protect the health and wellbeing of itsnational experts and has inter alia the citizens through ensuring and promotingfollowing far reaching responsibilities (2): effective public health.“In the context of continuing globaliza- Governments and their respective institu-tion, to protect and promote public and tions are responsible for ensuring basicanimal health by: human rights of citizens. In the event of research conducted within a country, they• developing efficient and transparent are expected to protect patients and trial procedures to allow rapid access by participants by maintaining effective users to safe and effective innovative systems for granting clinical research medicines and to generic and nonpre- authorization and oversight of trials. This scription medicines through a single challenging task involves assessment of European marketing authorization; whether the clinical research planned is based on scientific principles and consid-• controlling the safety of medicines for erations of safety and whether it will offer humans and animals, in particular the desired benefits to patients while through a pharmacovigilance network identifying and minimizing any possible and the establishment of safe limits for risks. This task forms the ethical dimen- residues in food-producing animals; sion of the government’s role.• facilitating innovation and stimulating Milestones in the current research, hence contributing to the ethical research environment competitiveness of the EU-based The International Covenant on Civil and pharmaceutical industry, and Political Rights (1966) states that ... “no one shall be subjected without his free• mobilizing and coordinating scientific consent to medical or scientific experi- resources throughout the EU to provide mentation”. These principles were devel- high-quality evaluation of medicinal oped with a particular focus on risk/ products, to advise on research and benefit in the World Medical Association’s development programmes, to perform Declaration of Helsinki and have been inspections for ensuring fundamental incorporated into national and interna- GXP (good clinical practice, good tional laws and regulations. manufacturing practice and good In 1949, the Council for International laboratory practice collectively) provi- Organizations of Medical Sciences sions are consistently achieved, and to (CIOMS) was founded under the aus- provide useful and clear information to pices of WHO and the United Nations users and healthcare professionals. Educational, Scientific and Cultural Organization (UNESCO). The mostThe ethical dimension important of CIOMS publications is itsIn addition to their role in ensuring the International Ethical Guidelines forsafety, efficacy and quality of medicines, Biomedical Research Involving Humangovernments are also tasked with the Subjects. The latest version was pub-responsibility of exerting an ethical lished in 2002 (3) and, based on theinfluence on processes in the develop- Declaration of Helsinki, is designed to bement and marketing of medicines. The of use in defining the ethics of biomedicalregulatory authority is responsible for research, applying ethical standards in100
  17. 17. WHO Drug Information Vol 23, No. 2, 2009 New Regulatory Challengeslocal circumstances, and establishing or Above all, governments have to ensureredefining adequate mechanisms for that only effective and safe good qualityethical review of research involving medicines are used to treat their citizens.human subjects. The Guidelines are Nowadays, all medicines are subject totargeted to ethics committees, and review marketing authorization prior to beingboards, sponsors and investigators. The prescribed. Approval is based on assess-CIOMS guidelines — to which several ment of quality, safety and efficacy of theclinical pharmacologists have contributed product. The safety monitoring of medi-— also provide the basis for government cines during their whole life-cycle (fromthinking about clinical research, espe- marketing authorization to potentialcially in resource poor settings. withdrawal from the market) is also a task for governments. Usually, these and otherGood clinical practice (GCP) is a “stand- medicines-related regulatory functionsard for the design, conduct, performance, are carried out by specialized govern-monitoring, auditing, recording, analysis mental agencies, such as the Food andand reporting of clinical trials that pro- Drug Administration (FDA) in the USA orvides assurance that the data and re- the European Medicines Agency (EMEA).ported results are credible and accurate,and that rights, integrity and confidential- Scientific dimensionity of trial subjects are protected.” Many It is important for regulators involved innational and regional GCP guidelines are the evaluation of medicines prior tobased on, or refer to, the Declaration of marketing to have the best possibleHelsinki, including WHO GCP Guidelines scientific education and background or topublished in 1995 (4) and the Interna- be able to call on expertise which istional Conference of Harmonization (ICH) relevant to the work in hand. A criticalGCP (E6) from 1996 (5). scientific review of the clinical data will address the known and unknown aspectsA priority requirement for the ethical of an assessment and provide relevantreview of a scientific study, research or conclusions. The larger regulatory agen-clinical trial involving human subjects is cies possess their own clinical pharma-submission of a research proposal for cology units. For example, the US FDAindependent evaluation by scientific, has in its Center for Drug Evaluation andregulatory and ethical review committees. Research (CDER) Office of ClinicalNowadays, many governments define Pharmacology. Safety surveillance andprocedural aspects of the work of the pharmacovigilance is also entrusted toethics committees in detail. regulatory agencies, and here, also, expertise in clinical pharmacology isFor example, the European Commission essential.has laid down strict timelines for process-ing research applications that affect the Governments, either directly or throughwork of ethical review committees in all their specialized agencies, are also27 European Union countries. This can involved in taking decisions about medi-be perceived as the European Commis- cines selection for public procurement,sion’s attempt to facilitate and promote developing national treatment guidelinesclinical research. Clinical pharmacologists and proposing inclusion of medicines incan be particularly valuable as members reimbursement lists. This work may alsoof the ethical review committee because involve composing and updating nationalof their extensive knowledge of the essential medicines lists as promoted byeffects of medicines and the related area WHO. The real life performance of drugsof clinical research. following regulatory approval requires a 101
  18. 18. New Regulatory Challenges WHO Drug Information Vol 23, No. 2, 2009cost-effectiveness assessment by highly hand evidence that electronic healthqualified specialists using different mod- records can offer added value for phar-els and again calls on the expertise of the macogenetic research and pharmacovigi-clinical pharmacologist. lance (7). Clinical pharmacologists should be actively involved in designing elec-These various activities support the tronic patient health records due to theirrational use of medicines, sometimes also potential for future clinical research use,called “quality use” (6). Governmental including monitoring of rational use andinstitutions involved in such activities safety.include the National Institute for Healthand Clinical Excellence (NICE) in the Government efforts to create a researchUnited Kingdom. Activities are based on friendly environment should include legalthe best possible scientific methodologies and other systems with effective function-and knowledge and are part of the ing and well-informed scientific govern-scientific dimension of the Government’s ment backup. Due to the relative lack ofobligation to its citizens. Clinical pharma- new therapies and pressure from patientcologists are well prepared to meet the groups and industry, governments havechallenges needed in the complex as- been exorted to grant “early marketsessment of medicines. approvals” under certain preconditions. However, effective methodologies forDevelopmental dimension pharmacovigilance and safety studies inLastly, governments carry the responsibil- the context of early market access haveity of improving the health of their citi- yet to be created and tested and clinicalzens. Stimulating the necessary research pharmacologists have an important roleand developing research capacities is to play here (8, 9). Clinical pharmacologytherefore a regulatory function. Action also contributes to the discipline ofshould be directed to facilitating research pharmacoepidemiology, which is some-in areas where lack of effective or safer times the only available method to evalu-health care interventions impedes im- ate the benefits and risks of long termprovement to public health. Recent pharmacotherapy. Similarly, pharmaco-examples provide evidence that private economics attempts to give a financialsector initiatives and funding are insuffi- cost and value to everyday medicines usecient in developing and promoting public and contributes to rational reimbursementhealth through medicines research. Thus, systems.governments may also be involved inproviding financial support to stimulate In the implementation of these variousclinical research in medicines. Clinical dimensions, governments create variouspharmacologists are well positioned to tools, including laws and regulations,help make appropriate judgements on the infrastructure and institutions, with sup-scientific value of government funding of porting resource allocations. A keyresearch proposals. resource is properly trained specialists who are capable of taking decisionsAn important emerging issue is the based on the best possible scientificadoption of electronic patient health methodology and evidence. Theserecords implemented or planned to be dimensions are interrelated and interde-implemented in many countries. Although pendent. Good ethics cannot do withoutthese may be perceived as mostly admin- good science and developmental goalsistrative tools, they hold scientific poten- cannot be achieved without followingtial for monitoring of safety and quality ethical principles and a sound sciencemedicines therapy. There is already first- base.102
  19. 19. WHO Drug Information Vol 23, No. 2, 2009 New Regulatory ChallengesThe clinical pharmacologist is thus a 3. The Council for International Organizationsunique specialist and ally who can serve of Medical Sciences (CIOMS). Internationalthe public best by ensuring that only safe Ethical Guidelines for Biomedical Researchand effective medicines are authorized for Involving Human Subjects, Geneva, 2002. http://www.cioms.ch/use, as well as facilitating cost effectiveprescribing and improving rational use of 4. World Health Organization. Guidelines fordrugs. In order to meet the needs of good clinical practice (GCP) for trials onvarious governmental services and pharmaceutical products. Technical Reportensure that the best scientific knowledge Series, No. 850, 1995. http://www.who.int/is used to make decisions, clinical phar- medicines/library/par/ggcp/GGCP.shtmlmacology as a discipline should beharmonized with the objectives and 5. International Conference of Harmonizationpolicies of governments to ensure a (ICH) E6: Good Clinical Practice: Consoli-benefit to public health dated Guideline. http://www.ich.org/cache/ compo/276–254–1.htmlEqually, governments of emerging econo- 6. Smith AJ, McGettigan P. Quality use ofmies and developing countries may medicines in the community: the Australianbenefit hugely from the expertise of experience. Br J Clin Pharmacol (2000) 50(6):clinical pharmacologists and experience 515–519.has shown that a qualified clinical phar-macologist can make a great difference at 7. Wang X, Hripcsak G, Markatou M, et al.country level. Active computerized pharmacovigilance using natural language processing, statistics andReferences electronic health records: a feasibility study. J Am Med Inform Assoc (2009).1. World Health Organization. WHO PolicyPerspective on Medicines No 7, “Effective 8. Lesko LJ. Paving the Critical Path: How canMedicines Regulation: Ensuring Safety, Clinical Pharmacology Help Achieve theEfficacy and Quality”, November 2003. http:// Vision? Clinical Pharmacology & Therapeuticswww.who.int/medicines/organization/mgt/ (2007) 81:170–177.PolicyPerspectives.shtml 9. Massol J, Puech A, Boissel JP. How to2. EMEA Mission Statement. http:// anticipate the assessment of the public healthwww.emea.eu.int/mission.htm benefit of new medicines? Therapie. (2007) 62(5):427–35. 103
  20. 20. WHO Drug Information Vol 23, No. 2, 2009Safety and Efficacy IssuesEtanercept: histoplasmosis Reference: Communication from Amgen. 21 April 2009 at Health Canada. http://www. hc-and invasive fungal infections sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/ _2009/index-eng.phpCanada — The manufacturer ofetanercept (Enbrel®) has informedhealthcare professionals of the risk of Zonisamide: metabolicinvasive fungal infections, including acidosishistoplasmosis. Etanercept is indicatedfor the treatment of rheumatoid arthritis, United States of America — Followingpsoriatic arthritis, juvenile idiopathic a review of updated clinical data, thearthritis, ankylosing spondylitis and Food and Drug Administration (FDA) hasplaque psoriasis. determined that treatment with zonis- amide can cause metabolic acidosis inThere have been reports of serious some patients. Zonisamide (Zonegran®pulmonary and disseminated histoplas- and generics) is indicated as adjunctivemosis, coccidioidomycosis, blastomycosis therapy in the treatment of partial sei-infections, sometimes with fatal out- zures in adults with epilepsy.comes, in patients taking TNF blockers,including etanercept. Histoplasmosis and Chronic metabolic acidosis can haveother invasive fungal infections have not adverse effects on the kidneys and onbeen recognized consistently in patients bones, and can retard growth in children.taking TNF blockers. This has led to Patients with predisposing conditions ordelays in instituting appropriate treatment, therapies, including renal disease, severesometimes resulting in death. respiratory disorders, diarrhoea, surgery, ketogenic diet, or certain other drugs mayFor a patient taking a TNF blocker who be at greater risk for developing meta-presents with signs and symptoms of bolic acidosis following treatment withsystemic illness, such as fever, malaise, zonisamide. The risk of zonisamide-weight loss, sweats, cough, dyspnoea, induced metabolic acidosis appears to beand/or pulmonary infiltrates, the health- more frequent and severe in youngercare professional should ascertain if the patients. Although not approved by thepatient has lived or worked in or travelled FDA, zonisamide is sometimes used into areas of endemic mycoses, and children. Metabolic acidosis increases theappropriate empiric antifungal treatment risk for slowed growth in children andmay be initiated while a diagnostic could reduce the overall height that theyworkup is being performed. As with any achieve.serious infection, the TNF blocker shouldbe stopped until the infection has been The FDA recommends that healthcarediagnosed and adequately treated. professionals measure serum bicarbo- nate before starting treatment and peri-Prescribers should discuss with patients odically during treatment, even in theand their caregivers the risk for infections absence of symptoms. If metabolicwhile receiving TNF blockers, including acidosis develops and persists, consid-infections caused by viruses, fungi, or eration should be given to reducing thebacteria including tuberculosis (TB). dose or discontinuing zonisamide (using104
  21. 21. WHO Drug Information Vol 23, No. 2, 2009 Safety and Efficacy Issuesdose tapering), and modifying the pa- ously identified an association betweentient’s antiepileptic treatment as appropri- PML and use of some monoclonal anti-ate. If the decision is made to continue, bodies such as natalizumab (Tysabri®,then alkali treatment should be consid- used to treat multiple sclerosis) andered. rituximab (MabThera®, indicated for non- Hodgkin lymphoma and severe activeReference: FDA Alert, 23 February 2009 at rheumatoid arthritis). An association hashttp://www.fda.gov/medwatch also now been identified between PML and efalizumab (Raptiva®).Progressive multifocalleukoencephalopathy Up to 6 January 2009, the MHRA has received 19 suspected reports of PML, inUnited Kingdom — Progressive three of which PML was listed as the fatalmultifocal leukoencephalopathy (PML) is suspected reaction.a rare and usually fatal re-infection of theCNS characterized by progressive Reference: Medicines and Healthcaredamage and inflammation of the white Products Regulatory Agency, Drug Safetymatter in the brain, in multiple locations. Update, Volume 2, Issue 8 March 2009 atPML is caused by a type of human http://www.mhra.gov.uk/Safetyinformation/polyoma virus known as the JC, or JohnCunningham virus. The JC virus is Severe adverse reactions withwidespread, with about 70–90% of adults intravenous immunoglobulinpresenting antibodies. Australia — Intravenous immunoglobu-The virus usually remains latent in lin, normal (human) (IVIG) is used to treathealthy individuals, only causing disease a variety of deficiencies and disorderswhen the immune system is severely with an immune (or presumed immune)compromised. PML has been studied in aetiology. IVIG preparations, includingpatients with HIV infection, where inci- Intragam P®, Sandoglobulin®, anddence is approximately 5% of the disease Octagam®, have been available since thepopulation. PML also occurs in patients 1980s. Use worldwide and in Australiawith cancer and those who have has more than doubled over the pastreceived kidney or bone-marrow trans- decade (1) partly due to increasing use inplants. In PML, gradual destruction of the off-label indications.myelin sheath covering nerve axons Nausea and vomiting are most commonlyleads to impaired transmission of nerve observed with IVIG, as are hypersensitiv-impulses. PML causes rapidly progres- ity reactions which may include anaphy-sive focal neurological deficits including: laxis. Those with IgA deficiency have a higher risk of hypersensitivity to IVIG due• cognitive and behavioural changes; to the presence of IgA antibodies. Less• paraesthesia; common but also serious reactions are aseptic meningitis, haemolysis and• visual problems; transfusion-related acute lung injury — one case has been reported in Australia• gait abnormalities and loss of limb coordination, and and one in Canada (2). Recently, Health Canada highlighted an association• hemiparesis. between IVIG and thromboembolic events (3).The Medicines and Healthcare ProductsRegulatory Agency (MHRA) has previ- To date, the Therapeutic Goods Adminis- tration (TGA) has received 356 reports of 105
  22. 22. Safety and Efficacy Issues WHO Drug Information Vol 23, No. 2, 2009adverse reactions associated with IVIG: Exenatide: risk of severeIVIG was the sole suspected agent in pancreatitis and renal failure90% of reports. Thirty-five per centdescribe serious reactions, including United Kingdom — Exenatide (Byetta®),where the outcome was fatal due to: an incretin mimetic, is a glucagon-like-stroke/myocardial infarction, myocardial peptide-1 analogue that stimulates insulininfarction, convulsions, hepatic and renal release from pancreatic cells in a glucosefailure, and respiratory failure respec- dependent manner. Exenatide is indi-tively. In fatal cases, patients generally cated for treatment of type 2 diabeteshad thrombogenic risk factors such as mellitus in combination with metformin,hypertension, obesity, increasing age, or with or without sulphonylureas in patientspast history of stroke. who have not achieved adequate glycae- mic control on maximally tolerated dosesThe TGA has also received substantial of these oral therapies.numbers of reports describing pyrexia(58), chills (41), haemolysis or anaemia Exenatide should not be used in patients(32), meningitis (20), neutropenia (12), with type 1 diabetes or for the treatmenthepatic disorders (11), and renal failure/ of diabetic ketoacidosis. It should not beimpairment (8). In some of the cases, the used in patients with type 2 diabetesreactions — particularly those suggesting who require insulin therapy due to cellhypersensitivity — occurred during the failure.IVIG infusion and improved with slowingor stopping the infusion. Suspected adverse reaction reports of necrotizing and haemorrhagic pancreatitisBefore and during the use of IVIG, any have been received in association withpre-existing thrombogenic risk factors exenatide. Some of these reports had ashould be assessed and all patients fatal outcome. If pancreatitis is diag-should be monitored closely during nosed, exenatide should be permanentlyinfusion. A slow infusion rate of IVIG discontinued. Reports of renal impair-should be considered for all patients with ment, including acute renal failure andrisk factors (as recommended in the PI). worsened chronic renal failure have alsoExtracted from the Australian Adverse been received. Exenatide is notDrug Reactions Bulletin, Volume 28, recommended for use in patients withNumber 2, April 2009 at http:// end-stage renal disease or severe renalwww.tga.gov.au/adr/aadrb/aadr0904.htm impairmentReferences Reference: Medicines and Healthcare Products Regulatory Agency, Drug Safety1. National Blood Authority. Criteria for the Update, Volume 2, Issue 8 March 2009 atclinical use of intravenous immunoglobulin in http://www.mhra.gov.uk/Safetyinformation/Australia. Australian Health Ministers’ Confer-ence. December 2007. Benefits of methylphenidate2. Case Presentation: Intravenous immune continue to outweigh risksglobulin – suspected association with transfu- United Kingdom — The EMEA’s Com-sion-related acute lung injury. Canadian mittee for Medicinal Products for HumanAdverse Reactions Newsletter Oct 2008; 18/4. Use (CHMP) concluded that on the basis3. Intravenous immune globulin: myocardial of currently available data, the benefits ofinfarction and cerebrovascular and thrombotic methylphenidate continue to outweigh theadverse reactions. Canadian Adverse Reac- risks when used in its licensed indication.tions Newsletter Jan 2008; 18/1. Methylphenidate is indicated as part of a106
  23. 23. WHO Drug Information Vol 23, No. 2, 2009 Safety and Efficacy Issuescomprehensive treatment programme for 2. Further information on brands ofattention deficit/hyperactivity disorder methylphenidate available in the UK, see(ADHD) in children aged 6 years or older BNF, p 216 (edn 56; www.bnf.org).and adolescents who are diagnosed 3. Information on DSM-IV criteria is ataccording to DSM-IV criteria or guidelines http://www.psychiatryonline.com/;in ICD-10 and when remedial measures information on ICD-10 is atalone are insufficient. http://www.cdc.gov/nchs/about/otheract/i cd9/abticd10.htmTreatment must be under the supervisionof a specialist in childhood behavioural 4. Medicines and Healthcare Productsdisorders. Patients should be monitored Regulatory Agency, Drug Safety Update,during treatment, which should be inter- Volume 2, Issue 8 March 2009 at http://rupted at least once a year to determine www.mhra.gov.uk/Safetyinforma tion/whether continuation is needed. Chromic phosphate P32:Contraindications—methylphenidate acute lymphocytic leukaemiashould not be used in patients with: Canada — Information has been pro-• Diagnosis or history of severe depres- vided on important new safety information sion, anorexia nervosa or anorexic concerning Chromic phosphate P32 disorders, suicidal tendencies, psychotic suspension (Phosphocol® P32) which is symptoms, mania, schizophrenia, authorized for intracavitary instillation for severe mood disorders, or psychopathic the treatment of peritoneal or pleural or borderline personality disorder. effusions caused by metastatic disease.• Diagnosis or history of severe and Physicians should be vigilant for signs episodic (type I) bipolar (affective) and symptoms of leukaemia in patients disorder that is not well-controlled. who have received Phosphocol® P32.• Pre-existing cerebrovascular disorders The Canadian product monograph will be — e.g., cerebral aneurysm and vascular updated to include the following warning. abnormalities, including vasculitis or stroke. Leukaemia: Phosphocol® P32 may increase the risk of leukaemia in certain• Unless specialist cardiac advice has situations. Two children (ages 9 and 14) been obtained, in pre-existing cardio- with haemophilia developed acute lym- vascular disorders, including severe phocytic leukaemia approximately 10 hypertension, heart failure, arterial months after intra-articular injections. occlusive disease, angina, haemody- Phosphocol® P32 is not indicated in the namically significant congenital heart treatment of haemarthroses. disease, cardiomyopathies, myocardial infarction, potentially life-threatening In addition, the product monograph will be arrhythmias, and dysfunction of cardiac updated to include post-marketing reports ion channels of radiation injury (necrosis and fibrosis) to the small bowel, caecum, and bladderReferences: following peritoneal administration of Phosphocol® P32.1. EMEA press release at http://www.emea.europa.eu/pdfs/human/ Reference: Health Canada, Alert dated 25referral/methylphenidate/2231509en.pdf; March 2009. at http://www.hc-sc.gc.ca/dhp-question-and-answer document at mps/medeff/advisories-avis/prof/_2009/index-http://www.emea.europa.eu/pdfs/human/ eng.php 107
  24. 24. Safety and Efficacy Issues WHO Drug Information Vol 23, No. 2, 2009Warning for metoclopramide- frequently than other agents. Prescriberscontaining drugs are advised to monitor all patients taking antipsychotics for adverse metabolicUnited States of America — The Food effects.and Drug Administration (FDA) hasannounced that manufacturers of meto- Referencesclopramide, a drug used to treat gastroin-testinal disorders, must add a boxed 1. http://www.bpac.org.nz/magazine/2007/ february/antipsychotics.aspwarning to labelling about the risk of long-term or high-dose use. Chronic use of 3. Prescriber Update 2009;30(2):12 at http://metoclopramide has been linked to www.medsafe.govt.nz/profs/PUarticles.asptardive dyskinesia even after the drugsare no longer taken. Cefaclor and serum sickness-Metoclopramide works by speeding up like reactions in childrenthe movement of the stomach muscles, Australia — The association betweenthus increasing the rate at which the cefaclor and serum sickness-like reac-stomach empties into the intestines. It is tions (SSLR), particularly in children, hasused as a short-term treatment of gastro- long been recognized (1). These reac-oesophageal reflux disease in patients tions are characterized by a variety ofwho have not responded to other thera- rashes, which include urticaria or ery-pies, and to treat diabetic gastro-paresis. thema multiforme, with or withoutIt is recommended that treatment not angioedema, accompanied by arthritis/exceed three months. arthralgia, with or without fever.Reference: FDA News, 26 February 2009 athttp://www.fda.gov The reactions are rare but occur more often after a second or subsequentMetabolic effects of course of treatment. Onset time is often a few days after cefaclor is commencedantipsychotics and signs and symptoms typically sub-New Zealand — Although schizophrenia side a few days after the drug is ceased.itself is associated with several adverse However, onset may also be delayed andmetabolic effects it is now clear that all occur 7–21 days after stopping cefaclor.antipsychotics, and in particular some Children are more susceptible thanatypical antipsychotics, are associated adults.with adverse effects on weight, bloodglucose, and lipid concentrations. All of The TGA continues to receive about 10these adverse effects have long-term reports per year of cefaclor-related SSLRconsequences in terms of life expectancy. in children. If cefaclor must be prescribed to a child, the parents/caregivers shouldWhile the effects of antipsychotics on be advised to remain alert for the devel-weight gain may be responsible for the opment of new or worsening symptomsincreased risk of diabetes and hyperlipi- that might indicate a hypersensitivitydaemia, a direct effect on glucose me- reaction to the drug and to contact theirtabolism may also occur. doctor immediately if there are concerns.Not all atypical antipsychotics are associ- Extracted from the Australian Adverseated with the same level of risk. Clozap- Drug Reactions Bulletin, Volume 28,ine and olanzapine are considered to Number 2, April 2009 at http://cause adverse metabolic effects more www.tga.gov.au/adr/aadrb/aadr0904.htm108
  25. 25. WHO Drug Information Vol 23, No. 2, 2009 Safety and Efficacy IssuesReference: ADRAC. Cefaclor in the young • If signs or symptoms that may bepatient: arthritis and arthralgia <http:// associated with cardiac arrhythmiawww.tga.gov.au/adr/aadrb/aadr9508.htm# occur during treatment with toremifene,cefaclor>. Aust Adv Drug React Bull 1995; 14 treatment should be stopped and an(3). ECG should be performed.Toremifene: prolongation Currently, toremifene 20 mg/day and 80of QTc interval mg/day are being studied in prostate cancer indications.United Kingdom/European Union —The manufacturer of toremifene Reference: Communication from Orion(Fareston®) has informed healthcare Pharma UK at http://www.mhra.gov.uk/professionals of new information on Safetyinformation/prolongation of the QTc interval related totoremifene. The approved therapeutic Atomoxetine: risk of psychoticindication for toremifene 60 mg/day is the or manic symptomsfirst line treatment of hormone dependentmetastatic breast cancer in postmeno- United Kingdom — Atomoxetinepausal patients. (Strattera®) is a selective noradrenaline reuptake inhibitor, authorized since 2004Both in preclinical investigations and in for use in the treatment of attention-humans, changes in cardiac electro- deficit/hyperactivity disorder (ADHD) asphysiology have been observed following part of a comprehensive treatmentexposure to toremifene, in the form of QT regimen. Continued case reports ofprolongation. Consequently: possible nervous-system and psychiatric adverse effects prompted a review of• Toremifene is therefore contraindicated data from all sources resulting in updated in patients with: information on the risk of new-onset or worsening of serious psychiatric disor- Congenital or documented acquired QT ders, including psychotic reactions, prolongation; electrolyte disturbances, hallucinations, mania, and agitation. particularly in uncorrected hypokalae- mia; clinically relevant bradycardia; Product information for prescribers has clinically relevant heart failure with been updated to reflect more fully the reduced left-ventricular ejection fraction; emerging safety information. Atomoxetine previous history of symptomatic arrhyth- is associated with treatment-emergent mias. psychotic or manic symptoms in children and adolescents without a history of such• Toremifene should not be used concur- disorders. If such symptoms occur, rently with other drugs that prolong the consideration should be given to a QT interval. possible causal role of atomoxetine and discontinuation of treatment.• Toremifene should be used with caution in patients with ongoing proarrhythmic Advice for healthcare professionals: conditions (especially elderly patients) such as acute myocardial ischaemia or • At normal doses, atomoxetine can be QT prolongation as this may lead to an associated with emergent psychotic or increased risk for ventricular arrhyth- manic symptoms (e.g., hallucinations, mias (including Torsade de Pointes) and delusional thinking, mania, or agitation) cardiac arrest. in children and adolescents without a history of psychotic illness or mania. 109
  26. 26. Safety and Efficacy Issues WHO Drug Information Vol 23, No. 2, 2009• If such symptoms occur, consideration In February 2008, the manufacturer should be given to a possible causal informed healthcare professionals of very role of atomoxetine and discontinuation rare liver injuries and serious skin reac- of treatment. tions associated with moxifloxacin. This was in response to a worldwide review of• It remains possible that atomoxetine serious, including fatal cases of hepato- might exacerbate pre-existing psychotic toxicity and bullous skin reactions such as or manic symptoms Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) reportedReference: Medicines and Healthcare for moxifloxacin.Products Regulatory Agency, Drug SafetyUpdate, Volume 2, Issue 8 March 2009 at To date, HSA has received 22 localhttp://www.mhra.gov.uk/Safetyinformation/ spontaneous adverse drug reaction reports associated with oral moxifloxacin.Lignocaine with chlorhexidine Patient exposure to moxifloxacin to date is estimated to be 230 577, according togel: anaphylaxis local figures provided by the manufac-United Kingdom — Lignocaine 2% gel turer. In the interpretation of the abovewith chlorhexidine 0.05% is an anaes- figures, there is a need to consider thethetic/antiseptic/disinfectant combination significant degree of under-reporting ofused as a lubricant for urology proce- adverse reactions as is the case with alldures and examination, and as sympto- spontaneous adverse drug reactionmatic treatment of painful urethritis. reporting programmes. ReferencesSince 1990, the TGA has received 19reports of suspected adverse reactions to 1. EMEA Press Release. European Medicineslignocaine with chlorhexidine gel. Eleven Agency recommends restricting the use of oralof these were of anaphylaxis. Some were moxifloxacin-containing medicines. http://life threatening, but there have been no www.emea. europa.eu/pdfs/human/press/fatalities. 2. Direct Healthcare Professional Communica-The MHRA warns of the potential for tion regarding moxifloxacin (Avelox®) and serious hepatic and bullous skin reactions.anaphylaxis or other hypersensitivity http://www.mhra.gov.uk/reactions with both lignocaine and chlor-hexidine. Users of local anaesthetic 3. HSA Safety News, 19 Mar 2009 at http://preparations should check which prod- www.hsa.gov.sgucts contain chlorhexidine and arereminded of the risk of severe allergicreactions to medicines, even when Codeine toxicityapplied topically. in breastfed infants Singapore — Codeine is found in manyReference: Medicines and Healthcare prescription and non-prescription painProducts Regulatory Agency, http://www.mhra.gov.uk/Safetyinforma tion/ relievers and cough syrups. Once in- gested, codeine is metabolised by cyto- chrome P450 2D6 (CYP2D6) to its activeMoxifloxacin safety update metabolite, morphine, which relieves painSingapore — Moxifloxacin (Avelox® and or cough. Limited evidence suggests thatVigamox®) is a broad-spectrum antibac- individuals with a specific CYP2D6terial that is available locally. genotype (otherwise known as ultra-rapid metabolisers) may convert codeine to110