Who drug information vol1

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Who drug information vol1

  1. 1. WHO Drug Information Vol 23, No. 1, 2009 World Health OrganizationWHO Drug Information ContentsQuality of Medicines Erlotinib: Use in hepatic impairment and advanced solid tumours 32WHO medicines prequalification: Generic piperacillin and tazobactam: progress in 2008 3 medication errors 33 Safety of artemisinin combination therapy:Herbal and Traditional pregnant women 33MedicinesWHO Congress on Traditional Medicine Regulatory Action and News and the Beijing Declaration 8 Efalizumab: suspension of marketing authorization 35 Contusugene ladenovec: withdrawal ofBiomedicines Update marketing application 36Global norms and standards for biological Paliperidone: withdrawal of application quality, safety and efficacy 12 for extension of indication 36 First EMEA meeting of Committee for Advanced Therapies 36Safety of MedicinesThe mobile laboratory: a new concept in medicines surveillance 16 Consultation document International PharmacopoeiaPharmacovigilance Focus Oxytocin 38 Oxytocin injection 43Monitoring the safety of off-label medicine use 21Drotrecogin alfa: what relation to Recent Publications, thrombosis? 22 Information and Events Low availability, high prices keepSafety and Efficacy Issues essential medicines out of reach 46Genetic basis of adverse drug events 26 Sources and prices of selectedAnaesthetic infusion with pain pumps: medicines for children 46 articular chondrolysis 26 Two international summer coursesAtomoxetine: serious liver injury 27 in the Netherlands 47Drotrecogin alfa: ongoing safety review 28 Global politics of pharmaceuticalClopidogrel bisulfate: ongoing safety monopoly 48 review 29Modafinil: adverse skin and psychiatric reactions 30 Recommended InternationalLevothyroxine update 30 Nonproprietary Names:Temsirolimus: hypersensitivity reactions 31Continued vaccination with Gardasil® 32 List 61 49 1
  2. 2. World Health Organization WHO Drug Information Vol 23, No. 1, 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)2
  3. 3. WHO Drug Information Vol 23, No. 1, 2009Quality of MedicinesWHO medicines prequalification: progress in 2008The WHO Prequalification Programme for considerable breakthrough in makingMedicines (PQP) was initiated in 2001 as user-friendly formulations available thata service provided by the World Health will also improve efficacy of treatment.Organization (WHO) to facilitate accessto medicines that meet unified interna- The number of products prequalified intional standards of quality, safety and 2008 was the highest in six years. Theefficacy for HIV/AIDS, malaria, tuberculo- main reasons for this were:sis and reproductive health. • Increasing number of well prepared newThe work is carried out through: submissions in 2007–2008.• Stringent assessment of pharmaceutical • Improved quality of evidence to demon- product dossiers. strate quality, safety and efficacy of products.• Inspection of pharmaceutical manufac- turing sites (both for finished dosage • Expanded staffing component in 2007. forms and active pharmaceutical ingre- • Implementation of management effi- dients) and contract research organiza- ciency tools which improve the evalua- tions (CROs). tion process.• Prequalification of pharmaceutical quality control laboratories (QCLs). List of prequalified medicines Inclusion in the list does not mean that• Advocacy for medicines of assured the prequalification status of a product is quality. assured indefinitely. All approved medi- cines have to be checked regularly toThe Bill & Melinda Gates Foundation as ensure that any changes undertaken bywell as UNITAID are the main financial manufacturers do not undermine thesupporters of PQP. quality, safety and efficacy of the product.Newly prequalified medicines In order to achieve this objective, WHOForty products were added to the list of carries out re-inspections of manufactur-prequalified medicines in 2008, an ing sites as well as random quality controlincrease from 21 products in 2007. The tests of prequalified medicines. Since thetotal number of prequalified medicines prequalified products list is constantlycurrently stands at 196. being added to, information maintenance and updating becomes crucial to theA major achievement in 2008 was the preservation of established internationalprequalification of new products specially standards.designed to treat HIV/AIDS in children, aswell as the first fixed-dose combination New submissions to PQPtablets of artesunate and amodiaquine to Certain product groups are urgently intreat malaria. These products represent a need of expansion to increase available 3
  4. 4. Quality of Medicines WHO Drug Information Vol 23, No. 1, 2009 In 2008, the WHO Medicines Prequalification Programme: • Prequalified a total of 40 medicinal products. The list of prequalified medicines now contains nearly 200 products. • Prequalified the first ever fixed-dose combination tablets of antiretroviral medi- cines designed for use in children to treat HIV/AIDS, and the first fixed-dose combination tablets of artesunate and amodiaquine to treat malaria. • Organized 11 training workshops for capacity building in resource-limited coun- tries for staff of regulatory authorities and pharmaceutical manufacturers. • Provided manufacturers with scientific advice and technical assistance to sup- port improvements in the quality of their products. • Implemented the biowaiver concept to facilitate evaluation of product dossiers. • Prequalified six quality control laboratories. • Planned and implemented three comprehensive medicines sampling and testing programmes in countries that were recipients of drug donations. • Revised and updated the procedure for prequalification to increase transparency and accountability of prequalification performance. • Contributed to the development of guidelines and standards to facilitate global quality assurance activities, including pharmacopoeial monographs and chemi- cal reference standards. • Opened prequalification to include zinc and influenza products and considerably expanded the invitation list of reproductive health products.treatment options (e.g., second-line required. Insufficient quality specificationsantituberculosis and paediatric antiretrovi- presented for reproductive health andral combination products). However, it antimalarial products and manufacturingwas again noted that the number of conditions are of particular concern.products submitted for evaluation withinthis category was insufficient to meet In recent years, documented qualitycurrent demand. This is mainly due to a assurance of medicines has become anlack of commercial incentives available to essential requirement of internationalmanufacturers to develop products funding agencies for successful bidding inintended for small or non-profitable procuring essential medicines for devel-markets. oping countries. Manufacturers should therefore be increasingly motivated toIn the past year, the number and quality invest in enhancing their own manufactur-of product dossiers submitted for assess- ing and control processes to improve thement continued to present many chal- quality of submissions to the PQP.lenges. Newcomer manufacturers havinglimited or no experience in production Technical assistance to manufacturersaccording to international standards have Time and resources are needed fromgreat difficulty in submitting the evidence applicants to obtain product prequalifica-4
  5. 5. WHO Drug Information Vol 23, No. 1, 2009 Quality of Medicinestion and this includes dedication to Capacity building ofimplementation of corrective action to regulatory authoritiesmeet international quality standards. It In 2008, the PQP continued to offerfollows that an increase in the number of national regulatory personnel fromavailable prequalified medicines can only resource-limited countries a three-monthbe achieved based on increased capacity full-time post at WHO. These rotationalbuilding and technical assistance activi- positions for quality assessors are aimedties. at creating links and form a network between WHO and the countries in-Consequently, since 2006, the PQP has volved, as well as enhance informationprovided coordinated technical assistance exchange between both parties.aimed at resolving specific practicalproblems encountered by manufacturers In addition, assessors from less re-or quality control laboratories. Assistance sourced regulatory authorities continue tois provided by qualified professionals in participate in PQP assessment sessionsthe form of an audit and training in where they account for one-third of thetechnical or regulatory areas. total external assessor contribution. Since 2008, inspectors from theseSuch action in resource-limited countries authorities are invited to take part inhas become one of the core activities of WHO inspections as observers. Regula-PQP since 2007 and will remain so for tors from the WHO Africa Region havethe following years. In 2008, PQP pro- been especially active in this process.vided eight technical assistance missionsto pharmaceutical manufacturers in five Dossier assessmentsdifferent countries. and expert advice In 2008, seven assessment sessionsTraining were organized at the UNICEF SupplyWHO recognizes the crucial role of Division in Copenhagen where productcapacity building through training and dossiers are received and stored. Thehands-on practice. In 2008, PQP organ- number of assessment reports for 2008ized 11 training courses and co-organized increased to 732 compared to 463 infour training activities together with other 2007. In addition to regular assessmentpartners in 10 different countries (see activities, provision of expert scientifictable on page 7). advice to applicants remained high on theThis tuition on general or specific techni- agenda. In 2008, a total of 13 bioequiva-cal issues is also offered to larger groups lence study protocols were reviewed,formed by manufacturers, national more than 60 bioequivalence queriesmedicines regulatory agency staff and answered, and close to 80 separateprofessionals from quality control labora- quality issues handled by the respectivetories. Training courses include group expert panels.sessions as well as focused communica-tion between the involved parties, such as Inspectionsmanufacturers and lecturers who are part A total of 38 inspections of pharmaceuti-of the assessment or inspection teams cal manufacturers and 14 inspections ofworking with PQP. In 2008, these courses CROs were carried out in seven differentinvolved more than 600 participants and countries in 2008. As in all previous46 lecturers and trainers provided by years, the national inspectorates fromPQP. well established regulatory authorities continued to provide staff inspectors for 5
  6. 6. Quality of Medicines WHO Drug Information Vol 23, No. 1, 2009Prequalification assessment and inspection statistics 2007 2008 Dossier Assessment Assessment sessions in Copenhagen 6 7 Total number of assessment days 42 46 Total number of assessment reports 463 732 Assessment reports on HIV/AIDS products 298 494 Assessment reports on TB products 100 100 Assessment reports on malaria products 54 115 Assessment reports on reproductive health products 11 19 Assessment reports on influenza products - 4 Inspections 46 62 Manufacturing sites of finished product manufacturers 26 27 Manufacturing sites of active pharmaceutical ingredients 6 11 Contract research organizations 13 14 Pharmaceutical quality control laboratories 1 10prequalification purposes. France was the of delivery to the recipient country. How-leading country in terms of providing ever, quality can deteriorate duringinspection support. transportation and storage. To verify that the quality of essential medicines isPrequalification of quality maintained throughout the supply chaincontrol laboratories until the medicines reach the end user,The prequalification of quality control several sampling and testing programmeslaboratories was restarted in 2007 when have been designed and implemented.12 laboratories expressed interest inprequalification. In 2008, PQP carried out Programme strengthening10 inspections of quality control laborato- and development of standardsries with six gaining prequalification Major procedural improvements to PQPstatus. in 2008 include:Testing of medicines • Revision and update of the procedureThe prequalification status of a medicinal for prequalification to increase transpar-product guarantees its quality at the time ency and accountability of PQP.Major medicines testing programmes organized by WHO PQP in 2008 Aim of sampling Countries involved Total number and testing of samples Quality survey of anti- Cameroon, Ethiopia, Ghana, malarial medicines Kenya, Nigeria, Tanzania 936 Quality monitoring of products Kenya, Tanzania, Uganda, funded by UNITAID Zambia 378 Quality survey of anti-TB Armenia, Azerbaijan, Belarus, medicines in Eastern Europe Kazakhstan, Ukraine, Uzbekistan 3606
  7. 7. WHO Drug Information Vol 23, No. 1, 2009 Quality of MedicinesTraining workshops organized by WHO PQP in 2008 Date Location Content of training 25–29 February Brasilia, Brazil New approaches to quality risk manage- ment in manufacture of medicines. 21–25 April Lahore, Pakistan Development of PQP submission dossiers. 28 April–1 May Mumbai, India Pharmaceutical development with a focus on paediatric formulations. 2–6 June Dar-es-Salaam, United Evaluation of generic products focusing Republic of Tanzania on bioequivalence and biowaiver data. 16–20 June Amman, Jordan Introduction to PQP and technical requirements. 16–20 June Teheran, The Islamic Introduction to PQP and technical Republic of Iran requirements. 23–27 June Beijing, China GMP for reproductive health products and dossier requirements. 8–11 July Rabat, Morocco GMP – air and water treatment systems 20–24 October Jakarta, Indonesia GMP for reproductive health products and dossier requirements. 3–7 November Accra, Ghana Regulatory requirements and data assessment of artemisinin-based fixed dose combination medicines. 1–5 December Nanchang, China GMP training for SFDA inspectors• Opening of new tracks for the prequalifi- development and updating of new and cation of zinc and influenza products. existing WHO guidelines and standards continued to facilitate global quality• Implementation of the biowaiver concept assurance activities. Such guidance to facilitate evaluation of product dossi- includes pharmacopoeial monographs ers. and chemical reference standards. The procedure for prequalification of active• Publication of the first “notices of con- pharmaceutical ingredients was approved cern” highlighting good manufacturing by the WHO Expert Committee on Phar- practice (GMP) violations observed maceutical Specifications for implementa- during inspections. tion in 2009.PQP activities are based on scientifically Reference: The Medicines Prequalificationsound and updated internationally ac- Programme (PQP). http://www. who.int/cepted quality standards. In 2008, prequal 7
  8. 8. WHO Drug Information Vol 23, No. 1, 2009Herbal and TraditionalMedicinesWHO Congress on Traditional Medicineand the Beijing Declaration Representatives of over 70 Member States attended the first WHO Congress on Traditional Medicine held on 7–9 November 2008 in Beijing, China. Satellite sympo- sia were held to discuss related technical topics. Presentations were given by repre- sentatives of organizations such as the World Self-Medication Industry (WSMI), the World Federation of Acupuncture-Moxibustion Societies (WFAS), the International Pharmaceutical Federation (FIP), and the World Federation of Chiropractic (WFC). Almost 1500 people were present at the events. Highlights of the Congress included adoption of the Beijing Declaration promoting the safe and effective use of traditional medicine and calling on WHO Member States and other stakeholders to take steps to integrate traditional medicine, complemen- tary and alternative medicines (TM/CAM) into national health systems. Sharing of national experience and information by Member States in five areas aimed at leveraging future action. • National policy on TM/CAM. • National regulation of traditional and herbal medicines. • TM use in Primary Health Care. • National regulation of TM/CAM practice. • Research on TM/CAM. Participants visited community health centres, clinics and hospitals for traditional medicine. These models showed how traditional and Western medicine can work together and be successfully integrated into China’s health system.In 2008, WHO marked its 60th anniver- health care by WHO and its Membersary and the 30th anniversary of the Alma States.Ata Declaration, adopted by UNICEF andWHO in 1978. Although traditional Use of traditional medicine has changedmedicine has been used for thousands dramatically over the past thirty years.of years and has made a fundamental Due to its affordability, availability andcontribution to human health, the Alma accessibility, traditional medicine hasAta Declaration was the first formal played an important role in meeting therecognition of the role of traditional demands of primary health care in manymedicine and its practitioners in primary developing countries.8
  9. 9. WHO Drug Information Vol 23, No. 1, 2009 Herbal and Traditional MedicinesSince the 1990s, the use of traditional and western medicine can blend togethermedicine has surged. It not only main- in beneficial harmony, using the besttains its function in primary health care in features of each system.developing countries (70–80% of thepopulation in Ethiopia and India still Delegates were welcomed by the Ministerdepend on traditional medicine and of Health, People’s Republic of China. Inpractitioners for primary health care), its their presentations, the Minister of Healthuse has expanded widely in many devel- of the Union of Myanmar and the Deputyoped countries where it is referred to as Minister of Health of South Africa ex-complementary or alternative medicine plored the role of integration of traditional(CAM). For instance, 70% of the popula- medicine into primary health care andtion in Canada and 80% in Germany have actions that their respective countriesused CAM. National health authorities have taken. The need for appropriatewere asked to consider how to integrate regulatory oversight of complementaryTM/CAM into their national health sys- medicine products was expressed by thetems and significant progress has been National Manager of the Therapeuticmade since initiation of the WHO Tradi- Goods Administration of Australia.tional Medicine Strategy in 2002. During the International Forum on Inte-WHO Congress on gration of Traditional Medicine/CAM intoTraditional Medicine Health Systems, 26 delegates presentedTo further assess the role of traditional short national reports outlining the regula-medicine/CAM, review the progress of the tory framework for traditional medicine,countries and help Member States products and practice in their respectiveintegrate traditional medicine/CAM into countries. To facilitate discussion, thetheir national health systems, the first presentations were separated into fiveWHO Congress on Traditional Medicine topic areas:on 7–9 November 2008, was organized inBeijing, China. The Congress was hosted • National Policy on TM/CAM and integra-by the Ministry of Health and the State tion into national health systems.Administration of Traditional ChineseMedicine of the Government of China, in • National regulation of traditional andcooperation with four nongovernmental herbal medicines.organizations (NGOs) in official relationswith WHO — the World Self-Medication • Traditional medicine in primary healthIndustry (WSMI), the World Federation of care.Acupuncture-Moxibustion Societies • National regulation of traditional medi-(WFAS), the International Pharmaceutical cine/CAM practice.Federation (FIP), and the World Federa-tion of Chiropractic (WFC). • Research and development of tradi- tional medicine.During the opening ceremony, the Direc-tor-General of WHO identified the impor- While presentations showed that it istance of traditional medicine in primary often necessary to tailor legislation andhealth care, the role of research, the need delivery to reflect the needs and traditionsfor appropriate licensing or registration of of individual countries, a number ofpractitioners and the importance of common themes and issues did emerge.patient-practitioner interaction. It was Most notable of these were the impor-noted that within the context of primary tance of practitioner training, issueshealth care, the two systems of traditional related to safety, need to enhance re- 9
  10. 10. Herbal and Traditional Medicines WHO Drug Information Vol 23, No. 1, 2009search into both products and practices, created to discuss and harmonize theimportance of labelling and information as comments submitted to WHO prior to theit relates to supporting informed choice, Congress and to enable the Declarationand the need for appropriate integration to be presented to the Congress.into primary health care. Congress delegates adopted the BeijingDelegates also heard from two WHO Declaration during the WHO Congress onpartners (The Nippon Foundation and the Traditional Medicine. In addition to aRegional Government of Lombardy) who preamble text noting a number of relateddescribed their work in this area. The four initiatives and reflecting the importance ofnongovernmental organizations hosting national contexts with regard to capacity,satellite conferences were also given the priorities and relevant legislation, theopportunity to make presentations and Beijing Declaration is set out below.observe the Congress. The Beijing Declaration will serve toA key outcome of the Congress was the promote the safe and effective use ofBeijing Declaration, which identified traditional medicine, and calls on WHOcommon aims and principles reached by Member States and other stakeholders toparticipants at the Congress. Preparation take steps to integrate traditional medi-of the declaration was structured, starting cine/CAM into national health systems.some months prior to the Congress with During the closing of the Internationalcirculation of the first draft. Comments Forum the WHO Assistant Director-were collected and modifications made General for Health Systems and Serviceswith a subsequent draft sent to partici- said, “This is a landmark declaration, afterpants before the Congress. During the a landmark Congress.”Congress, an ad hoc drafting team was Beijing Declaration Adopted by the WHO Congress on Traditional Medicine, Beijing, China, 8 November 2008 Participants at the World Health Organization Congress on Traditional Medicine, meeting in Beijing this eighth day of November in the year two thousand and eight: Recalling the International Conference on Primary Health Care at Alma Ata thirty years ago and noting that people have the right and duty to participate individually and collectively in the planning and implementation of their health care, which may include access to traditional medicine. Recalling World Health Assembly resolutions promoting traditional medicine, includ- ing WHA56.31 on Traditional Medicine of May 2003. Noting that the term “traditional medicine” covers a wide variety of therapies and practices which may vary greatly from country to country and from region to region, and that traditional medicine may also be referred to as alternative or complementary medicine. .../ .../ Continued10
  11. 11. WHO Drug Information Vol 23, No. 1, 2009 Herbal and Traditional MedicinesBeijing Declaration (continued) Recognizing traditional medicine as one of the resources of primary health care services to increase availability and affordability and to contribute to improve health outcomes including those mentioned in the Millennium Development Goals. Recognizing that Member States have different domestic legislation, approaches, regulatory responsibilities and delivery models. Noting that progress in the field of traditional medicine has been obtained in a number of Member States through implementation of the WHO Traditional Medicine Strategy 2002-2005. Expressing the need for action and cooperation by the international community, governments, and health professionals and workers, to ensure proper use of traditional medicine as an important component contributing to the health of all people, in accordance with national capacity, priorities and relevant legislation. In accordance with national capacities, priorities, relevant legislation and circum- stances, hereby make the following Declaration: I. The knowledge of traditional medicine, treatments and practices should be respected, preserved, promoted and communicated widely and appropriately based on the circumstances in each country. II. Governments have a responsibility for the health of their people and should formulate national policies, regulations and standards, as part of comprehensive national health systems to ensure appropriate, safe and effective use of tradi- tional medicine. III. Recognizing the progress of many governments to date in integrating tradi- tional medicine into their national health systems, we call on those who have not yet done so to take action. IV. Traditional medicine should be further developed based on research and innovation in line with the “Global strategy and plan of action on public health, innovation and intellectual property” adopted at the Sixty-first World Health Assembly in resolution WHA61.21 in 2008. Governments, international organiza- tions and other stakeholders should collaborate in implementing the global strategy and plan of action. V. Governments should establish systems for the qualification, accreditation or licensing of traditional medicine practitioners. Traditional medicine practitioners should upgrade their knowledge and skills based on national requirements. VI. The communication between conventional and traditional medicine providers should be strengthened and appropriate training programmes be established for health professionals, medical students and relevant researchers. 11
  12. 12. WHO Drug Information Vol 23, No. 1, 2009Biomedicines UpdateGlobal norms and standards forbiological quality, safety and efficacy WHO Expert Committee on Biological Standardization Established in 1947, the Expert Committee on Biological Standardization (ECBS) is one of the longest standing World Health Organization (WHO) committees and has overall responsibility for setting written standards and establishing reference prepa- ration materials. Standards developed through the ECBS relate to the production and quality control of safe and effective biological products. They provide guidance for national regulatory authorities and manufacturers and serve as the standard for prequalification of vaccines for supply to countries through international agencies. Reference preparation materials are available from designated WHO laboratories and provide the basis for comparison of materials used in biologicals worldwide. Members of the ECBS are scientists from national control agencies, academia, re- search institutes and public health bodies. These scientists act as individual experts and not as representatives of their respective organizations or employers. The deci- sions and recommendations of the ECBS are based entirely on scientific principles and public health considerations. The ECBS reports directly to the WHO Executive Board, which is the executive arm of the World Health Assembly. The outcome of each ECBS meeting is subsequently published in a technical report. This report provides updated information on stand- ards for assuring the quality, safety and efficacy of biological products as well as on the establishment of new or updated WHO international standards for designating the activity of biological substances. ECBS technical reports are available at: http://www.who.int/biologicals/publications/trs/en/index.htmlHighlights of the The WHO Expert Committee on Biologi-2008 ECBS meeting cal Standardization (ECBS) establishes global norms and standards that helpBiological medical products such as define products of assured quality. Thevaccines, blood products, biotherapeutics ECBS meets annually and their mostand associated diagnostics save lives, recent meeting was held in Geneva fromreduce suffering and improve health, but 13 to 17 October 2008. During the meet-only if these products and technologies ing, 57 agenda items were considered.are of good quality, are safe, effective, This was accomplished, as in previousavailable, affordable and properly used. years, by running two parallel tracks, oneWHO is working with it’s Member States dedicated to vaccines and selected otherto use only biological medicines of biological medicines; one dedicated toassured quality in national health sys- blood products and related in vitro diag-tems. nostic devices.12
  13. 13. WHO Drug Information Vol 23, No. 1, 2009 Biomedicines UpdateThe most important outcomes of the 2008 Yellow fever vaccineECBS meeting were: An amendment to the written standard for yellow fever vaccine was also estab-Snake antivenom immunoglobulins lished. This requires that the expressionA new written standard for production, of potency of such vaccines be in Interna-control and regulation of snake antivenom tional Units (IU) per dose. The doseimmunoglobulins was established. Snake recommended for use in humans shallantivenom immunoglobulins (antivenoms) not be less than 3.0 log10 IU. This neware the only therapeutic products for the expression of potency should be ap-treatment of envenomings due to snake- proved by National Control Authorities,bite. The lack of availability of effective and will also be used as the standard forsnake antivenom immunoglobulins to WHO prequalification of yellow fevertreat specific types of envenomings vaccines.encountered in various regions of theworld has become a critical health issue Abbreviated licensing pathways forat global level. The crisis has reached its certain biological therapeutic productsgreatest intensity in sub-Saharan Africa, The Expert Committee also discussed abut other regions, such as South-east proposal to establish abbreviated licens-Asia, are also suffering from a lack of ing pathways for certain biological thera-effective and affordable products. peutic products. Control of chronic diseases is a major challenge for publicThe complexity of the production of health systems in WHO Member States.efficient antivenoms, in particular the Innovative biological medicines devel-importance of preparing appropriate oped by modern molecular biologicalsnake venom mixtures for the production approaches have been successful inof hyperimmune plasma (source of treating many life-threatening diseasesantivenom immunoglobulins), the de- and the market for these products iscreasing number of producers and the rapidly growing.fragility of the production systems indeveloping countries further jeopardize However, such innovative biologicalthe availability of efficient antivenoms in medicines are expensive. This has limitedAfrica, Asia, the Middle East, and South their use, particularly in developingAmerica. Also, most of the remaining countries. The expiration of patents onproducers are located in countries where key biological drugs such as recombinantthe application of quality and safety insulin, human growth hormone andstandards needs to be improved. erythropoietin is opening the door for copies of these drugs to be made byThe new Guidelines cover all the steps developing country manufacturers. Thisinvolved in the production, control and may contribute to a substantial increaseregulation of venoms and antivenoms. It in their availability at an affordable price.is hoped that this document, by coveringcomprehensively current existing experi- Generic versions of expired-patentence in manufacture, control, and pre- chemical drugs are well known. However,clinical and clinical assessment of these copy biological medicines are far moreproducts will serve as a guide to national complicated products for which thecontrol authorities and manufacturers to current generic regulatory pathway issupport worldwide production of these unsuitable. Nevertheless it is essential toessential medicines. ensure that there is appropriate regula- tory oversight in place. Regulatory over- 13
  14. 14. Biomedicines Update WHO Drug Information Vol 23, No. 1, 2009Proposals to establish new or replacement International Standards or WHOreference reagents: October 2008 Name of preparation Proposed status VACCINES AND RELATED SUBSTANCES Influenza H5N1 antibody (human) lst International Standard Human papillomavirus type 16 DNA lst International Standard Human papillomavirus type 18 DNA lst International Standard Rabies vaccine 6th International Standard Acellular Pertussis vaccine Modified Kendrick Test lst International Standard Pertussis antiserum (human) lst International Standard Pertussis antiserum (human) WHO Reference Reagent BLOOD PRODUCTS AND RELATED SUBSTANCES Anti-hepatitis B immunoglobulin 2nd International Standard Blood coagulation factor IX, concentrate 4th International Standard Factor VIIa concentrate 2nd International Standard Parvovirus B19 DNA 2nd International Standard Anti-A and anti-B antibodies, human WHO Reference Reagents Anti-hepatitis C core antigen (HBcAg), antibodies, human lst International Standard Extended use for the International Standard for alpha-1-antitrypsin (05/162) 1st International Standard DIAGNOSTIC REAGENTS AND RELATED SUBSTANCES Haemophilia A intron 22 inversion for molecular genetic diagnosis lst reference panel Fragile X syndrome for molecular genetic diagnosis lst reference panel CYTOKINES, GROWTH FACTORS AND ENDOCRINOLOGICAL SUBSTANCES Insulin-like growth factor (IGF-1) 2nd International Standard .../Continued14
  15. 15. WHO Drug Information Vol 23, No. 1, 2009 Biomedicines UpdateProposals to establish new or replacement International Standards or WHOreference reagents: October 2008 (Continued) Name of preparation Proposed status ANTIBIOTICS Gramicidin 2nd International Standard ITEMS PROPOSED IN MARCH 2008 BUT SUBSEQUENTLY WITHDRAWN Human papillomavirus type 16 antibody (human) 1st Reference Reagent to 1st International Standard Thromboplastin, human, plain International Standard Soluble serum transferrin receptor (STFR), recombinant lst International Standard Vancomycin 2nd International Standard Parathyroid hormone 1-84, human recombinant lst International Standard Poliovirus type 1 (Sabin) for MAPREC lst International Standardsight should not be so lax that ineffective Global reference preparationsor dangerous products are allowed into A total of 18 new or replacement globalthe market place or so restrictive that safe reference preparations were established.and effective products face regulations These are the primary calibrant againstthat are too stringent. which regional or national measurement standards are benchmarked. An updatedThe ECBS affirmed that reduced data list is available at http://www.who.int/packages may be suitable to provide biologicals/en/.sufficient assurance about the quality,safety and efficacy of certain products, Referencesbut it recommended that WHO and 1. World Health Organization. Biologicals:countries move forward cautiously. Based http://www.who.int/biologicals/en/on the outcome of discussions andfollowing consideration by the Committee, 2. World Health Organization. Blood productsthe ECBS therefore recommended that and related biologicals: http://www.who.int/the current document be strengthened bloodproducts/en/index.htmland some issues further clarified. Arevised version should be re-submitted to 3. World Health Organization. Immunization,the Committee in 2009. Vaccines and Biologicals: http://www.who.int/ immunization/en/ 15
  16. 16. WHO Drug Information Vol 23, No. 1, 2009Safety of MedicinesThe mobile laboratory: crack down on the manufacturing and marketing of counterfeit pharmaceuticala new concept in products, the Chinese Government hasmedicines surveillance implemented a number of drug surveil- lance programs. In China, fake andAccording to the World Health Organiza- substandard drugs mainly appear at thetion (WHO), about 6 to 10% of medicines retail level in the supply chain, andworldwide are counterfeit; a market worth therefore these programmes generally32 billion US dollars in annual sales. The require samples to be collected from thephenomenon has grown in recent years market and analysed in quality controldue to methods of counterfeiting becom- laboratories at the provincial or districting more sophisticated and to an increase level.in the quantity of counterfeit drugs cross-ing borders. Trade in fake medicines Common methods used on-site by localmainly occurs in developing countries, but authorities include basic tests, such ascounterfeiting is now also increasingly appearance, colour and weight, identifica-becoming a problem in developed coun- tion by thin-layer chromatography (TLC),tries. and basic functional group tests using wet chemical analysis techniques. SamplesIn response to the challenge presented suspected of being counterfeit are thenby the public health crisis caused by a sent to quality control laboratories at theglobal increase in counterfeit drugs, WHO district level for analysis using morehas launched a special taskforce, the specific methods such as high perform-International Medical Products Anti- ance liquid chromatography (HPLC).Counterfeiting Taskforce (IMPACT). The Such programmes have their merits, butmain purpose of IMPACT is to build a are not very effective in detecting thecoordinated network across and between more sophisticated high technologycountries in order to halt the production, counterfeit products.trading and sale of fake medicines aroundthe world. IMPACT is a partnership To reinforce surveillance, medicines arecomprising all the major anti-counterfeit- also routinely sampled from the marketing players, including international organi- and sent to district laboratories for testing,zations, nongovernmental organizations, but this can be costly. Moreover, counter-enforcement agencies, pharmaceutical feit drugs are often deliberately made tomanufacturers associations and drug pass tests defined in the Chinese Phar-regulatory authorities. macopoeia to avoid being caught by the Chinese State Food and Drug Administra-As elsewhere in the world, fake and tion (SFDA) surveillance programme.substandard drugs in China are driven by There is therefore a demand to improvehuge profits, and have consequently on-site analysis so that more sophisti-become quite sophisticated. In order to cated counterfeits can be reliably de- tected, and resources at the district levelArticle prepared by Professor Shaohong Jin, can be better utilized. Reliable on-siteNational Institute for the Control of Pharma- analysis will also allow resources to beceutical and Biological Products, China. efficiently targeted at those cases where16
  17. 17. WHO Drug Information Vol 23, No. 1, 2009 Safety of MedicinesMobile laboratories in Chinalaw enforcement already has evidence • To provide a platform for the deploymentthat counterfeit products are being of modern high-technology analyticaldistributed. methods that would both aid in the crackdown on the sale and distributionObjectives and development of the of counterfeit drug products, and pro-mobile laboratories vide reliable evidence for law enforce-In January 2003, in response to a call ment.from the SFDA for drug monitoring inpredominantly rural areas, the Chinese • To reduce the high cost and increaseNational Institute for the Control of the efficiency of routine drug qualityPharmaceutical and Biological Products post-marketing surveillance.(NICPBP) proposed that mobile laborato-ries be used for quality testing. The On 30 November 2003, less than 10laboratories are specially designed vans months after the initial proposal fromequipped to perform various quick analy- NICPBP, the first mobile laboratory forses. The primary objectives of the mobile drug quality testing was unveiled. Onlaboratories are: 5 January 2004, the former Vice Premier of China inspected the mobile laboratory• To utilize the mobility of the laboratories and watched a live demonstration of a to extend drug surveillance into China’s high technology screening method. The remote countryside. Vice Premier was very impressed with the new technology and the concept of such• To increase consumer confidence in the a mobile laboratory and requested that quality of pharmaceutical products the Ministry of Finance, the State Com- available on the Chinese market. mittee of Reform and Development and the National Bureau of Quality and• To provide quick, easy-to-use, and Standards provide the programme with effective screening methods for on-site full support and assistance. drug testing. 17
  18. 18. Safety of Medicines WHO Drug Information Vol 23, No. 1, 2009Operating the mobile laboratory modern analytical instruments that canCurrently, the only internationally avail- quickly and non-destructively analyseable system for quick screening of coun- drug products. The mobile laboratoriesterfeits on-site is the Minilab test kit, provide an effective screening tool for thewhich is capable of testing less than 50 crackdown on counterfeit drugs.common products, such as antibiotics orantimalarials, but the Minilab test kit is not Reliability of the NIR methodsufficient to address the problem of for drug screeningcounterfeits in China. The scientific During 2006 and 2007, mobile laborato-equipment in the mobile laboratory ries tested a total of 10 340 batches ofincludes a near-infrared spectrometer, pharmaceutical products, of which 329TLC, colorimetry, digital photography, batches were known to be fake. Of thevisible microscopy, and test kits for 10 340 batches tested, 1087 (aboutspecific chemical reactions. The main 10.5%) failed the NIR screening, includ-screening tool is based on a near-infrared ing all 329 batches that were known to bespectrometer and a pre-developed fake. In addition to the fake products,standard analytical method that uses a some non-counterfeit products failed tolibrary of near-infrared (NIR) spectra pass the NIR screening because of(developed by the NICPBP) of all the changes in product formulations. Allregistered pharmaceutical products in products that failed the NIR screeningChina. This near-infrared based system is were sent to district laboratories forquick, accurate, non-destructive, and further testing using more specific meth-versatile. ods. These results show that NIR screen- ing is a very reliable method for theApart from analytical instrumentation, detection of counterfeit drugs, and alsoanother important tool in the mobile dramatically decreases the number oflaboratory is the information system, products that need to be tested in districtwhich includes manufacturer information laboratories.for officially registered products, includingthe registration numbers, formulations, Results of using mobile laboratoriesdosages and labelling, etc. as well as a for drug testinglist of known counterfeits. Dedicated From April 2004 to November 2005, fieldsoftware for the mobile laboratory allows tests of the mobile laboratories wereeasy access to the information, even in carried out in 5 provinces in China: Anhui,remote areas. The software is also used Hubei, Hunan, Sichuan and Yunnan.to support the near-infrared instruments Suitability, accuracy and efficiency of theby providing automatic analysis of the analytical equipment was evaluatednear-infrared spectrum using pre-loaded under real conditions. The evaluationanalysis methods, and generation and included the effect of vibration on thelogging of all test reports. equipment when the van was driven on rough roads in the countryside. Field testsIn addition, the software includes a were used to look for possible areas fordatabase of analytical methods, digital improvement.manuals, and predefined standard formsto record and manage mobile laboratory As an example of these trials, starting inactivities such as when and where the August 2004, a mobile laboratory wasmobile laboratories have been dis- dispatched 165 times in Zhumadianpatched. The mobile laboratory thus Prefecture of Henan Province. Thecombines modern information technology, mobile laboratory visited 8 of 11 countiesscientific management systems, and in the prefecture as well as 42 of 18618
  19. 19. WHO Drug Information Vol 23, No. 1, 2009 Safety of Medicinesvillages, and covered a total distance of also result in significant cost-savings.17 000 km, including highways between Currently, the mobile laboratory pro-cities and rough roads in the countryside. gramme covers about 80% of essential medicine products commonly used inThe mobile laboratory examined a total of rural areas.260 pharmacies and clinics and screened3965 batches of 408 different drug The mobile laboratory programme hasproducts. Of these, 57 batches were also shown its utility in response tosuspected to be fake and were further emergencies caused by fake drugs. As antested by analytical methods in district example, in the summer of 2006, insteadlaboratories resulting in five batches that of propylene glycol, the toxic ingredientwere confirmed as counterfeit. The diethylene glycol was used by mistake inmobile laboratories also visited AIDS a few batches of Armillarisin A® forprevention stations in Zhumadian Prefec- injection, resulting in 11 deaths. Immedi-ture, clinics in all 24 villages with a high ately after the incidents were reported,population of AIDS patients, and in all the mobile laboratories were dispatchednine villages with a moderate population to screen all suspected products thatof AIDS patients. No fake or substandard were still on the market. Gas chromatog-drugs were found in the 1347 batches raphy (GC) was later used to verify thethat were tested. The extensive surveil- results for medicines screened positivelance that is possible with mobile labora- for diethylene glycol by the mobile labora-tories thus ensures the quality and safety tories. In this case, the NIR-based quickof drug products used by at-risk groups screening method demonstrated 100%such as AIDS patients. accuracy.To date, 379 mobile laboratories have Future development of the mobilebeen deployed across China. They have laboratory programmevisited over 77 000 drug dispensaries, A second generation of mobile laborato-and have travelled over 2 000 000 km. ries is currently under development whichThey have screened more than 379 000 incorporate a patented green HPLCbatches of drugs, of which approximately system that is suitable for mobile opera-37 000 were suspected of being fake or tion. The key to this new HPLC is that thesubstandard. Of these, approximately solvents are close-loop recycled inside14 000 batches were later confirmed to the van. The advantage of implementingbe counterfeit. The average analysis cost the HPLC system in the mobile laboratoryper batch in the district laboratory is about is that if a drug product tests positive600 RMB. If the traditional test pro- using the NIR-based prescreeninggramme were used for the 379 000 method, then an on-site verification canbatches, they would have cost almost be performed immediately.230 million RMB. The new, targetedanalysis of only those batches that were Incorporating the HPLC technologysuspect based on pre-screening results should further improve the accuracy andreduced the cost of analysis in the district efficiency of the mobile laboratory pro-laboratories by about 90%, to approxi- gramme, especially in remote areasmately 22 million RMB. where the local Food and Drug Adminis- tration or other analytical laboratories areThese data show that the mobile labora- far away. A combination of the NIR-basedtories not only increase the successful quick and non-destructive screeningsampling rate and improve the efficiency method and on-site verification capabilityof the drug surveillance programme, but using the new HPLC technology may also 19
  20. 20. Safety of Medicines WHO Drug Information Vol 23, No. 1, 2009play an important role in counterfeit drug surveillance programme and reduceddetection in many developing countries. costs. They have also expanded the monitoring area of the programme andConclusions have improved the ability of the authori-The mobile laboratory is a new monitoring ties to rapidly respond when there issystem that provides in-time information evidence of adverse reactions to druggathering, quick screening, targeted products on the market. In the future,sampling based on drug law-enforcement mobile laboratories will continue to playefforts, and accurate analytical tests. an important role in increasing the effi-These mobile laboratories have demon- ciency of government efforts to crackstrated considerable success in ensuring down on the manufacture and marketingmedicines safety. The laboratories have of counterfeit products in China.increased the efficiency of the drug20
  21. 21. WHO Drug Information Vol 23, No. 1, 2009Pharmacovigilance FocusMonitoring the safety of safety of medicines when used off-label.off-label medicine use First and foremost, monitoring the safety of medicines in off-label settings isMedicine labels contain important infor- necessary to gain information on themation on the conditions of use. These usage of medicines in these settings.conditions typically include the indication, While formal study of medication safetydosage, frequency of administration, and would be optimal in these settings, suchroute of administration. Other important studies are often not available. Thus,conditions of use can include the age safety monitoring plays a critical role.range of patients, duration of treatment, Data derived from monitoring safety in anand contraindications to use of the off-label setting can also potentially bemedicine. Deviations from the conditions relevant to the safety of the medicineof use set forth in the label constitute off- when used according to the label. Inlabel use. addition, data derived in the off-label setting may serve as a stimulus for moreIn the USA, off-label use is legal. While formal study.the Food and Drug Administration (FDA)regulates the marketing of medicines, it There are many specific concerns thatdoes not regulate prescribing practices. In need to be addressed when monitoringone study (1), approximately 21 per cent the safety of medicines in an off-labelof drug use in office-based practice was setting. Many factors that could affect thefor off-label use. Off-label use may occur safety of the medicine could be differentfor a variety of reasons. For example, in the off-label compared to the on-labelthere are some diseases for which no setting. These factors include the age ofadequate, labelled treatment exists. In patients, range of co-morbidities, use ofthese situations, prescribers use medi- concomitant medication, drug-diseasecines for off-label indications. In the case interactions and differences in pharma-of medicines for children, many drugs cokinetics and pharmacodynamics.have never been studied in children, sothere has been extensive off-label use in Despite the importance of monitoring thechildren, although there are ongoing safety of medicines in an off-label setting,efforts to correct this situation. In some there are many challenges that thiscases, there may be a reasonable body situation presents. First, spontaneousof published evidence to support off-label reports do not always contain the indica-use. In other cases, such use is specula- tion for use or other details that wouldtive. However, off-label use may become allow one to determine that the medicinepart of accepted practice, and may be was used in a manner not consistent withpart of professional society guidelines. the product’s label. Second, the identifica- tion of an adverse drug reaction in the off-Because off-label use is common, there is label setting does not necessarily meana public health imperative to monitor the that this reaction is limited to that setting.Article prepared by Gerald J. Dal Pan, MD, MHS, Food and Drug Administration, USA. (Viewsexpressed are those of the author, and not necessarily those of the US Food and Drug Adminis-tration.) 21
  22. 22. Pharmacovigilance Focus WHO Drug Information Vol 23, No. 1, 2009Despite these limitations, spontaneous used by persons without epilepsy, andreports can be useful in determining that these persons experienced seizuresadverse drug reactions when medicines after tiagabine was started. The product’sare used off-label. label was updated to include this informa- tion.Drug utilization databases may be helpfulin monitoring off-label use of medicines. In summary, the off-label use of medi-Though such databases do not typically cines is common. Monitoring of adversecontain information on indications for use, events in this setting is important, thoughthey can be helpful in identifying other there are many challenges in doing so.aspects of off-label use. For example, Reference: Radley et al. Arch Intern Meddrug utilization data may shed light on the 2006; 166:1021-1026.age range of patients using a medicine,the duration of therapy, concomitantmedication used, and dosages pre- Drotrecogin alfa: whatscribed. Review of such data may indi- relation to thrombosis?cate that there is substantial off-label useand this may provide valuable information Drotrecogin alfa (activated) is a recom-for safety monitoring purposes. binant form of human activated protein C that has antithrombotic, anti-inflammatoryDrug use databases typically do not have and profibrinolytic activities. It is usedany information on medical diagnoses, so mainly in intensive care as a treatment forthey are not suitable for identifying severe sepsis (sepsis associated withadverse events. Nonetheless, they can acute organ dysfunction). It is adminis-be useful for identifying trends that may tered in multiple slow infusions, as a rule,require further study. Administrative at a dose of 24 µg/kg/hour for four dayshealthcare databases that contain infor- (1).mation both on drug use data and medi- Sepsis is a complex illness involving bothcal diagnoses can also be useful for infection and inflammation when theidentifying trends in off-label use, though body’s response is systemic, instead ofmedical record review may be necessary being localized to the site of infection.to determine the indication for usage. This “overreaction” to the infection mayElectronic medical records may be more result in organ damage and is moreuseful than administrative healthcare dangerous than the initial infection itselfdatabases if indication for use is linked to (2).the drug prescribed. Finally, publishedclinical trials studying off-label use may Patients who die during episodes ofbe a valuable source of information on sepsis are more likely to have coagulationadverse drug reactions. However, the defects, including lower levels of circulat-limitations of clinical trials for ascertaining ing antithrombin III and protein C. Theadverse event information are well latter is a vitamin K-dependent anticoagu-known. lant protease. In sepsis, protein C defi- ciency appears before the onset ofOne example of the importance of moni- observable indicators of septic shock.toring for adverse events in the off-labelsetting is seen with the drug tiagabine, The administration of an exogenouswhose labelled indication in the USA is for analogue may modulate the patient’sadjunctive therapy in adults and childrenover 12 years of age in the treatment of Article prepared by Tamás Paál, Hungary.partial seizures. Post-marketing reports (Signal Reviewer for the WHO Programme forindicated that this medicine was being International Drug Monitoring.)22
  23. 23. WHO Drug Information Vol 23, No. 1, 2009 Pharmacovigilance Focusresponse during sepsis (1, 3). The only day of drotrecogin treatment were deepserious adverse reaction observed in venous thrombophlebitis and thrombosis.clinical trials to drotrecogin alfa wasbleeding (3, 4). 5. A pharmacist described a 45-year-old female who was administered drotrecoginDescription of new ADR reports alfa for four days. Concomitant medica-Thirteen non-duplicate reports of throm- tion comprised dopamine and norepine-botic events in septic patients treated with phrine. Adverse effects described weredrotrecogin alfa were reported to intestinal ischaemia, decreased pro-VigiBase, the database of the WHO thrombin level and thrombosis.Collaborating Centre for InternationalDrug Monitoring, in the period 2002 to 6. A pharmacist described a 72-year-old2007. There were 12 reports from the male treated with drotrecogin alfa for fourUSA and one from the United Kingdom. days. Concomitant medication comprisedThe reports are summarized below. sodium bicarbonate, pantoprazole, norepinephrine, vasopressin, paraceta-1. A General Practitioner (GP) described mol, dopamine, amiodarone, vancomycina 66-year-old male who developed and piperacillin-tazobactam combination.thrombosis after administration of Adverse reactions described were anae-drotrecogin alfa. No details were re- mia, discoloured faeces and thrombosis.ported. 7. A 68-year-old male was administered2. A 72-year-old male was treated with drotrecogin alfa for five days. Concomi-drotrecogin alfa for three days. On the tant medication comprised cefotaxime,second day of treatment, pulmonary clarithromycin, amiodarone for two days,haemorrhage and thrombosis were hydrocortisone for eight days andobserved. lorazepam for two days. One day after termination of drotrecogin treatment the3. A 34-year-old male was treated with patient developed thrombosis.drotrecogin alfa for six days in 2002.Concomitant medication comprised 8. A pharmacist described an 86-year-oldantibiotics as well as paracetamol and male who was treated with drotrecoginhydrocodone bitartrate. The report, sent alfa for two days. No concomitant medi-by a GP, specified thrombosis, multiple cation was reported. Life-threateningorgan failure and gangrene as adverse adverse reactions comprised hypoten-effects. Onset appeared eight days after sion, gastrointestinal haemorrhage andtermination of treatment. thrombosis. Positive dechallenge was also observed.4. A 66-year-old male was treated withdrotrecogin alfa for three days. Concomi- 9. A physician reported the case of atant medication comprised paracetamol, female treated with drotrecogin alfa whocodeine, atenolol, lorazepam, triamci- developed thrombosis. No details werenolone, propofol, dopamine, levofloxacin, disclosed.morphine, famotidine, salbutamol, meto- 10. A pharmacist described a 63-year-oldclopramide, diazepam, midazolam, female treated with drotrecogin alfa forthiamine, piperacillin-tazobactam three days. Concomitant medicationcombination and heparin. The dosage comprised ranitidine, azithromycin,and other treatment data were missing. ceftriaxone, dopamine and norepine-Adverse reactions observed on the last phrine. Adverse reactions reported were 23
  24. 24. Pharmacovigilance Focus WHO Drug Information Vol 23, No. 1, 2009increased blood chloride and urea, associated with bleeding, related to itshypernatraemia, hypokalaemia, antithrombotic and profibrinolytic proper-hyperglycaemia, peripheral oedema, ties (1). In a Phase III placebo controlledthrombocythaemia and thrombosis. clinical trial, the incidence of thromboticDechallenge appeared to be negative. No events was similar in the drotrecogin andfurther information was provided. placebo arms (4). This was confirmed by analysis of results from combined clinical11. A physician described a 70-year-old trials. When compared with placebo,female treated with drotrecogin alfa for patients in the active treatment armstwo days. Reported adverse effects were experienced numerically fewer thromboticrash, jaundice, rectal disorders, bacterial events, although the difference was notinfection, peritonitis and thrombosis. statistically significant (7).12. A health professional reported the Thrombosis frequently occurs in patientscase of a 29-year-old female treated with with severe sepsis (7). Disseminateddrotrecogin alfa for two days. Concomi- intravascular coagulation (DIC) maytant medication comprised norepine- develop in 30-50% of patients with severephrine and dobutamine. Adverse reac- sepsis and septic shock, especially whentions were haemorrhage and thrombosis. caused by Gram negative bacteria. The mortality of sepsis is correlated with the13. A physician reported a 30-year-old development and severity of DIC (8).female who was administered drotrecogin Protein C serves as an important antico-alfa (no other information was available). agulant compensatory mechanism. TheThe adverse reaction was thrombosis. cytokines produced in sepsis incapacitate the protein C pathway. One of the criticalEvaluation of reports mediators of DIC is the release of aSix of the thirteen reports do not mention transmembrane glycoprotein tissue factor.concomitant medication. Because of the This is released in response to exposureclinical situation in which drotrecogin is to cytokines or endotoxin and plays aused, it is almost certain that other major role in the development of DIC inmedicines were co-administered. Thus, it septic conditions. For this reason,is possible that some concomitantly used drotrecogin alfa is recommended in thebut undisclosed medicine might have therapy of DIC (8, 9). Additionally, acontributed to the adverse effect. retrospective subgroup analysis of a clinical trial demonstrated a lower mortal-Seven reports (3, 4, 5, 6, 7, 10 and 12) ity rate among patients treated withdescribe a range of concomitant medica- drotrecogin alfa who met the criteria fortions. According to European Union DIC (10).Summaries of Product Characteristics(SPCs) as well as an international data- Hence, the conclusion is that in thesebase (5) of these medicines, only propofol spontaneous reports a manifestation of(administered in a single case) has the the underlying disease was reported as arecognized, although very rare, adverse possible adverse drug reaction. Thiseffect of thrombophlebitis (6). hypothesis is further supported by the following.Signal assessmentOn the basis of pharmacological proper- • Clinical manifestation of DIC is ex-ties of drotrecogin alfa, administration is tremely variable (9). The pathologicalunlikely to lead to thrombosis. On the processes involved deplete the body ofcontrary, drotrecogin use is frequently its platelets and coagulation factors and24
  25. 25. WHO Drug Information Vol 23, No. 1, 2009 Pharmacovigilance Focus so, paradoxically, may lead to both 2. Sepsis.com – understanding sepsis and thrombus formation and haemorrhage. severe sepsis. www.sepsis.com/family_ friends/ understanding.jsp?reqNavId=5.2,• Septic patients are generally treated in downloaded 03.01.2008. intensive care units but the adverse 3. Cada DJ, Levien T. Drotrecogin Alfa. effect reporters (if disclosed) were Hospital Pharmacy 2002;37(5):511–517. mostly GPs, pharmacists and other health professionals, possibly not 4. Bernard GR, Vincent Jl, Laterre PF. Efficacy possessing detailed information. and safety of recombinant human activated protein C for severe sepsis. New England• On consulting the WHO database, it can Journal of Medicine 2001;344:699–709. be seen that other reports on drotre- cogin alfa between 2002 and 2007 5. 1974-–2207 Thomson MICROMEDEX specified various haemorrhages (the Database. well-known adverse effects of dro- 6. Propofol. Merck Manual. www.merck.com/ trecogin alfa), as well as 43 reports of mmpe/lexicomp/propofol,htm, downloaded 08. DIC itself. 08.2008.Conclusion 7. GR Bernard et al. Extended evaluation ofIn 13 reports of thrombosis associated Recombinant Human Activated Protein Cwith the use of drotrecogin alfa, retrieved United States Trial (ENHANCE US). Chestfrom VigiBase, it appears likely that the 2004;125:2206-2216.reported thrombotic events represent amanifestation of the underlying disease 8. Becker JU, Wira CR. Disseminated Intra- vascular Coagulation. www.emedicine.com/process (severe sepsis), rather than an emerg/topic150.htm, downloaded 07.08.2008.adverse reaction to any administeredmedicine. This analysis underlines the 9. Aysola A , Lopez-Plaza I. Disseminatedimportance of considered assessment of Intravascular Coagulation. www.itxm.org/all reported adverse drug reactions data. TMU1998/tmu3-99.htm, downloaded 07.08.2008.References 10. Dhainaut JF et al. Treatment effects of1. Goshman L. Drotrecogin Alfa, Activated. drotrecogin alfa (activated) in patients withJournal of the Pharmacy Society of Wisconsin severe sepsis with or without disseminatedMar/Apr 2002;3335. intravascular coagulation. Journal of Thrombo- sis and Haemostasis 2004;2(11):1924–1933. 25
  26. 26. WHO Drug Information Vol 23, No. 1, 2009Safety and Efficacy IssuesGenetic basis of Anaesthetic infusion with painadverse drug events pumps: articular chondrolysisUnited States of America — The first Canada — Postoperative pain pumps aredata offering health care professionals a infusion devices designed to continuouslybetter look into the genetic basis of deliver controlled amounts of medicationcertain types of adverse drug events has (1, 2). They can be used to infuse localbeen released by the Food and Drug anaesthetic solutions directly into opera-Administration (FDA) and the Interna- tive sites for pain management followingtional Serious Adverse Event Consortium surgical procedures. The device consists(SAEC). Data are focused on the genet- of a reservoir containing the local anaes-ics associated with drug-induced serious thetic solution which is delivered byskin rashes, such as Stevens-Johnson gravity or by electric pump through asyndrome and toxic epidermal necrolysis, catheter implanted directly into theand help better predict an individual’s risk surgical wound. Bupivacaine is an anaes-of developing these reactions. thetic commonly used with postoperative pain pumps (3). A combination ofBoth skin conditions appear as allergic- bupivacaine and epinephrine is alsolike skin reactions associated with blister- used, with the epinephrine inducinging and peeling, and are considered life- vasoconstriction and slowing down thethreatening. Medications causing these absorption of bupivacaine.serious allergic reactions should be As of July 2008, Health Canada hasdiscontinued. If such signs and symptoms received 8 incident reports of articularare not quickly recognized, these reac- chondrolysis following shoulder surgerytions can be fatal. that were suspected of being associated with the use of postoperative pain pumps.The SAEC is a non-profit partnership of The pain pumps were used for about 48pharmaceutical companies, the Wellcome hours after surgery. All of the patientsTrust, and academic institutions focused received bupivacaine with epinephrine.on research relating to the genetics of Chondrolysis was diagnosed betweendrug-induced serious adverse events. one month and one year after surgery and use of the pain pumps.Researchers who enter into a data useagreement can obtain free access to the Chondrolysis is a progressive degenera-data to generate custom data inquiries tion of the cartilage for which the cause isand obtain immediate results on the not fully understood (4, 5). Chondrolysisgenetic basis of adverse drug events. of the shoulder results in narrowing of the joint space, leading to pain and loss ofReferences motion; it is a debilitating condition that requires medical attention and possibly1. FDA News, 10 February 2009. www.fda.gov surgery (3, 4). Chondrolysis is listed2. International Serious Adverse Event among the possible adverse incidents inConsortium at http://www.saeconsortium.org the device labelling of pain pumps (1, 2). The device labelling states that the26
  27. 27. WHO Drug Information Vol 23, No. 1, 2009 Safety and Efficacy Issuescontinuous intra-articular infusion of 7. van Huyssteen AL, Bracey DJ. Chlorhexi-anaesthetics, particularly when epine- dine and chondrolysis in the knee. J Bonephrine is also used, is not recommended. Joint Surg Br 1999;81(6):995–6.The association between postoperative 8. Leclair A, Gangi A, Lacaze F, et al. Rapidpain pumps and the development of chondrolysis after an intra-articular leak of bone cement in treatment of a benign aceta-chondrolysis is difficult to identify. Indeed, bular subchondral cyst: an unusual complica-chondrolysis may appear many months tion of percutaneous injection of acrylicafter the use of a pain pump (3–5). In cement. Skeletal Radiol 2000;29(5): 275–8.addition, confounders such as the con-comitant use of health products (e.g., 9. Jerosch J, Aldawoudy AM. Chondrolysis ofgentian violet, chlorhexidine, bone ce- the glenohumeral joint following arthroscopicment) and radiofrequency devices may capsular release for adhesive capsulitis: abe responsible for causing chondrolysis case report. Knee Surg Sports Traumatolafter shoulder surgery (5–10). Arthrosc 2007;15(3):292–4. 10. Ciccone WJ II, Weinstein DM, Elias JJ.Health care professionals are encouraged Glenohumeral chondrolysis following thermalto follow the instructions for use and capsulorrhaphy. Orthopedics 2007;30(2):158–refrain from using postoperative pain 60.pumps for continuous intra-articularinfusion of local anaesthetics, particularlywith epinephrine, after shoulder surgery Atomoxetine: serious(1, 2). liver injuryExtracted from the Canadian Adverse United States of America — The FoodReactions Newsletter, Volume 19 , and Drug Administration (FDA) continuesNumber 1 (2009). to receive reports of serious liver injury in patients given atomoxetine. AtomoxetineReferences received FDA approval on 26 November 2002 as the first non-stimulant medication1. On-Q PainBuster [Canadian instructions for used for the treatment of attention deficituse]. Lake Forest (CA): I-Flow Corporation; hyperactivity disorder (ADHD) in children2008. (aged 6 years and above) and adults (1).2. Donjoy Pain Control Device [Canadianinstructions for use]. Huntington Beach (CA): Atomoxetine’s therapeutic action isCurlin Medical Inc; 2007. believed to be due to its selective inhibi-3. Hansen BP, Beck CL, Beck EP, et al. tion of norepinephrine reuptake. From thePostarthroscopic glenohumeral chondrolysis. year 2002 to 2007, approximately 3.3Am J Sports Med 2007;35(10):1628–34. million patients received a prescription for atomoxetine in the United States. Of4. Yarbrough R, Gross R. Chondrolysis: an those, approximately 2.1 million patientsupdate. J Pediatr Orthop 2005;25(5):702–4. (64%) were children aged 17 years and5. Petty DH, Jazrawi LM, Estrada LS, et al. younger (2).Glenohumeral chondrolysis after shoulderarthroscopy: case reports and review of the While a signal for serious liver injury wasliterature. Am J Sports Med 2004;32(2):509– not detected during premarket clinical15. trials of atomoxetine, two published post-6. Shibata Y, Midorikawa K, Koga T, et al. marketing reports did identify instances ofChondrolysis of the glenohumeral joint atomoxetine-induced hepatitis (3, 4). Infollowing a color test using gentian violet. one of these reports, there was a positiveInt Orthop 2001;25(6):401–3. rechallenge with atomoxetine. Subse- 27
  28. 28. Safety and Efficacy Issues WHO Drug Information Vol 23, No. 1, 2009quent to these reports, a bolded warning 2. Bangs ME, Ling J, Zhang S, et al. Hepaticwas added in 2004 to the atomoxetine events associated with atomoxetine treatmentlabel indicating an increased risk for for attention deficit hyperactivity disorder. Drugsevere liver injury. Safety. 2008;31(4): 345–54. 3. Stojanovski SD, Casavant MJ, Hayat MM,Since the 2004 labelling change, FDA et al. Atomoxetine-induced hepatitis in a child.has received six additional reports of Clin Toxicol (Phila). 2007;45 (1):51–5.serious liver injury in patients takingatomoxetine. Following an evaluation of 4. Lim JR, Faught PR, Chalasani NP. Severethe information from the drug sponsor liver injury after initiating therapy with atomox-and additional literature articles submitted etine in two children. J Pediatr. 2006;148(6):to FDA, the atomoxetine product label 831–4.was again revised in 2007. The warningsand precautions section of the drug label Drotrecogin alfa:advises prescribers about the risk for ongoing safety reviewsevere liver injury with this drug (1). United States of America — The FoodPost-marketing reports indicate that and Drug Administration (FDA) is awareatomoxetine is associated with serious of a retrospective study (1) which hasidiosyncratic liver injury. Some of the reported an increased risk of seriouscases reported additional confounding bleeding events and death in patientsfactors, such as occasional acetami- with sepsis (a severe illness related to anophen use. Some of the cases lacked bloodstream infection) and baselinesufficient clinical detail to convincingly bleeding risk factors who receiveddetail the relationship between the use of drotrecogin alfa. Drotrecogin alfa (acti-atomoxetine and liver injury. The mecha- vated) (Xigris®) is a recombinant humannism of atomoxetine-induced liver injury activated protein C indicated for theremains unknown. reduction of mortality in adult patients with severe sepsis who have a high riskFDA encourages physicians to: of death (2). The baseline bleeding risk factors as defined by this study are the• Inform patients to immediately contact their physician at the first sign or symp- same as those described in the drotre- tom of fatigue, loss of appetite, nausea, cogin alfa prescribing information. vomiting, pruritus, dark urine, jaundice of the sclerae or skin, right upper An editorial (3) accompanying the article quadrant tenderness, or unexplained stated that one approach to increasing the safety of drotrecogin alfa would be to “flu–like” symptoms. not administer it to any patients with• Determine liver enzyme levels when a sepsis and baseline bleeding risk factors, patient presents with signs or symptoms effectively changing a warning in the of liver injury. product labelling to a contraindication. Under FDA regulations, contraindications• Discontinue and not resume atomoxet- in the prescribing information describe ine treatment if patients present with situations where the risks are known (that jaundice or laboratory evidence of liver is, are not theoretical) and where the risks injury of use clearly outweigh any possible benefit.References1. Atomoxetine (Strattera®) product labelling. The study was a retrospective medicalhttp://www.fda.gov/cder/foi/label/2008/ record review of 73 patients who received021411s024s025s026lbl.pdf drotrecogin alfa. Serious bleeding events28
  29. 29. WHO Drug Information Vol 23, No. 1, 2009 Safety and Efficacy Issuesoccurred in 7 of 20 patients (35%) who Clopidogrel is an antiplatelet drug that ishad a bleeding risk factor vs only 2 of 53 used to prevent blood clots that could(3.8%) patients without any bleeding risk lead to heart attacks or strokes in patientsfactors. More patients with baseline at risk for these problems. The drugbleeding risk factors died (13/20; 65%) clopidogrel is a “pro-drug” which meanscompared to patients without any bleed- that it has to be metabolized by the bodying risk factors (13/53; 24.5%). The before it can be biologically active andauthors acknowledge that there are have the effect of preventing blood clots.limitations to this study, such as its Understanding that there are differencesretrospective design and the small size of in how the body metabolizes clopidogrelthe patient population, that limit the ability and there are effects that other drugsto draw definitive conclusions from the may have on its metabolism is importantdata. because decreases in the effectiveness of clopidogrel might be avoided, in part,References by using other drugs with clopidogrel that do not interfere with its metabolism.1. Gentry CA, Gross KB, Sud B, Drevets DA.Adverse outcomes associated with the use of One class of drugs commonly used withdrotrecogin alfa (activated) in patients with clopidogrel is proton pump inhibitorssevere sepsis and baseline bleeding precau-tions. Crit Care Med 2009;37(1):19-25. (PPIs). Some reports suggest that use of certain PPIs may make clopidogrel less2. APACHE II score >25. The APACHE II effective (3, 4) by inhibiting the enzymescore (Acute Physiology and Chronic Health that converts clopidogrel to the activeEvaluation II) is a commonly-used severity of form of the drug. Other reports do notdisease classification system calculated for suggest this effect (5, 6). Proton pumpcritically ill patients after admission to an inhibitors decrease stomach acid and areintensive care unit. used to treat frequent heartburn and stomach ulcers. Clopidogrel can irritate3. Sweeney DA, Natanson C, Eichacker PQ. the stomach so PPIs are commonly usedRecombinant human activated protein C,package labeling, and hemorrhage risks. Crit with clopidogrel to help reduce thisCare Med 2009; 37 (1):327-328. irritation. Currently, there is no evidence that other drugs that reduce stomach4. Early communication of ongoing safety acid, such as H2 blockers or antacidsreview. http://www.fda.gov/medwatch interfere with the antiplatelet activity of clopidogrel.Clopidogrel bisulfate: Referencesongoing safety review 1 Frere C et al. Effect of cytochrome P450United States of America — The Food polymorphisms on platelet reactivity afterand Drug Administration (FDA) is aware treatment with clopidogrel in acute coronaryof published reports that clopidogrel syndrome. Am J Cardiol 2008; 101:1088–93.(Plavix®) is less effective in some pa-tients than it is in others. Differences in 2 Trenk et al. Cytochrome P450 2C19 681G Aeffectiveness may be due to genetic polymorphism and high on-clopidogrel plateletdifferences in the way the body metabo- reactivity associated with adverse 1-yearlizes clopidogrel (1, 2) or that using clinical outcome of elective percutaneouscertain other drugs with clopidogrel can coronary intervention with drug eluting orinterfere with how the body metabolizes bare-metal stents. J Am Coll Cardiol 2008; 51: 1925–34.clopidogrel (3). 29

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