WHO Drug Information Vol 23, No

WHO Drug Information Vol 23, No. 1, 2009 World Health Organization

WHO Drug Information

Contents Quality of Medicines Erlotinib: Use in hepatic impairment and advanced solid tumours 32 WHO medicines prequalification: Generic piperacillin and tazobactam: progress in 2008 3 medication errors 33 Safety of artemisinin combination therapy: Herbal and Traditional pregnant women 33 Medicines WHO Congress on Traditional Medicine Regulatory Action and News and the Beijing Declaration 8 Efalizumab: suspension of marketing authorization 35 Contusugene ladenovec: withdrawal of Biomedicines Update marketing application 36 Global 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 Safety of Medicines Advanced Therapies 36 The mobile laboratory: a new concept in medicines surveillance 16 Consultation document International Pharmacopoeia Pharmacovigilance Focus Oxytocin 38 Oxytocin injection 43 Monitoring the safety of off-label medicine use 21 Drotrecogin alfa: what relation to Recent Publications, thrombosis? 22 Information and Events Low availability, high prices keep Safety and Efficacy Issues essential medicines out of reach 46 Genetic basis of adverse drug events 26 Sources and prices of selected Anaesthetic infusion with pain pumps: medicines for children 46 articular chondrolysis 26 Two international summer courses Atomoxetine: serious liver injury 27 in the Netherlands 47 Drotrecogin alfa: ongoing safety review 28 Global politics of pharmaceutical Clopidogrel bisulfate: ongoing safety monopoly 48 review 29 Modafinil: adverse skin and psychiatric reactions 30 Recommended International Levothyroxine update 30 Nonproprietary Names: Temsirolimus: hypersensitivity reactions 31 List 61 Continued vaccination with Gardasil¨ 32 49

1 World Health Organization WHO Drug Information Vol 23, No. 1, 2009

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Quality of Medicines

WHO medicines prequalification: progress in 2008

The WHO Prequalification Programme for considerable breakthrough in making Medicines (PQP) was initiated in 2001 as user-friendly formulations available that a service provided by the World Health will also improve efficacy of treatment. Organization (WHO) to facilitate access to medicines that meet unified interna- The number of products prequalified in tional standards of quality, safety and 2008 was the highest in six years. The efficacy for HIV/AIDS, malaria, tuberculo- main reasons for this were: sis and reproductive health. ¥ Increasing number of well prepared new The work is carried out through: submissions in 2007Ð2008.

¥ Stringent assessment of pharmaceutical ¥ Improved quality of evidence to demon- product dossiers. strate quality, safety and efficacy of products. ¥ Inspection of pharmaceutical manufacturing 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 medicines have to be checked regularly to The Bill & Melinda Gates Foundation as ensure that any changes undertaken by well as UNITAID are the main financial manufacturers do not undermine the supporters of PQP. quality, safety and efficacy of the product.

Newly prequalified medicines In order to achieve this objective, WHO Forty 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 control increase from 21 products in 2007. The tests of prequalified medicines. Since the total number of prequalified medicines prequalified products list is constantly currently stands at 196. being added to, information maintenance and updating becomes crucial to the A major achievement in 2008 was the preservation of established international prequalification of new products specially standards. designed to treat HIV/AIDS in children, as well as the first fixed-dose combination New submissions to PQP tablets of artesunate and amodiaquine to Certain product groups are urgently in treat malaria. These products represent a need of expansion to increase available

3 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 medicines 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 countries for staff of regulatory authorities and pharmaceutical manufacturers. ¥ Provided manufacturers with scientific advice and technical assistance to support 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 chemical 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 specifications antituberculosis and paediatric antiretrovi- presented for reproductive health and ral combination products). However, it antimalarial products and manufacturing was again noted that the number of conditions are of particular concern. products submitted for evaluation within this category was insufficient to meet In recent years, documented quality current demand. This is mainly due to a assurance of medicines has become an lack of commercial incentives available to essential requirement of international manufacturers to develop products funding agencies for successful bidding in intended for small or non-profitable procuring essential medicines for devel- markets. oping countries. Manufacturers should therefore be increasingly motivated to In 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 the ment continued to present many chal- quality of submissions to the PQP. lenges. Newcomer manufacturers having limited or no experience in production Technical assistance to manufacturers according to international standards have Time and resources are needed from great difficulty in submitting the evidence applicants to obtain product prequalifica-

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tion and this includes dedication to Capacity building of implementation of corrective action to regulatory authorities meet international quality standards. It In 2008, the PQP continued to offer follows that an increase in the number of national regulatory personnel from available prequalified medicines can only resource-limited countries a three-month be achieved based on increased capacity full-time post at WHO. These rotational building and technical assistance activi- positions for quality assessors are aimed ties. at creating links and form a network between WHO and the countries in- Consequently, since 2006, the PQP has volved, as well as enhance information provided coordinated technical assistance exchange between both parties. aimed at resolving specific practical problems encountered by manufacturers In addition, assessors from less re- or quality control laboratories. Assistance sourced regulatory authorities continue to is provided by qualified professionals in participate in PQP assessment sessions the form of an audit and training in where they account for one-third of the technical or regulatory areas. total external assessor contribution. Since 2008, inspectors from these Such action in resource-limited countries authorities are invited to take part in has 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 have the following years. In 2008, PQP pro- been especially active in this process. vided eight technical assistance missions to pharmaceutical manufacturers in five Dossier assessments different countries. and expert advice In 2008, seven assessment sessions Training were organized at the UNICEF Supply WHO recognizes the crucial role of Division in Copenhagen where product capacity building through training and dossiers are received and stored. The hands-on practice. In 2008, PQP organ- number of assessment reports for 2008 ized 11 training courses and co-organized increased to 732 compared to 463 in four training activities together with other 2007. In addition to regular assessment partners in 10 different countries (see activities, provision of expert scientific table on page 7). advice to applicants remained high on the This 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 queries medicines regulatory agency staff and answered, and close to 80 separate professionals from quality control labora- quality issues handled by the respective tories. Training courses include group expert panels. sessions as well as focused communication between the involved parties, such as Inspections manufacturers and lecturers who are part A total of 38 inspections of pharmaceuti- of the assessment or inspection teams cal manufacturers and 14 inspections of working with PQP. In 2008, these courses CROs were carried out in seven different involved more than 600 participants and countries in 2008. As in all previous 46 lecturers and trainers provided by years, the national inspectorates from PQP. well established regulatory authorities continued to provide staff inspectors for

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Prequalification 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 10 prequalification purposes. France was the of delivery to the recipient country. How- leading country in terms of providing ever, quality can deteriorate during inspection support. transportation and storage. To verify that the quality of essential medicines is Prequalification of quality maintained throughout the supply chain control laboratories until the medicines reach the end user, The prequalification of quality control several sampling and testing programmes laboratories was restarted in 2007 when have been designed and implemented. 12 laboratories expressed interest in prequalification. In 2008, PQP carried out Programme strengthening 10 inspections of quality control laborato- and development of standards ries with six gaining prequalification Major procedural improvements to PQP status. in 2008 include: Testing of medicines ¥ Revision and update of the procedure The 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 360

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Training workshops organized by WHO PQP in 2008 Date Location Content of training

25Ð29 February Brasilia, Brazil New approaches to quality risk management in manufacture of medicines.

21Ð25 April Lahore, Pakistan Development of PQP submission dossiers.

28 AprilÐ1 May Mumbai, India Pharmaceutical development with a focus on paediatric formulations.

2Ð6 June Dar-es-Salaam, United Evaluation of generic products focusing Republic of Tanzania on bioequivalence and biowaiver data.

16Ð20 June Amman, Jordan Introduction to PQP and technical requirements.

16Ð20 June Teheran, The Islamic Introduction to PQP and technical Republic of Iran requirements.

23Ð27 June Beijing, China GMP for reproductive health products and dossier requirements.

8Ð11 July Rabat, Morocco GMP Ð air and water treatment systems

20Ð24 October Jakarta, Indonesia GMP for reproductive health products and dossier requirements.

3Ð7 November Accra, Ghana Regulatory requirements and data assessment of artemisinin-based fixed dose combination medicines.

1Ð5 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 Prequalification sound and updated internationally ac- Programme (PQP). http://www. who.int/ cepted quality standards. In 2008, prequal

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Herbal and Traditional Medicines

WHO Congress on Traditional Medicine and the Beijing Declaration

Representatives of over 70 Member States attended the first WHO Congress on Traditional Medicine held on 7Ð9 November 2008 in Beijing, China. Satellite sympo- sia were held to discuss related technical topics. Presentations were given by representatives 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, complementary 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 Member sary and the 30th anniversary of the Alma States. Ata Declaration, adopted by UNICEF and WHO in 1978. Although traditional Use of traditional medicine has changed medicine has been used for thousands dramatically over the past thirty years. of years and has made a fundamental Due to its affordability, availability and contribution to human health, the Alma accessibility, traditional medicine has Ata Declaration was the first formal played an important role in meeting the recognition of the role of traditional demands of primary health care in many medicine and its practitioners in primary developing countries.

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Since the 1990s, the use of traditional and western medicine can blend together medicine has surged. It not only main- in beneficial harmony, using the best tains its function in primary health care in features of each system. developing countries (70Ð80% of the population in Ethiopia and India still Delegates were welcomed by the Minister depend on traditional medicine and of Health, People’s Republic of China. In practitioners for primary health care), its their presentations, the Minister of Health use has expanded widely in many devel- of the Union of Myanmar and the Deputy oped 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 and tion in Canada and 80% in Germany have actions that their respective countries used CAM. National health authorities have taken. The need for appropriate were asked to consider how to integrate regulatory oversight of complementary TM/CAM into their national health sys- medicine products was expressed by the tems and significant progress has been National Manager of the Therapeutic made 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 into Traditional Medicine Health Systems, 26 delegates presented To 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 respective integrate traditional medicine/CAM into countries. To facilitate discussion, the their national health systems, the first presentations were separated into five WHO Congress on Traditional Medicine topic areas: on 7Ð9 November 2008, was organized in Beijing, 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 Chinese Medicine of the Government of China, in ¥ National regulation of traditional and cooperation with four nongovernmental herbal medicines. organizations (NGOs) in official relations with WHO — the World Self-Medication ¥ Traditional medicine in primary health Industry (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 traditional medicine. During the opening ceremony, the Direc- tor-General of WHO identified the impor- While presentations showed that it is tance of traditional medicine in primary often necessary to tailor legislation and health care, the role of research, the need delivery to reflect the needs and traditions for appropriate licensing or registration of of individual countries, a number of practitioners 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, issues health care, the two systems of traditional related to safety, need to enhance re-

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search into both products and practices, created to discuss and harmonize the importance of labelling and information as comments submitted to WHO prior to the it relates to supporting informed choice, Congress and to enable the Declaration and the need for appropriate integration to be presented to the Congress. into primary health care. Congress delegates adopted the Beijing Delegates also heard from two WHO Declaration during the WHO Congress on partners (The Nippon Foundation and the Traditional Medicine. In addition to a Regional Government of Lombardy) who preamble text noting a number of related described their work in this area. The four initiatives and reflecting the importance of nongovernmental organizations hosting national contexts with regard to capacity, satellite conferences were also given the priorities and relevant legislation, the opportunity to make presentations and Beijing Declaration is set out below. observe the Congress. The Beijing Declaration will serve to A key outcome of the Congress was the promote the safe and effective use of Beijing Declaration, which identified traditional medicine, and calls on WHO common aims and principles reached by Member States and other stakeholders to participants 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 International circulation of the first draft. Comments Forum the WHO Assistant Director- were collected and modifications made General for Health Systems and Services with a subsequent draft sent to partici- said, “This is a landmark declaration, after pants 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, including 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. .../

.../ Continued

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Beijing 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 circumstances, 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 traditional medicine.

III. Recognizing the progress of many governments to date in integrating traditional 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 organizations 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.

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Biomedicines Update

Global norms and standards for biological 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 preparation 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, research 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 standards 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.html

Highlights of the The WHO Expert Committee on Biologi- 2008 ECBS meeting cal Standardization (ECBS) establishes global norms and standards that help Biological medical products such as define products of assured quality. The vaccines, blood products, biotherapeutics ECBS meets annually and their most and associated diagnostics save lives, recent meeting was held in Geneva from reduce 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 previous available, affordable and properly used. years, by running two parallel tracks, one WHO is working with it’s Member States dedicated to vaccines and selected other to use only biological medicines of biological medicines; one dedicated to assured quality in national health sys- blood products and related in vitro diag- tems. nostic devices.

12 WHO Drug Information Vol 23, No. 1, 2009 Biomedicines Update

The most important outcomes of the 2008 Yellow fever vaccine ECBS meeting were: An amendment to the written standard for yellow fever vaccine was also estab- Snake antivenom immunoglobulins lished. This requires that the expression A 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 dose immunoglobulins was established. Snake recommended for use in humans shall antivenom immunoglobulins (antivenoms) not be less than 3.0 log10 IU. This new are 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 for snake antivenom immunoglobulins to WHO prequalification of yellow fever treat specific types of envenomings vaccines. encountered in various regions of the world has become a critical health issue Abbreviated licensing pathways for at global level. The crisis has reached its certain biological therapeutic products greatest intensity in sub-Saharan Africa, The Expert Committee also discussed a but 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 public The 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 biological snake venom mixtures for the production approaches have been successful in of hyperimmune plasma (source of treating many life-threatening diseases antivenom immunoglobulins), the de- and the market for these products is creasing number of producers and the rapidly growing. fragility of the production systems in developing countries further jeopardize However, such innovative biological the availability of efficient antivenoms in medicines are expensive. This has limited Africa, Asia, the Middle East, and South their use, particularly in developing America. Also, most of the remaining countries. The expiration of patents on producers are located in countries where key biological drugs such as recombinant the application of quality and safety insulin, human growth hormone and standards needs to be improved. erythropoietin is opening the door for copies of these drugs to be made by The new Guidelines cover all the steps developing country manufacturers. This involved in the production, control and may contribute to a substantial increase regulation of venoms and antivenoms. It in their availability at an affordable price. is hoped that this document, by covering comprehensively current existing experi- Generic versions of expired-patent ence in manufacture, control, and pre- chemical drugs are well known. However, clinical and clinical assessment of these copy biological medicines are far more products will serve as a guide to national complicated products for which the control authorities and manufacturers to current generic regulatory pathway is support worldwide production of these unsuitable. Nevertheless it is essential to essential medicines. ensure that there is appropriate regulatory oversight in place. Regulatory over-

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Proposals to establish new or replacement International Standards or WHO reference 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

.../Continued

14 WHO Drug Information Vol 23, No. 1, 2009 Biomedicines Update

Proposals to establish new or replacement International Standards or WHO reference 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 Standard sight should not be so lax that ineffective Global reference preparations or dangerous products are allowed into A total of 18 new or replacement global the market place or so restrictive that safe reference preparations were established. and effective products face regulations These are the primary calibrant against that are too stringent. which regional or national measurement standards are benchmarked. An updated The 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, References but 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 and following consideration by the Committee, 2. World Health Organization. Blood products the ECBS therefore recommended that and related biologicals: http://www.who.int/ the current document be strengthened bloodproducts/en/index.html and some issues further clarified. A revised version should be re-submitted to 3. World Health Organization. Immunization, the Committee in 2009. Vaccines and Biologicals: http://www.who.int/ immunization/en/

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Safety of Medicines

The mobile laboratory: crack down on the manufacturing and marketing of counterfeit pharmaceutical a new concept in products, the Chinese Government has medicines surveillance implemented a number of drug surveillance programs. In China, fake and According to the World Health Organiza- substandard drugs mainly appear at the tion (WHO), about 6 to 10% of medicines retail level in the supply chain, and worldwide are counterfeit; a market worth therefore these programmes generally 32 billion US dollars in annual sales. The require samples to be collected from the phenomenon has grown in recent years market and analysed in quality control due to methods of counterfeiting becom- laboratories at the provincial or district ing 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 local mainly occurs in developing countries, but authorities include basic tests, such as counterfeiting 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. Samples In response to the challenge presented suspected of being counterfeit are then by the public health crisis caused by a sent to quality control laboratories at the global increase in counterfeit drugs, WHO district level for analysis using more has 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, but main purpose of IMPACT is to build a are not very effective in detecting the coordinated network across and between more sophisticated high technology countries in order to halt the production, counterfeit products. trading and sale of fake medicines around the world. IMPACT is a partnership To reinforce surveillance, medicines are comprising all the major anti-counterfeit- also routinely sampled from the market ing 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 to manufacturers 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 improve huge 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 level Article prepared by Professor Shaohong Jin, can be better utilized. Reliable on-site National Institute for the Control of Pharma- analysis will also allow resources to be ceutical and Biological Products, China. efficiently targeted at those cases where

16 WHO Drug Information Vol 23, No. 1, 2009 Safety of Medicines

Mobile laboratories in China

law enforcement already has evidence ¥ To provide a platform for the deployment that counterfeit products are being of modern high-technology analytical distributed. methods that would both aid in the crackdown on the sale and distribution Objectives 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 in predominantly rural areas, the Chinese ¥ To reduce the high cost and increase National Institute for the Control of the efficiency of routine drug quality Pharmaceutical and Biological Products post-marketing surveillance. (NICPBP) proposed that mobile laboratories be used for quality testing. The On 30 November 2003, less than 10 laboratories are specially designed vans months after the initial proposal from equipped to perform various quick analy- NICPBP, the first mobile laboratory for ses. The primary objectives of the mobile drug quality testing was unveiled. On laboratories 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 Safety of Medicines WHO Drug Information Vol 23, No. 1, 2009

Operating the mobile laboratory modern analytical instruments that can Currently, the only internationally avail- quickly and non-destructively analyse able system for quick screening of coun- drug products. The mobile laboratories terfeits on-site is the Minilab test kit, provide an effective screening tool for the which is capable of testing less than 50 crackdown on counterfeit drugs. common products, such as antibiotics or antimalarials, but the Minilab test kit is not Reliability of the NIR method sufficient to address the problem of for drug screening counterfeits in China. The scientific During 2006 and 2007, mobile laborato- equipment in the mobile laboratory ries tested a total of 10 340 batches of includes a near-infrared spectrometer, pharmaceutical products, of which 329 TLC, colorimetry, digital photography, batches were known to be fake. Of the visible microscopy, and test kits for 10 340 batches tested, 1087 (about specific 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 be spectrometer and a pre-developed fake. In addition to the fake products, standard analytical method that uses a some non-counterfeit products failed to library of near-infrared (NIR) spectra pass the NIR screening because of (developed by the NICPBP) of all the changes in product formulations. All registered pharmaceutical products in products that failed the NIR screening China. This near-infrared based system is were sent to district laboratories for quick, accurate, non-destructive, and further testing using more specific meth- versatile. ods. These results show that NIR screening is a very reliable method for the Apart from analytical instrumentation, detection of counterfeit drugs, and also another important tool in the mobile dramatically decreases the number of laboratory is the information system, products that need to be tested in district which includes manufacturer information laboratories. for officially registered products, including the registration numbers, formulations, Results of using mobile laboratories dosages and labelling, etc. as well as a for drug testing list of known counterfeits. Dedicated From April 2004 to November 2005, field software for the mobile laboratory allows tests of the mobile laboratories were easy 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 the by providing automatic analysis of the analytical equipment was evaluated near-infrared spectrum using pre-loaded under real conditions. The evaluation analysis methods, and generation and included the effect of vibration on the logging of all test reports. equipment when the van was driven on rough roads in the countryside. Field tests In addition, the software includes a were used to look for possible areas for database of analytical methods, digital improvement. manuals, and predefined standard forms to record and manage mobile laboratory As an example of these trials, starting in activities such as when and where the August 2004, a mobile laboratory was mobile laboratories have been dis- dispatched 165 times in Zhumadian patched. The mobile laboratory thus Prefecture of Henan Province. The combines modern information technology, mobile laboratory visited 8 of 11 counties scientific management systems, and in the prefecture as well as 42 of 186

18 WHO Drug Information Vol 23, No. 1, 2009 Safety of Medicines

villages, 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 in The mobile laboratory examined a total of rural areas. 260 pharmacies and clinics and screened 3965 batches of 408 different drug The mobile laboratory programme has products. Of these, 57 batches were also shown its utility in response to suspected to be fake and were further emergencies caused by fake drugs. As an tested by analytical methods in district example, in the summer of 2006, instead laboratories resulting in five batches that of propylene glycol, the toxic ingredient were confirmed as counterfeit. The diethylene glycol was used by mistake in mobile laboratories also visited AIDS a few batches of Armillarisin A¨ for prevention 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 dispatched nine villages with a moderate population to screen all suspected products that of 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 the that were tested. The extensive surveil- results for medicines screened positive lance that is possible with mobile labora- for diethylene glycol by the mobile laboratories thus ensures the quality and safety tories. In this case, the NIR-based quick of 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 mobile been deployed across China. They have laboratory programme visited over 77 000 drug dispensaries, A second generation of mobile laborato- and have travelled over 2 000 000 km. ries is currently under development which They have screened more than 379 000 incorporate a patented green HPLC batches 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 the substandard. Of these, approximately solvents are close-loop recycled inside 14 000 batches were later confirmed to the van. The advantage of implementing be counterfeit. The average analysis cost the HPLC system in the mobile laboratory per batch in the district laboratory is about is that if a drug product tests positive 600 RMB. If the traditional test pro- using the NIR-based prescreening gramme were used for the 379 000 method, then an on-site verification can batches, they would have cost almost be performed immediately. 230 million RMB. The new, targeted analysis of only those batches that were Incorporating the HPLC technology suspect based on pre-screening results should further improve the accuracy and reduced the cost of analysis in the district efficiency of the mobile laboratory pro- laboratories by about 90%, to approxi- gramme, especially in remote areas mately 22 million RMB. where the local Food and Drug Adminis- tration or other analytical laboratories are These data show that the mobile labora- far away. A combination of the NIR-based tories not only increase the successful quick and non-destructive screening sampling rate and improve the efficiency method and on-site verification capability of the drug surveillance programme, but using the new HPLC technology may also

19 Safety of Medicines WHO Drug Information Vol 23, No. 1, 2009

play an important role in counterfeit drug surveillance programme and reduced detection in many developing countries. costs. They have also expanded the monitoring area of the programme and Conclusions have improved the ability of the authori- The mobile laboratory is a new monitoring ties to rapidly respond when there is system that provides in-time information evidence of adverse reactions to drug gathering, quick screening, targeted products on the market. In the future, sampling based on drug law-enforcement mobile laboratories will continue to play efforts, and accurate analytical tests. an important role in increasing the effi- These mobile laboratories have demon- ciency of government efforts to crack strated considerable success in ensuring down on the manufacture and marketing medicines safety. The laboratories have of counterfeit products in China. increased the efficiency of the drug

20 WHO Drug Information Vol 23, No. 1, 2009

Pharmacovigilance Focus

Monitoring 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 is Medicine labels contain important infor- necessary to gain information on the mation on the conditions of use. These usage of medicines in these settings. conditions typically include the indication, While formal study of medication safety dosage, frequency of administration, and would be optimal in these settings, such route 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 an and contraindications to use of the off-label setting can also potentially be medicine. Deviations from the conditions relevant to the safety of the medicine of use set forth in the label constitute off- when used according to the label. In label use. addition, data derived in the off-label setting may serve as a stimulus for more In 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 that does not regulate prescribing practices. In need to be addressed when monitoring one study (1), approximately 21 per cent the safety of medicines in an off-label of drug use in office-based practice was setting. Many factors that could affect the for off-label use. Off-label use may occur safety of the medicine could be different for a variety of reasons. For example, in the off-label compared to the on-label there are some diseases for which no setting. These factors include the age of adequate, labelled treatment exists. In patients, range of co-morbidities, use of these situations, prescribers use medi- concomitant medication, drug-disease cines 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, so there has been extensive off-label use in Despite the importance of monitoring the children, although there are ongoing safety of medicines in an off-label setting, efforts to correct this situation. In some there are many challenges that this cases, there may be a reasonable body situation presents. First, spontaneous of 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 would tive. However, off-label use may become allow one to determine that the medicine part of accepted practice, and may be was used in a manner not consistent with part 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 mean a 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. (Views expressed are those of the author, and not necessarily those of the US Food and Drug Adminis- tration.)

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Despite these limitations, spontaneous used by persons without epilepsy, and reports can be useful in determining that these persons experienced seizures adverse drug reactions when medicines after tiagabine was started. The product’s are used off-label. label was updated to include this information. Drug utilization databases may be helpful in 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 adverse contain information on indications for use, events in this setting is important, though they can be helpful in identifying other there are many challenges in doing so. aspects of off-label use. For example, drug utilization data may shed light on the Reference: Radley et al. Arch Intern Med 2006; 166:1021-1026. age range of patients using a medicine, the duration of therapy, concomitant medication used, and dosages pre- Drotrecogin alfa: what scribed. Review of such data may indi- relation to thrombosis? cate that there is substantial off-label use and 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-inflammatory Drug use databases typically do not have and profibrinolytic activities. It is used any information on medical diagnoses, so mainly in intensive care as a treatment for they are not suitable for identifying severe sepsis (sepsis associated with adverse 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 days healthcare databases that contain infor- (1). mation both on drug use data and medi- Sepsis is a complex illness involving both cal diagnoses can also be useful for infection and inflammation when the identifying trends in off-label use, though body’s response is systemic, instead of medical record review may be necessary being localized to the site of infection. to determine the indication for usage. This “overreaction” to the infection may Electronic medical records may be more result in organ damage and is more useful than administrative healthcare dangerous than the initial infection itself databases if indication for use is linked to (2). the drug prescribed. Finally, published clinical trials studying off-label use may Patients who die during episodes of be a valuable source of information on sepsis are more likely to have coagulation adverse drug reactions. However, the defects, including lower levels of circulat- limitations of clinical trials for ascertaining ing antithrombin III and protein C. The adverse event information are well latter is a vitamin K-dependent anticoagu- known. lant protease. In sepsis, protein C defi- ciency appears before the onset of One example of the importance of moni- observable indicators of septic shock. toring for adverse events in the off-label setting is seen with the drug tiagabine, The administration of an exogenous whose labelled indication in the USA is for analogue may modulate the patient’s adjunctive therapy in adults and children over 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 for indicated that this medicine was being International Drug Monitoring.)

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response during sepsis (1, 3). The only day of drotrecogin treatment were deep serious adverse reaction observed in venous thrombophlebitis and thrombosis. clinical trials to drotrecogin alfa was bleeding (3, 4). 5. A pharmacist described a 45-year-old female who was administered drotrecogin Description 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 were drotrecogin alfa were reported to intestinal ischaemia, decreased pro- VigiBase, the database of the WHO thrombin level and thrombosis. Collaborating Centre for International Drug Monitoring, in the period 2002 to 6. A pharmacist described a 72-year-old 2007. There were 12 reports from the male treated with drotrecogin alfa for four USA and one from the United Kingdom. days. Concomitant medication comprised The reports are summarized below. sodium bicarbonate, pantoprazole, norepinephrine, vasopressin, paraceta- 1. A General Practitioner (GP) described mol, dopamine, amiodarone, vancomycin a 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 administered 2. 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 and observed. lorazepam for two days. One day after termination of drotrecogin treatment the 3. 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-old antibiotics as well as paracetamol and male who was treated with drotrecogin hydrocodone bitartrate. The report, sent alfa for two days. No concomitant medi- by a GP, specified thrombosis, multiple cation was reported. Life-threatening organ failure and gangrene as adverse adverse reactions comprised hypoten- effects. Onset appeared eight days after sion, gastrointestinal haemorrhage and termination of treatment. thrombosis. Positive dechallenge was also observed. 4. A 66-year-old male was treated with drotrecogin alfa for three days. Concomi- 9. A physician reported the case of a tant medication comprised paracetamol, female treated with drotrecogin alfa who codeine, atenolol, lorazepam, triamci- developed thrombosis. No details were nolone, propofol, dopamine, levofloxacin, disclosed. morphine, famotidine, salbutamol, meto- 10. A pharmacist described a 63-year-old clopramide, diazepam, midazolam, female treated with drotrecogin alfa for thiamine, piperacillin-tazobactam three days. Concomitant medication combination 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 Pharmacovigilance Focus WHO Drug Information Vol 23, No. 1, 2009

increased blood chloride and urea, associated with bleeding, related to its hypernatraemia, hypokalaemia, antithrombotic and profibrinolytic proper- hyperglycaemia, peripheral oedema, ties (1). In a Phase III placebo controlled thrombocythaemia and thrombosis. clinical trial, the incidence of thrombotic Dechallenge appeared to be negative. No events was similar in the drotrecogin and further information was provided. placebo arms (4). This was confirmed by analysis of results from combined clinical 11. A physician described a 70-year-old trials. When compared with placebo, female treated with drotrecogin alfa for patients in the active treatment arms two days. Reported adverse effects were experienced numerically fewer thrombotic rash, jaundice, rectal disorders, bacterial events, although the difference was not infection, peritonitis and thrombosis. statistically significant (7).

12. A health professional reported the Thrombosis frequently occurs in patients case of a 29-year-old female treated with with severe sepsis (7). Disseminated drotrecogin alfa for two days. Concomi- intravascular coagulation (DIC) may tant medication comprised norepine- develop in 30-50% of patients with severe phrine and dobutamine. Adverse reac- sepsis and septic shock, especially when tions were haemorrhage and thrombosis. caused by Gram negative bacteria. The mortality of sepsis is correlated with the 13. 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. The The adverse reaction was thrombosis. cytokines produced in sepsis incapacitate the protein C pathway. One of the critical Evaluation of reports mediators of DIC is the release of a Six of the thirteen reports do not mention transmembrane glycoprotein tissue factor. concomitant medication. Because of the This is released in response to exposure clinical situation in which drotrecogin is to cytokines or endotoxin and plays a used, it is almost certain that other major role in the development of DIC in medicines were co-administered. Thus, it septic conditions. For this reason, is possible that some concomitantly used drotrecogin alfa is recommended in the but undisclosed medicine might have therapy of DIC (8, 9). Additionally, a contributed 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 with describe a range of concomitant medica- drotrecogin alfa who met the criteria for tions. According to European Union DIC (10). Summaries of Product Characteristics (SPCs) as well as an international data- Hence, the conclusion is that in these base (5) of these medicines, only propofol spontaneous reports a manifestation of (administered in a single case) has the the underlying disease was reported as a recognized, although very rare, adverse possible adverse drug reaction. This effect of thrombophlebitis (6). hypothesis is further supported by the following. Signal assessment On the basis of pharmacological proper- ¥ Clinical manifestation of DIC is ex- ties of drotrecogin alfa, administration is tremely variable (9). The pathological unlikely to lead to thrombosis. On the processes involved deplete the body of contrary, drotrecogin use is frequently its platelets and coagulation factors and

24 WHO Drug Information Vol 23, No. 1, 2009 Pharmacovigilance Focus

so, paradoxically, may lead to both 2. Sepsis.com Ð 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):511Ð517. 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;344:699Ð709. be seen that other reports on drotrecogin alfa between 2002 and 2007 5. 1974-Ð2207 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 of In 13 reports of thrombosis associated Recombinant Human Activated Protein C with the use of drotrecogin alfa, retrieved United States Trial (ENHANCE US). Chest from VigiBase, it appears likely that the 2004;125:2206-2216. reported thrombotic events represent a manifestation of the underlying disease 8. Becker JU, Wira CR. Disseminated Intra- process (severe sepsis), rather than an vascular Coagulation. www.emedicine.com/ emerg/topic150.htm, downloaded 07.08.2008. adverse reaction to any administered medicine. This analysis underlines the 9. Aysola A , Lopez-Plaza I. Disseminated importance 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 of 1. Goshman L. Drotrecogin Alfa, Activated. drotrecogin alfa (activated) in patients with Journal of the Pharmacy Society of Wisconsin severe sepsis with or without disseminated Mar/Apr 2002;3335. intravascular coagulation. Journal of Thrombo- sis and Haemostasis 2004;2(11):1924Ð1933.