2. 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
Advanced Therapies 36
Safety of Medicines
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
Continued vaccination with Gardasil® 32
List 61
49
1

3. World Health Organization WHO Drug Information Vol 23, No. 1, 2009
WHO Drug Information
is also available online at
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4. WHO Drug Information Vol 23, No. 1, 2009
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 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 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

5. 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 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-
4

6. WHO Drug Information Vol 23, No. 1, 2009 Quality of Medicines
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 communica-
tion 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
5

7. Quality of Medicines WHO Drug Information Vol 23, No. 1, 2009
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
6

8. WHO Drug Information Vol 23, No. 1, 2009 Quality of Medicines
Training 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 Prequalification
sound and updated internationally ac- Programme (PQP). http://www. who.int/
cepted quality standards. In 2008, prequal
7

9. WHO Drug Information Vol 23, No. 1, 2009
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 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 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.
8

10. WHO Drug Information Vol 23, No. 1, 2009 Herbal and Traditional Medicines
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 (70–80% 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 7–9 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 tradi-
tional 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-
9

11. Herbal and Traditional Medicines WHO Drug Information Vol 23, No. 1, 2009
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, 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.
.../
.../ Continued
10

12. WHO Drug Information Vol 23, No. 1, 2009 Herbal and Traditional Medicines
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 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

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

14. 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 regula-
tory oversight in place. Regulatory over-
13

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

16. 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/
15

17. WHO Drug Information Vol 23, No. 1, 2009
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 surveil-
lance 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

18. 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 laborato-
ries 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

19. 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 screen-
ing 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

20. 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 labora-
tories 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

21. 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

22. 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.)
21

23. Pharmacovigilance Focus WHO Drug Information Vol 23, No. 1, 2009
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 informa-
tion.
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,
Reference: Radley et al. Arch Intern Med
drug utilization data may shed light on the
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.)
22

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

25. 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

26. 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 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-
vascular Coagulation. www.emedicine.com/
process (severe sepsis), rather than an
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):1924–1933.
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27. WHO Drug Information Vol 23, No. 1, 2009
Safety and Efficacy Issues
Genetic basis of Anaesthetic infusion with pain
adverse drug events pumps: articular chondrolysis
United States of America — The first Canada — Postoperative pain pumps are
data offering health care professionals a infusion devices designed to continuously
better look into the genetic basis of deliver controlled amounts of medication
certain types of adverse drug events has (1, 2). They can be used to infuse local
been released by the Food and Drug anaesthetic solutions directly into opera-
Administration (FDA) and the Interna- tive sites for pain management following
tional 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 by
skin rashes, such as Stevens-Johnson gravity or by electric pump through a
syndrome and toxic epidermal necrolysis, catheter implanted directly into the
and 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 of
Both skin conditions appear as allergic- bupivacaine and epinephrine is also
like skin reactions associated with blister- used, with the epinephrine inducing
ing and peeling, and are considered life- vasoconstriction and slowing down the
threatening. Medications causing these absorption of bupivacaine.
serious allergic reactions should be
As of July 2008, Health Canada has
discontinued. If such signs and symptoms
received 8 incident reports of articular
are not quickly recognized, these reac-
chondrolysis following shoulder surgery
tions 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 48
pharmaceutical companies, the Wellcome
hours after surgery. All of the patients
Trust, and academic institutions focused
received bupivacaine with epinephrine.
on research relating to the genetics of
Chondrolysis was diagnosed between
drug-induced serious adverse events.
one month and one year after surgery
and use of the pain pumps.
Researchers who enter into a data use
agreement 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 is
and obtain immediate results on the not fully understood (4, 5). Chondrolysis
genetic basis of adverse drug events. of the shoulder results in narrowing of the
joint space, leading to pain and loss of
References motion; it is a debilitating condition that
requires medical attention and possibly
1. FDA News, 10 February 2009. www.fda.gov surgery (3, 4). Chondrolysis is listed
2. International Serious Adverse Event
among the possible adverse incidents in
Consortium at http://www.saeconsortium.org the device labelling of pain pumps (1, 2).
The device labelling states that the
26

28. WHO Drug Information Vol 23, No. 1, 2009 Safety and Efficacy Issues
continuous intra-articular infusion of 7. van Huyssteen AL, Bracey DJ. Chlorhexi-
anaesthetics, particularly when epine- dine and chondrolysis in the knee. J Bone
phrine 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. Rapid
pain 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 acrylic
after 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 of
gentian violet, chlorhexidine, bone ce- the glenohumeral joint following arthroscopic
ment) and radiofrequency devices may capsular release for adhesive capsulitis: a
be responsible for causing chondrolysis case report. Knee Surg Sports Traumatol
after 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 thermal
to follow the instructions for use and capsulorrhaphy. Orthopedics 2007;30(2):158–
refrain from using postoperative pain 60.
pumps for continuous intra-articular
infusion of local anaesthetics, particularly
with epinephrine, after shoulder surgery
Atomoxetine: serious
(1, 2). liver injury
Extracted from the Canadian Adverse United States of America — The Food
Reactions Newsletter, Volume 19 , and Drug Administration (FDA) continues
Number 1 (2009). to receive reports of serious liver injury in
patients given atomoxetine. Atomoxetine
References received FDA approval on 26 November
2002 as the first non-stimulant medication
1. On-Q PainBuster [Canadian instructions for used for the treatment of attention deficit
use]. Lake Forest (CA): I-Flow Corporation; hyperactivity disorder (ADHD) in children
2008.
(aged 6 years and above) and adults (1).
2. Donjoy Pain Control Device [Canadian
instructions for use]. Huntington Beach (CA): Atomoxetine’s therapeutic action is
Curlin 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 the
Postarthroscopic glenohumeral chondrolysis. year 2002 to 2007, approximately 3.3
Am J Sports Med 2007;35(10):1628–34. million patients received a prescription for
atomoxetine in the United States. Of
4. Yarbrough R, Gross R. Chondrolysis: an those, approximately 2.1 million patients
update. J Pediatr Orthop 2005;25(5):702–4. (64%) were children aged 17 years and
5. Petty DH, Jazrawi LM, Estrada LS, et al. younger (2).
Glenohumeral chondrolysis after shoulder
arthroscopy: case reports and review of the While a signal for serious liver injury was
literature. Am J Sports Med 2004;32(2):509– not detected during premarket clinical
15. trials of atomoxetine, two published post-
6. Shibata Y, Midorikawa K, Koga T, et al.
marketing reports did identify instances of
Chondrolysis of the glenohumeral joint atomoxetine-induced hepatitis (3, 4). In
following a color test using gentian violet. one of these reports, there was a positive
Int Orthop 2001;25(6):401–3. rechallenge with atomoxetine. Subse-
27

29. Safety and Efficacy Issues WHO Drug Information Vol 23, No. 1, 2009
quent to these reports, a bolded warning 2. Bangs ME, Ling J, Zhang S, et al. Hepatic
was added in 2004 to the atomoxetine events associated with atomoxetine treatment
label indicating an increased risk for for attention deficit hyperactivity disorder. Drug
severe 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 taking
atomoxetine. Following an evaluation of 4. Lim JR, Faught PR, Chalasani NP. Severe
the 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 warnings
and precautions section of the drug label Drotrecogin alfa:
advises prescribers about the risk for ongoing safety review
severe liver injury with this drug (1).
United States of America — The Food
Post-marketing reports indicate that and Drug Administration (FDA) is aware
atomoxetine is associated with serious of a retrospective study (1) which has
idiosyncratic liver injury. Some of the reported an increased risk of serious
cases reported additional confounding bleeding events and death in patients
factors, such as occasional acetami- with sepsis (a severe illness related to a
nophen use. Some of the cases lacked bloodstream infection) and baseline
sufficient clinical detail to convincingly bleeding risk factors who received
detail the relationship between the use of drotrecogin alfa. Drotrecogin alfa (acti-
atomoxetine and liver injury. The mecha- vated) (Xigris®) is a recombinant human
nism of atomoxetine-induced liver injury activated protein C indicated for the
remains unknown. reduction of mortality in adult patients
with severe sepsis who have a high risk
FDA 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.
References
1. Atomoxetine (Strattera®) product labelling. The study was a retrospective medical
http://www.fda.gov/cder/foi/label/2008/ record review of 73 patients who received
021411s024s025s026lbl.pdf drotrecogin alfa. Serious bleeding events
28

30. WHO Drug Information Vol 23, No. 1, 2009 Safety and Efficacy Issues
occurred in 7 of 20 patients (35%) who Clopidogrel is an antiplatelet drug that is
had 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 patients
factors. More patients with baseline at risk for these problems. The drug
bleeding risk factors died (13/20; 65%) clopidogrel is a “pro-drug” which means
compared to patients without any bleed- that it has to be metabolized by the body
ing risk factors (13/53; 24.5%). The before it can be biologically active and
authors acknowledge that there are have the effect of preventing blood clots.
limitations to this study, such as its Understanding that there are differences
retrospective design and the small size of in how the body metabolizes clopidogrel
the patient population, that limit the ability and there are effects that other drugs
to draw definitive conclusions from the may have on its metabolism is important
data. 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 with
drotrecogin alfa (activated) in patients with
clopidogrel is proton pump inhibitors
severe 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 less
2. APACHE II score >25. The APACHE II effective (3, 4) by inhibiting the enzyme
score (Acute Physiology and Chronic Health that converts clopidogrel to the active
Evaluation II) is a commonly-used severity of form of the drug. Other reports do not
disease classification system calculated for suggest this effect (5, 6). Proton pump
critically ill patients after admission to an inhibitors decrease stomach acid and are
intensive care unit. used to treat frequent heartburn and
stomach ulcers. Clopidogrel can irritate
3. Sweeney DA, Natanson C, Eichacker PQ.
the stomach so PPIs are commonly used
Recombinant human activated protein C,
package labeling, and hemorrhage risks. Crit with clopidogrel to help reduce this
Care Med 2009; 37 (1):327-328. irritation. Currently, there is no evidence
that other drugs that reduce stomach
4. Early communication of ongoing safety acid, such as H2 blockers or antacids
review. http://www.fda.gov/medwatch interfere with the antiplatelet activity of
clopidogrel.
Clopidogrel bisulfate:
References
ongoing safety review
1 Frere C et al. Effect of cytochrome P450
United States of America — The Food
polymorphisms on platelet reactivity after
and Drug Administration (FDA) is aware treatment with clopidogrel in acute coronary
of 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 A
effectiveness may be due to genetic polymorphism and high on-clopidogrel platelet
differences in the way the body metabo- reactivity associated with adverse 1-year
lizes clopidogrel (1, 2) or that using clinical outcome of elective percutaneous
certain other drugs with clopidogrel can coronary intervention with drug eluting or
interfere with how the body metabolizes bare-metal stents. J Am Coll Cardiol 2008; 51:
1925–34.
clopidogrel (3).
29