2. WHO Drug Information Vol 23, No. 2, 2009 World Health Organization
WHO Drug Information
Contents
Pharmacovigilance Focus Sodium valproate and fetal malformations 113
Abacavir: determining risk of heart attack 114
Biosimilar medicines and safety: new
Carbamazepine: serious adverse skin
challenges for pharmacovigilance 87
reactions 114
Electronic adverse reaction reporting tool 115
Blood and Biomedicines Intensive monitoring of varenicline 116
Availability, quality and safety of blood
and blood products 95 Regulatory Action and News
Influenza virus vaccines: 2009–2010
New Regulatory Challenges season 117
Contribution of clinical pharmacologists Sale of efalizumab suspended 117
to government: opportunities and Efalizumab: voluntary withdrawal 118
challenges 99 Oseltamivir: extension of shelf life 118
Antiviral medicines in an influenza
pandemic 119
Safety and Efficacy Issues European Union and Health Canada:
Etanercept: histoplasmosis and invasive confidentiality arrangement 119
fungal infections 104 Ixabepilone: withdrawal of application
Zonisamide: metabolic acidosis 104 for marketing authorization 120
Progressive multifocal leuko- Peginterferon alfa–2b: withdrawal of
encephalopathy 105 application for marketing authorization 120
Severe adverse reactions with Levodopa/carbidopa/entacapone:
intravenous immunoglobulin 105 withdrawal of application for
Exanatide: risk of severe pancreatitis extension of indication 120
and renal failure 106
Benefits of methylphenidate continue to Medicines Strategy
outweigh risks 106
Chromic phosphate P32: acute and Policies
lymphocytic leukaemia 107 Good Governance for Medicines
Warning for metoclopramide-containing Programme 122
drugs 108
Metabolic effects of antipsychotics 108
Cefaclor and serum sickness-like Recent Publications,
reactions in children 108 Information and Events
Toremifene: prolongation of QTc interval 109 ASEAN: mutual recognition arrangement
Atomoxetine: risk of psychotic or manic for GMP 127
symptoms 109 Losing artemisinin? 127
Lignocaine with chlorhexidrine gel: International drug price indicator guide 128
anaphylaxis 110
Moxifloxacin safety update 110
Codeine toxicity in breastfed infants 110 Proposed International
Atypical antipsychotics: risk of stroke 111
Biphosphonates: atypical stress fractures 112
Nonproprietary Names: 129
Effects of MRI on implantable drug pumps113 List 101
85

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4. WHO Drug Information Vol 23, No. 2, 2009
Pharmacovigilance Focus
Biosimilar medicines and Biological medicinal products (biopharma-
ceuticals) have a successful record in
safety: new challenges for treating many life threatening and chronic
pharmacovigilance diseases. However, their cost has often
been high, thereby limiting their access to
Regulatory experience of approving and patients, notably in developing countries.
monitoring the safety of biosimilar medi- More recently, the expiration of patents
cines varies across the world. Recently, and/or data protection for the first major
the European Union (EU) took the lead in group of innovative biotherapeutics is
establishing a transparent regulatory stimulating development of products
process for approving biosimilars. To “similar” to the original biological products
date, the EU has approved a number of which rely for their licensing, in part, on
biosimilars such as formulations of data from originator products licensed on
somatotropin, epoietin and, most recently, a full registration dossier.
filgrastim. The prevailing view among
regulators is that proteins are much more A variety of terms, such as ‘biosimilars’,
complex than small molecule medicines ‘follow-on protein products’ and ‘subse-
and it may not be possible to demonstrate quent-entry biologics’ have been used by
the identical nature of two biological different jurisdictions to describe these
products originating from different manu- products. The term ‘generic’ medicine is
facturing sources solely based on quality used extensively for chemical, small
information. molecule medicinal products that are
structurally and therapeutically equivalent
This has led to the view that follow-on to an originator product whose patent
biological products manufactured by and/or data protection period has expired.
generic manufacturers after expiry of
patent and other exclusivity rights cannot Current situation
be approved using the same simplified In many countries, a regulatory pathway
regulatory procedures as applied for for the approval of generic medicines has
small molecule-based generic drugs. been established. Since biological medici-
Generating additional nonclinical and nal products consist of large and highly
clinical data to demonstrate that these complex molecular entities that are
medicines have an equivalent, or similar, difficult to characterize, the approach
safety and efficacy profile to the originator established for small molecule generic
product is needed. However, several medicines is not fully appropriate for
parties have raised concerns that such development, evaluation and licensing of
regulatory procedures may not be enough biosimilars — as they are called in the
to ensure the safety and efficacy of these EU. The fine structure of a biotherapeutic
products. This article gives an overview of medicine is very sensitive to various
regulatory experience as well as the main production parameters and the full
principles and issues concerning quality, understanding of all processes involved is
safety and efficacy of these products. complicated. Thus, it is unlikely that one
* This article does not necessarily reflect the policies and views of the World Health Organiza-
tion.
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5. Pharmacovigilance Focus WHO Drug Information Vol 23, No. 2, 2009
manufacturer will be able to precisely regulation was formally recognized by the
reproduce a biotherapeutic medicine World Health Organization (WHO) in
manufactured by another company. 2007. Since then, WHO has been work-
Indeed, an increasingly wide range of ing with regulators from many countries
biosimilars are under development or on a draft document that provides guid-
already licensed in many countries. ance for the development and evaluation
of biological therapeutic products that
As stated, the EU has taken the lead in may be subject to abbreviated licensing
establishing a regulatory process for pathways [11]. The document is expected
approving biosimilars and EU legislation to be finalized later in 2009.
now differentiates between “generic
medicinal products” and “similar biological Generic medicines and biosimilars:
medicinal products”. It also defines the similarities and differences
regulatory approach for EU marketing Multisource (generic) medicines are
authorization of biosimilar medicinal formulated when patent and other exclu-
products. Both general [1–3] and product- sivity rights expire. These medicines have
specific guidelines dealing with recom- an important role to play in public health
binant erythropoietin [4], granulocyte as they are well known to the medical
colony stimulating factor (G-CSF) [5], community and usually more affordable
human somatotropin [6] and human due to competitive availability.
insulin [7] have been issued by the
Committee for Medicinal Products for The key requirement for authorization of
Human Use (CHMP) of the European generic medicines is therapeutic inter-
Medicines Agency (EMEA). Draft guide- changeability with the originator product.
lines have also been issued for interferon To ensure therapeutic interchangeability,
alfa [8] and low molecular weight generic products must contain the same
heparins [9]. All these guidelines have amount of active ingredient and have the
one common feature — identifying the same dosage form and be bioequivalent
need for at least some clinical data to to the originator product. Bioequivalence
support the approval of biosimilar medici- is usually established using comparative
nal products. in vivo pharmacokinetic studies with the
originator product (or reference product).
In the USA, there is currently no set of A detailed description of how this is
guidelines comparable to those of the EU carried out is described in respective
for biosimilars. The Food and Drug WHO and national regulatory guidelines
Administration (FDA) has approved [12, 13]. Well-resourced regulatory
Omnitrope®, a growth hormone biosimilar, authorities require that a multisource
but this was done using the abbreviated (generic) medicine must meet certain
new drug application (ANDA) procedure regulatory requirements. In a well estab-
which essentially defines biosimilars as lished setting, a generic medicine in
“chemical” generic drugs rather than general must:
biopharmaceuticals [10]. However, this
method of approval is rather exceptional • contain the same active ingredients as
as specific US regulatory guidelines for the innovator drug;
approval of biosimilars do not currently
exist. Also, in most other countries a • be identical in strength, dosage form,
comparative set of guidelines to those of and route of administration;
the EU is absent. • have the same use indications;
The need for additional global regulatory • be bioequivalent (as a surrogate marker
guidelines for evaluation and overall for therapeutic interchangeability).
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6. WHO Drug Information Vol 23, No. 2, 2009 Pharmacovigilance Focus
• meet the same batch requirements for necessarily implies different host cell
identity, strength, purity and quality, and impurities as a minimum but the regulator
has accepted the product as biosimilar
• be manufactured under the same [14]. Differences with other products have
standards of good manufacturing been justified as being within the range of
practice (GMP) required for innovator natural variants without major clinical
products. impact.
Traditional generic medicines are small, Originator products can go through a
organic molecules with a well-character- number of variations during product
ized structure which can be more easily development and the post marketing
defined by their atomic structure than period. However, it is difficult to ascertain
their manufacturing processes. In the whether major process variations (e.g.
case of more complicated generic medi- cloning, selection of a suitable cell line,
cines, processes of synthesis are used. fermentation, purification and formulation)
For example, biotechnological methods will affect the end product. Thus, a bio-
are applied to produce large molecule similar may differ significantly from the
medicines such as antibiotics (for exam- originator product. In principle, some of
ple, streptomycin). Sometimes, several the variations applied by originators can
methods of synthesis are combined, be more substantial than those applied by
including the use of genetically engi- generic manufacturers. When assessing
neered microorganisms in fermentation. and accepting variations applied to the
What makes a difference is how well the manufacture of originator products,
resulting active pharmaceutical ingredient regulators can acquire valuable informa-
(API) can be characterized without risking tion for assessing biosimilars.
unidentified impurities and subtle struc-
tural changes resulting in different safety At present, lack of consistency between
and efficacy profiles. originator epoietins and products manu-
factured in countries outside well regu-
The current challenge facing international lated markets (such as the EU and USA)
development of a programme for bio- was demonstrated at the World Congress
similars is that there is no way of confirm- of Nephrology in 2007 [15, 16]. Some
ing that the reference product on the products were identified as containing
market in one region complies with additional basic isoforms — more than
requirements in other regions. It is true 4% aggregates and bacterial endotoxin
that even identifying a global comparator contamination. These findings may affect
for generic “chemical” medicines is efficacy, immunogenicity and patient
sometimes very challenging. Above all, safety, respectively [16, 17]. Finally, some
the essential characteristics of a bio- of these biosimilar products were not
similar are not yet perfectly defined. For approved under a specific well-defined
example, some consider that only fully and transparent regulatory framework.
characterized proteins with no major Biopharmaceutical safety and efficacy
differences in their structure or impurity data are difficult to transcribe into a
profile can be considered biosimilar. discernable format and it is a challenge
However, EU regulators have accepted a demonstrating that a biosimilar product is
degree of difference provided it can be as safe or effective as the originator. It is
justified. For example, Valtropin® (soma- hoped that rapid advances in science and
totropin) is expressed from yeast whereas knowledge obtained from regulatory
its reference product, Humotrope®, is practice may make this task easier in the
expressed from Escherichia coli. This future.
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7. Pharmacovigilance Focus WHO Drug Information Vol 23, No. 2, 2009
Safety of biosimilars: specific Another important factor is potential
points of concern contamination during manufacturing.
The two main issues of concern with Impurities in biopharmaceuticals may
biosimilar agents involve variable po- derive from chemicals or antibiotics used
tency/response and immunogenicity during manufacture or may result from
thought to be due to one of three main microbial or viral contamination. Impurities
mechanisms: glycosylation, contamina- such as endotoxins or denatured pro-
tion or changes to three-dimensional teins, for example, may give a danger
structure. Immunogenicity is generally the signal to T cells which may then send
primary safety concern, but variation in activating signals to B cells leading to an
potency can also raise safety issues in immune response.
the case of substitution of the original
molecule with biosimilars, e.g. variability An important lesson was learned in the
in haemoglobin values seen with original case of an increasing incidence of anti-
epoietin [18] and its possible association body-mediated pure red cell aplasia
with increased mortality in dialysis pa- (PRCA) observed outside the USA
tients [19]. The issues of safety and between 2000 and 2002 which revealed
efficacy cannot easily be separated as that a small change in the formulation of a
binding of an agent by immune system well-established innovator biopharma-
molecules will often decrease its clinical ceutical product (epoietin alfa) with
effect and changes to the shape or extensive patient years experience may
structure of a protein can alter binding to have significant clinical consequences
immune system receptors as well as to its [22]. The sharp increase in incidence
physiological target. Therefore, biosimi- occurred primarily among those on
lars could induce immune responses Eprex®/Erypo®, and coincided with
which may be either clinically irrelevant or replacement of human serum albumin as
could have severe and potentially lethal a stabilizer by glycine and polysorbate 80.
consequences. Subsequent withdrawal of the SC formu-
lation of epoietin alfa led to a consider-
The glycosylation of recombinant proteins able decrease in the incidence of PRCA
can influence degradation, exposure of cases. A number of possible mechanisms
antigenic sites and solubility, as well as have been proposed to explain the
immunogenicity. Changes in degradation observed upsurge of PRCA but it is likely
can produce novel antigenic epitopes not the modification in formulation played a
found in the parent molecule with poten- major role [23].
tially increased immunogenicity and
biological activity and metabolic half-life Alterations to the three-dimensional
also affected. The degree of glycosylation structure of a protein may also have
depends primarily on the host cell expres- important effects on immunogenicity.
sion system. For example, recombinant Major sources of such changes include
G-CSF expressed in Escherichia coli is protein aggregation (which has been
non-glycosylated, whereas that ex- suggested as one possible explanation of
pressed in Chinese hamster ovary cells is the PRCP epidemic described above),
glycosylated. Similarly, proteins manufac- oxidation and deamidation. Likely aggre-
tured in yeast cells contain high levels of gation is of particular concern as it may
mannose sugar groups, rendering them lead to the immune system recognizing
more prone to degradation and thereby the protein as non-self and mounting a
decreasing their half-life. [See references response [24]. This is probably because
20 and 21 for more details about effects the repeating structure of protein aggre-
of immunogenicity.] gates more closely resembles the micro-
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8. WHO Drug Information Vol 23, No. 2, 2009 Pharmacovigilance Focus
bial structures that the immune system is even very small changes in manufactur-
primed to act against [25]. The process ing can have major consequences for a
by which the body becomes reactive to product’s adverse effects [27]. Pharma-
the protein can be very slow: antibodies covigilance is thus likely to be a long-term
to products such as interferon and eryth- project for any biosimilar medicine.
ropoietin may be detected for more than a Overall, routine pharmacovigilance is
year after treatment cessation [26]. recommended for products where no
special concerns have arisen, whereas
Clinical safety data additional pharmacovigilance activities
and pharmacovigilance and action plans will be required for
The concerns raised above have been medicinal products with important estab-
addressed, as far as possible and in line lished risks, potential risks or missing
with present scientific knowledge, in EU information.
regulatory guidance. For example,
erythropoietin is a more complex mole- Spontaneous reporting still remains the
cule compared to either insulin or growth cornerstone of pharmacovigilance but has
hormone. The respective guidelines several weaknesses. Often, only the
reflect this complexity and, in order to international nonproprietary name (INN)
identify potential immunogenicity, advo- is used as the sole product identifier and
cate conducting at least two randomized in the case of several products with the
controlled trials confirming safety data same INN (originator, plus generics or
collected over a minimum of 12 months biosimilars) it may be difficult to trace the
from at least 300 patients. Within the EU exact manufacturer of the product. A
authorization procedure, the applicant much better traceability of products is
should present a risk management needed [28], particularly in the case of
programme/pharmacovigilance plan in biosimilars.
accordance with current EU legislation
and pharmacovigilance guidelines. Recent developments within the Interna-
tional Conference on Harmonization of
In order to further study the safety profile Technical Requirements for Registration
of the biosimilar medicinal product, data of Pharmaceuticals for Human Use (ICH)
for rare adverse events should be col- raise hopes that a harmonized set of
lected from a cohort of patients represent- product identifiers will become available
ing all approved therapeutic indications. soon and could improve future traceabil-
Specific reference is made to include ity. Recently, the ICH Steering Committee
assessment of the incidence of PRCA recognized the benefits of continuing to
within the pharmacovigilance plan for work with International Standard Develop-
epoietin biosimilars [4]. It is clear that with ment Organizations in developing harmo-
300 patients PRCA may not be detected nized electronic messages to transfer
due to the relatively small number of regulatory information with a view to
patients involved as compared to the developing harmonized formats for
rarity of this complication. Consequently, Individual case safety reports (ICSR) and
EMEA guidelines for epoietins also identification of medicinal products [29]
require immunogenicity testing and
pharmacovigilance programmes to Different versions of biopharmaceuticals
monitor the efficacy and safety of have been available in both India and
biosimilar products during post-approval. China for several years [30]. It is impor-
tant to note that both India and China are
Nonetheless, some adverse effects may considered to have less stringent regula-
take more than a year to appear [26] and tory standards than the EU and the USA.
91

9. Pharmacovigilance Focus WHO Drug Information Vol 23, No. 2, 2009
Unfortunately, both countries have under- but patients should not be expected to
developed pharmacovigilance systems bear the burden of excessive trial-error
and provide only small number of adverse incidents.
drug reaction reports to the WHO Interna-
tional Programme on Drug Monitoring References
database managed by the Uppsala 1. European Medicines Agency. Guideline on
Monitoring Centre [31]. Similar Biological Medicinal Products, CPMP/
437/04, October 2005. www.emea.europa. eu/
Conclusions pdfs/human/biosimilar/043704en.
The cost of providing effective therapies
in different disease areas increases 2. European Medicines Agency. Guideline on
progressively and biosimilar medicines Similar Biological Medicinal Products Contain-
ing Biotechnology-derived Proteins as Drug
may offer considerable advantages to Substance – Non Clinical and Clinical Issues,
hard-pressed health-care budgets glo- CHMP/42832/05, February 2006. www.emea.
bally. Regulatory decisions to permit europa.eu/pdfs/human/biosimilar 4283205en.
clinical use should be based on rigorous
and highly competent case by case 3. European Medicines Agency. Similar
scientific assessments and presence of Biological Medicinal Products Containing
appropriate systems for pharmacovigi- Biotechnology-derived Proteins as Active
Substance: Quality Issues, CHMP/49348/05,
lance. Clearly this area of rapidly evolving February 2006. www.emea.europa.eu/pdfs/
regulatory science would benefit from human/biosimilar/4934805en.
better cooperation and information
exchange between different regulators 4. European Medicines Agency. Annex
internationally. Safety has to come first Guideline on Similar Biological Medicinal
and effective pre- and post-marketing Products Containing Biotechnology-derived
safety monitoring remains the key. Proteins as Drug Substance – Non Clinical
and Clinical Issues containing Recombinant
Human Erythtropoietin, CHMP/94526/05,
Sufficient regulatory tools are currently March 2006. www.emea.europa.eu/pdfs/
available to ensure safety of biosimilars human/biosimilar/9452605en.
but the proper implementation of these
tools may prove challenging, particularly 5. European Medicines Agency. Annex
outside well established and resourced Guideline on Similar Biological Medicinal
regulatory settings. Even in the EU, Products Containing Biotechnology-derived
applying pharmacovigilance programmes Proteins as Drug Substance –Non Clinical and
with uniform excellence across the region Clinical Issues containing Recombinant
remains a challenge. Pharmacovigilance Granylocyte Colony-Stimulating Factor,
CHMP/313297/05, February 2006. www.
is a responsibility that is shared among emea.europa.eu/pdfs/human/biosimilar/
actors in the pharmaceutical industry, 313297/05en.
physicians and pharmacists, with input
from appropriately educated and informed 6. European Medicines Agency. Annex
patients. Much better cooperation be- Guideline on Similar Biological Medicinal
tween all stakeholders is needed to Products Containing Biotechnology-derived
ensure that everyone involved fully Proteins as Drug Substance – Non Clinical
understands the complex scientific and Clinical Issues containing Recombinant
arguments and regulatory decisions Human Growth Hormone, CHMP/94528/05,
applying to biosimilar products. This February 2006. www.emea.europa.eu/pdfs/
human/biosimilar/9452805en.
would hopefully lead to safer use and
better qualitative and quantitative report- 7. European Medicines Agency. Annex
ing of suspected adverse reactions. Guideline on Similar Biological Medicinal
Biosimilar medicines clearly have a future Products Containing Biotechnology-derived
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10. WHO Drug Information Vol 23, No. 2, 2009 Pharmacovigilance Focus
Proteins as Drug Substance – Non Clinical 16. Singh AK. Gaps in the quality and potential
and Clinical Issues. Guidance on Similar safety of Biosimilar epoetins in the developing
Medicinal Products Containing Recombinant world: an international survey. Abstract S-PO-
Human Insulin CHMP/BMWP/32775/05, 0412. World Congress of Nephrology, April
February 2006. www.emea.europa.eu/pdfs/ 21–25, 2007, Brazil, Rio de Janeiro. Available
human/biosimilar/3277505en. at: http://www.wcn2007.org
8. European Medicines Agency. Guideline on 17. Hermeling S, Schellekens SH, Crommelin
Similar Biological Medicinal Products Contain- DJ et al. Micelle-associated protein in epoetin
ing Low-molecular Weight Heparins EMEA/ formulations: a risk factor for immunogenicity?
CHMP/BMWP/118264/07. Draft released for Pharm Res 2003, 20:1903–1907.
consultation in April 2008. www.emea.europa.
eu/pdfs/human/biosimilar/11826407en. 18. Berns JS, Elzein H, Lynn RI et al.
Hemoglobin variability in epoetin-treated
9. European Medicines Agency. Guideline on hemodialysis patients. Kidney Int 2003
Similar Biological Medicinal Products Contain- 64:1514–1521.
ing Recombinant Interferone Alpha EMEA/
CHMP/BMWP/102046/06. Draft released for 19. Yang W, Israni RK, Brunelli SM, et al.
consultation in October 2007. www.emea. Hemoglobin variability and mortality in ESRD.
europa.eu/pdfs/human/biosimilar/ J Am Soc Nephrol 2007 18:3164–3170.
10204606en.
10. Belsey MJ, Harris LM, Das RR et al. 20. Kessler M, Goldsmith D, Schellekens H.
Biosimilars: initial excitement gives way to Immunogenicity of biopharmaceuticals.
reality. Nat Rev Drug Discov 2006, 5:535–536 Nephrology Dialysis Transplantation 2006
21(5:v9-v12). http://ndt.oxfordjournals.org/cgi/
11. World Health Organization. Regulatory content/full/21/suppl_5/v9
pathways for biosimilar products. WHO Drug
Information 2008 22(1). www.who.int/ 21. Biosimilars and biopharmaceuticals: what
druginformation the nephrologists need to know—a position
paper by the ERA–EDTA Council. Nephrology
12. World Health Organization. Multisource Dialysis Transplantation 2008 23(12):3731–
(generic) pharmaceutical products: guidelines 3737 http://ndt.oxfordjournals.org/cgi/content/
on registration requirements to establish inter- full/23/12/3731
changeability. In: WHO Expert Committee on
Specifications for Pharmaceutical Prepara- 22. Casadevall H, Nataf J, Viron B et al. Pure
tions. Fortieth Report. Technical Report red-cell aplasia and anti-erythropoietin
Series, 937, Annex 7, 347–390. antibodies in patients treated with recombinant
erythropoietin. N Engl J Med 2002 346:469–
13. European Medicines Agency. Guideline on 475.
the Investigation of Bioequivalence, CPMP/
EWP/QWP/1401/98 Rev. 1. Draft released for 23. Schellekens H. Immunologic mechanisms
consultation in July 2008. www.emea.europa. of EPO-associated pure red cell aplasia. Best
eu/pdfs/human/qwp/140198enrev1. Pract Res Clin Haematol 2005 18:473–480.
14. European Medicines Agency. Valtropin.
24. Rosenberg AS. Effects of protein aggre-
European Public Assessment Report, Revi-
gates: an immunologic perspective. AAPS
sion 1. www.emea.europa.eu/humandocs/
Journal 2006 8: E501–E507.
Humans/EPAR/valtropin/valtropin.htm.
25. Schellekens H. Immunogenicity of thera-
15. Park SS, Deechongkit S, Patel SK.
peutic proteins: clinical implications and future
Analytical comparisons of certain erythropoi-
prospects. Clin Ther 2002 24:1720–1740.
etin products from Asia and Amgen’s epoetin
alfa. Abstract M-PO-0592. World Congress of
26. Schellekens H. The first biosimilar epoetin:
Nephrology, April 21–25, 2007, Rio de
but how similar is it? Clin J Am Soc Nephrol
Janeiro, Brazil. Available at: http://www.wcn
2008 3:174–178.
2007.org
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11. Pharmacovigilance Focus WHO Drug Information Vol 23, No. 2, 2009
27. Schellekens H. Erythropoietic proteins and Brussels, Belgium, Novermber 8–13, 2008,
antibody-mediated pure red cell aplasia: a http://www.ich.org/cache/compo/276-254-
potential role for micelles. Nephrol Dial 1.html
Transplant 2004 19:2422.
30. Frost and Sullivan. Biogenerics demand to
28. Lamarque V, Merle L. Generics and go up in Asia. Express Pharma Pulse October
Substitution Modalities: Proposed Methods for 7 (2004), Available at: http://www.express
the Evaluation of Equivalence, Traceability pharmaonline.com/20041007/biogenerics01.
and Pharmacovigilance Reporting. Thérapie
2008 63:311–319 31. The Uppsala Monitoring Centre. http://
www.who-umc.org/DynPage.aspx
29. ICH Steering Committee Press Release.
Evolving Science in Drug Safety and Quality,
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12. WHO Drug Information Vol 23, No. 2, 2009
Blood and Biomedicines
Availability, quality and manufacture of medicinal products and in
supply of other blood components such
safety of blood and blood as platelets and red cells.
products Developed countries have implemented
Blood has been collected, stored, tested, procedures, policies and methods to
and transfused as a therapeutic since the ensure the safety, quality and availability
beginning of the Twentieth century. Until of all products derived from blood. This
the 1950s, activities concentrated on has facilitated wider access to a compre-
improving storage of cells and ensuring hensive range of safe blood products for
blood group compatibility. Thereafter, patients with bleeding, immunological or
methods were developed for preparing other severe diseases. Additionally, good
therapeutic products from human blood manufacturing practices (GMP) have
and plasma, for use in treating life- been introduced into plasma fractionation
threatening diseases, and to support centres and are now also applied in blood
complex surgical procedures and trans- establishments. Improvements in health
plantation. and transfusion safety have been docu-
mented by haemovigilance and phar-
For the past 25 years, efforts have macovigilance programmes. Conversely,
focused on improving the safety and comparable levels of availability, quality
efficacy of components derived from and safety do not yet exist in many
blood and plasma, developing and developing countries (1).
validating new methods, and seeking new
therapeutic uses. Blood products such as Equitable and universal access to blood
blood clotting factors and human and blood products of assured quality
immunoglobulins (polyvalent and specific) and efficacy will contribute to achieve-
are now included in the World Health ment of the UN Millennium Development
Organization’s (WHO) Model List of Goals relating to reduction of maternal
Essential Medicines. This reflects the and child mortality, as well as to efforts to
importance of blood and blood products prevent HIV, HBV and HCV transmission.
in treating congenital, immune-acquired
life-threatening diseases, and conditions Specific issues requiring
such as bleeding or trauma. In vitro action
diagnostic devices for sensitive detection
of infectious disease markers play a role Wastage of blood plasma
in successfully screening donor blood and Several reasons account for the lack of
testing plasma pools prior to fractionation, blood products in developing countries.
as well as in clinical diagnosis. Plasma collected in developed countries
is restricted and the potential for generat-
Transmission of infectious diseases by ing surplus products sufficient to meet the
blood (notably HIV, hepatitis B (HBV) and needs of developing countries is small.
hepatitis C (HCV)) has underscored the Moreover, such products would be too
importance of quality systems and effec- expensive. Developing countries must
tive regulation in the preparation of therefore create their own sustainable
plasma as a raw material for use in the supplies of blood products using blood
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13. Blood and Biomedicines WHO Drug Information Vol 23, No. 2, 2009
plasma collected by their own blood material. Substantial improvement will
establishments from their own popula- prevail through introduction and enforce-
tions. Currently, however, a large percent- ment of appropriate independent and
age of the plasma collected in developing transparent quality assurance regulations
countries is categorized as a waste and inspection procedures.
material and destroyed. This is because
appropriate technology and enforcement Cross-border threats
of GMP are not available. Fractionation The risks of disease migration are esca-
capacity could, however, become avail- lating due to changes in habitat, increas-
able if plasma production complied with ing mobility of populations, wars and
internationally-agreed standards. global climate change. Pandemic infec-
tions may also affect the supply of blood
Risk of transfusion-transmitted and blood products in different ways.
diseases These factors underscore the need to
If rigorous standards for donor selection, introduce and strengthen quality assur-
testing and donation are not applied, ance regulations in developing countries.
blood products and blood transfusion The trend towards global regulatory
remain potent vectors for transmission of convergence favours sharing of best
infectious diseases. Unfortunately, current practices and the creation of internation-
arrangements for blood plasma collection, ally agreed regulations. International
processing and testing are inadequate in coordination, notably in areas such as the
a vast number of developing countries. In manufacture of blood products, is there-
addition, increasing international mobility fore becoming increasingly important.
of populations and globalization of the
blood industry highlight the need to WHO activities
introduce and strengthen quality assur- For more than 50 years, WHO has been
ance regulations. closely involved in setting quality and
safety standards and training regulators
The history of blood transfusion has in the manufacture and quality control of
amply demonstrated the risks. Examples biological and blood products. The overall
include transmission of HIV, HCV and technical responsibility for these activities
HBV, bacteria, trypanosoma and malarial lies with the WHO Expert Committee on
parasites, as well as emerging and re- Biological Standardization (ECBS).
emerging diseases. Although worldwide Guidelines on the manufacture and
expansion of human blood plasma quality control of blood and blood prod-
collection and processing of blood prod- ucts have been developed, updated and
ucts has the capacity to save lives, promoted by WHO (2–4). They represent
without appropriate control and standardi- global consensus on the part of manufac-
zation it can also amplify public health turers, regulators, professional interna-
risks. tional societies and national blood pro-
grammes with respect to production and
Poor regulation of blood products in quality assurance procedures for blood
developing countries and blood products.
Developing countries recognize the need
to regulate blood products and assure International biological reference prepara-
blood safety. Blood establishments tions (5) to assist in establishing the
should be subject to inspection and audit quality and safety of blood products and
by national regulatory authorities and related in vitro diagnostic devices have
fractionators should demonstrate effective also been adopted following validation in
control and traceability of plasma raw global coordinated studies. The value of
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14. WHO Drug Information Vol 23, No. 2, 2009 Blood and Biomedicines
reliable internationally agreed reference As a first step, up-to-date mechanisms for
materials is that manufacturers, regula- implementing and enforcing quality
tors and blood establishments can standards relating to blood products and
compare results worldwide despite the blood safety-related in vitro diagnostic
increasing diversity of products. devices will need to be introduced in
countries. Activities should be supported
Public health challenges demonstrate the by WHO guidelines for the production of
need for international collaboration and blood plasma for fractionation, comple-
cooperation and the need to create mented with additional guidelines to
regulatory networks to support dissemina- promote and support implementation of
tion of regulatory actions, knowledge GMP. Work should also be undertaken to
transfer and organization of training review existing national regulations for
programmes. The International Confer- blood products and to support and further
ence on Drug Regulatory Authorities develop technical upgrading of medicines
(ICDRA) provides regulatory authorities of regulatory authorities. Furthermore,
WHO Member States with a forum to strategies should be sought to share the
meet and discuss ways to strengthen expertise and experience already gener-
collaboration. In 2005, the WHO Blood ated in developed countries and to
Regulators Network was established in develop regional regulatory networks.
response to the request by ICDRA
participants and the ECBS. The Network The dimension and complexity of the
was set up to foster development of situation requires a multifaceted strategy
international consensus on effective incorporating input from partners at
regulatory approaches. national, regional and international levels.
Recognizing the importance of the WHO is well placed to secure the support
provision of safe blood, blood compo- of international and nongovernmental
nents and plasma derivatives, the Fifty- organizations, international professional
eighth World Health Assembly in 2005 associations and other agencies devoted
(Resolution 58.13) expressed its support to finding solutions for health problems.
for “full implementation of well organized,
nationally coordinated and sustainable Creating sustainable blood and plasma
blood programmes with appropriate programmes with appropriate regulatory
regulatory systems” and stressed the role systems will ensure both specific and
of “voluntary, non-remunerated blood wider public health benefits including:
donors from low-risk populations”.
• optimal use of donated blood plasma;
Improving access to blood • safer blood components;
and blood products • sustainable and affordable supply of
In order to ensure the availability of safe safe essential products for the treatment
blood products in developing countries,
of congenital diseases, trauma and
Member States should be alerted to the immunologically mediated conditions;
risks of inadequate regulation and guid-
ance should be provided on establishing • reduction of infectious disease transmis-
regulatory oversight of blood systems. sion via blood-borne pathogens, both
Efforts should be made to increase the within countries and across national
transfer of validated technology and to borders;
build capacity with the overall aim of
improving access to safe, effective and • improved quality and safety of all
affordable blood products. products from blood establishments
97

15. Blood and Biomedicines WHO Drug Information Vol 23, No. 2, 2009
through the enforcement of national References
(and international) quality assurance
regulations; 1. Global Database on Blood Safety.
http://www.who.int/bloodsafety/global_
• substantial contribution to national/ database/en/
regional public health programmes
through, for example, improved popula- 2. World Health Organization. Requirements
tion epidemiology for infectious dis- for the collection, processing and quality
control of blood, blood components and
eases such as HIV, HBV and HCV,
plasma derivatives. Technical Report Series,
prevention and control of disease No. 840 (1994).
transmission, and blood donor health
monitoring; 3. World Health Organization. WHO Recom-
mendations for the production, control and
• potential application of quality systems regulation of human plasma for fractionation.
and GMP principles to other medical Technical Report Series, No. 941 (2007).
laboratory disciplines, and
4. World Health Organization. Guidelines on
• inclusion of developing countries in the viral inactivation and removal procedures
international transfusion community and intended to assure the viral safety of human
in activities of associated plasma blood plasma products. Technical Report
fractionation industries. Series, No. 924 (2004).
The strategic goal is to improve public 5. World Health Organization. WHO Interna-
health by providing safe and effective tional Biological Standards: http://www.who.
medicine to the world’s population. A risk– int/bloodproducts/catalogue/en/index.html
benefit analysis must ensure that suffi-
cient quantities of the required products
are available at a cost that does not limit
access.
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16. WHO Drug Information Vol 23, No. 2, 2009
New Regulatory Challenges
Contribution of clinical pharmacologists to government:
opportunities and challenges
.
Clinical pharmacology is a scientific discipline that focuses on evaluating the effect
of medicines in humans. Within a wider context of promoting safety, maximizing
efficacy and minimizing side-effects, the work of the clinical pharmacologist is par-
ticularly valuable in clinical trials. Other branches of the discipline involve pharma-
covigilance, pharmacokinetics, drug metabolism, pharmacoepidemiology and, more
recently, pharmacoeconomics. The clinical pharmacologist collaborates closely with
other clinicians, pharmacists, biologists, analytical chemists, statisticians, epidemi-
ologists and health economists. The clinical pharmacologist receives training in the
evaluation of drug therapy and drug products and this makes the profession valu-
able in a number of public activities such as drug approval, post-marketing surveil-
lance, drug therapy selection, reimbursement decisions and ethical review of re-
search projects.
Faced with the task of regulating increasingly complex medicines and biomedicines
markets, many regulatory authorities and health departments in developing coun-
tries rely for advice on pharmacists who may have a limited medical background and
lack the resources to access and assess information on the latest clinical research.
On the other hand, clinical pharmacologists have a rigorous medical and scientific
training which enables them to evaluate evidence and produce new data through
well designed studies and interaction with other healthcare professionals. A clinical
pharmacologist can provide the link between government and health care outcomes,
serving also as a powerful advocate of evidence-based medicine. They can be in-
valuable in addressing current challenges such as assessing new medicines, pro-
viding unbiased medicines-related information, contributing to treatment guideline
development, identifying preventable adverse drug reactions through promoting ra-
tional use of medicines and improving prescribing practices. Politicians are often
unaware of the valuable role that clinical pharmacology can play in improving per-
formance of regulatory and health systems through closing the gap between current
medical practices and latest clinical science.
Regulation and clinical tary and provide the means of attaining
pharmacology: emerging the health and wellbeing of citizens.
alliances In a broad sense, the role of regulatory
As a function of protecting and promoting agencies is multidimensional. The World
public health, a government must con- Health Organization (WHO) proposes that
sider the ethical, scientific and develop- regulatory goals are achieved through
mental aspects of medicines. Activities in ensuring the safety, efficacy and quality of
these three dimensions are complimen- medicines, rational use, and providing
99

17. New Regulatory Challenges WHO Drug Information Vol 23, No. 2, 2009
appropriate medicines information to the many essential and interrelated activities
public and health professionals (1). which underpin the most important role of
Similarly, the European Medicines the government in the broader sense: i.e.,
Agency (EMEA) coordinates the work of to protect the health and wellbeing of its
national experts and has inter alia the citizens through ensuring and promoting
following far reaching responsibilities (2): effective public health.
“In the context of continuing globaliza- Governments and their respective institu-
tion, to protect and promote public and tions are responsible for ensuring basic
animal health by: human rights of citizens. In the event of
research conducted within a country, they
• developing efficient and transparent are expected to protect patients and trial
procedures to allow rapid access by participants by maintaining effective
users to safe and effective innovative systems for granting clinical research
medicines and to generic and nonpre- authorization and oversight of trials. This
scription medicines through a single challenging task involves assessment of
European marketing authorization; whether the clinical research planned is
based on scientific principles and consid-
• controlling the safety of medicines for erations of safety and whether it will offer
humans and animals, in particular the desired benefits to patients while
through a pharmacovigilance network identifying and minimizing any possible
and the establishment of safe limits for risks. This task forms the ethical dimen-
residues in food-producing animals; sion of the government’s role.
• facilitating innovation and stimulating Milestones in the current
research, hence contributing to the ethical research environment
competitiveness of the EU-based The International Covenant on Civil and
pharmaceutical industry, and Political Rights (1966) states that ... “no
one shall be subjected without his free
• mobilizing and coordinating scientific consent to medical or scientific experi-
resources throughout the EU to provide mentation”. These principles were devel-
high-quality evaluation of medicinal oped with a particular focus on risk/
products, to advise on research and benefit in the World Medical Association’s
development programmes, to perform Declaration of Helsinki and have been
inspections for ensuring fundamental incorporated into national and interna-
GXP (good clinical practice, good tional laws and regulations.
manufacturing practice and good In 1949, the Council for International
laboratory practice collectively) provi- Organizations of Medical Sciences
sions are consistently achieved, and to (CIOMS) was founded under the aus-
provide useful and clear information to pices of WHO and the United Nations
users and healthcare professionals. Educational, Scientific and Cultural
Organization (UNESCO). The most
The ethical dimension important of CIOMS publications is its
In addition to their role in ensuring the International Ethical Guidelines for
safety, efficacy and quality of medicines, Biomedical Research Involving Human
governments are also tasked with the Subjects. The latest version was pub-
responsibility of exerting an ethical lished in 2002 (3) and, based on the
influence on processes in the develop- Declaration of Helsinki, is designed to be
ment and marketing of medicines. The of use in defining the ethics of biomedical
regulatory authority is responsible for research, applying ethical standards in
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18. WHO Drug Information Vol 23, No. 2, 2009 New Regulatory Challenges
local circumstances, and establishing or Above all, governments have to ensure
redefining adequate mechanisms for that only effective and safe good quality
ethical review of research involving medicines are used to treat their citizens.
human subjects. The Guidelines are Nowadays, all medicines are subject to
targeted to ethics committees, and review marketing authorization prior to being
boards, sponsors and investigators. The prescribed. Approval is based on assess-
CIOMS guidelines — to which several ment of quality, safety and efficacy of the
clinical pharmacologists have contributed product. The safety monitoring of medi-
— also provide the basis for government cines during their whole life-cycle (from
thinking about clinical research, espe- marketing authorization to potential
cially in resource poor settings. withdrawal from the market) is also a task
for governments. Usually, these and other
Good clinical practice (GCP) is a “stand- medicines-related regulatory functions
ard for the design, conduct, performance, are carried out by specialized govern-
monitoring, auditing, recording, analysis mental agencies, such as the Food and
and reporting of clinical trials that pro- Drug Administration (FDA) in the USA or
vides assurance that the data and re- the European Medicines Agency (EMEA).
ported results are credible and accurate,
and that rights, integrity and confidential- Scientific dimension
ity of trial subjects are protected.” Many It is important for regulators involved in
national and regional GCP guidelines are the evaluation of medicines prior to
based on, or refer to, the Declaration of marketing to have the best possible
Helsinki, including WHO GCP Guidelines scientific education and background or to
published in 1995 (4) and the Interna- be able to call on expertise which is
tional Conference of Harmonization (ICH) relevant to the work in hand. A critical
GCP (E6) from 1996 (5). scientific review of the clinical data will
address the known and unknown aspects
A priority requirement for the ethical of an assessment and provide relevant
review of a scientific study, research or conclusions. The larger regulatory agen-
clinical trial involving human subjects is cies possess their own clinical pharma-
submission of a research proposal for cology units. For example, the US FDA
independent evaluation by scientific, has in its Center for Drug Evaluation and
regulatory and ethical review committees. Research (CDER) Office of Clinical
Nowadays, many governments define Pharmacology. Safety surveillance and
procedural aspects of the work of the pharmacovigilance is also entrusted to
ethics committees in detail. regulatory agencies, and here, also,
expertise in clinical pharmacology is
For example, the European Commission essential.
has laid down strict timelines for process-
ing research applications that affect the Governments, either directly or through
work of ethical review committees in all their specialized agencies, are also
27 European Union countries. This can involved in taking decisions about medi-
be perceived as the European Commis- cines selection for public procurement,
sion’s attempt to facilitate and promote developing national treatment guidelines
clinical research. Clinical pharmacologists and proposing inclusion of medicines in
can be particularly valuable as members reimbursement lists. This work may also
of the ethical review committee because involve composing and updating national
of their extensive knowledge of the essential medicines lists as promoted by
effects of medicines and the related area WHO. The real life performance of drugs
of clinical research. following regulatory approval requires a
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19. New Regulatory Challenges WHO Drug Information Vol 23, No. 2, 2009
cost-effectiveness assessment by highly hand evidence that electronic health
qualified specialists using different mod- records can offer added value for phar-
els and again calls on the expertise of the macogenetic research and pharmacovigi-
clinical pharmacologist. lance (7). Clinical pharmacologists should
be actively involved in designing elec-
These various activities support the tronic patient health records due to their
rational use of medicines, sometimes also potential for future clinical research use,
called “quality use” (6). Governmental including monitoring of rational use and
institutions involved in such activities safety.
include the National Institute for Health
and Clinical Excellence (NICE) in the Government efforts to create a research
United Kingdom. Activities are based on friendly environment should include legal
the best possible scientific methodologies and other systems with effective function-
and knowledge and are part of the ing and well-informed scientific govern-
scientific dimension of the Government’s ment backup. Due to the relative lack of
obligation to its citizens. Clinical pharma- new therapies and pressure from patient
cologists are well prepared to meet the groups and industry, governments have
challenges needed in the complex as- been exorted to grant “early market
sessment of medicines. approvals” under certain preconditions.
However, effective methodologies for
Developmental dimension pharmacovigilance and safety studies in
Lastly, governments carry the responsibil- the context of early market access have
ity of improving the health of their citi- yet to be created and tested and clinical
zens. Stimulating the necessary research pharmacologists have an important role
and developing research capacities is to play here (8, 9). Clinical pharmacology
therefore a regulatory function. Action also contributes to the discipline of
should be directed to facilitating research pharmacoepidemiology, which is some-
in areas where lack of effective or safer times the only available method to evalu-
health care interventions impedes im- ate the benefits and risks of long term
provement to public health. Recent pharmacotherapy. Similarly, pharmaco-
examples provide evidence that private economics attempts to give a financial
sector initiatives and funding are insuffi- cost and value to everyday medicines use
cient in developing and promoting public and contributes to rational reimbursement
health through medicines research. Thus, systems.
governments may also be involved in
providing financial support to stimulate In the implementation of these various
clinical research in medicines. Clinical dimensions, governments create various
pharmacologists are well positioned to tools, including laws and regulations,
help make appropriate judgements on the infrastructure and institutions, with sup-
scientific value of government funding of porting resource allocations. A key
research proposals. resource is properly trained specialists
who are capable of taking decisions
An important emerging issue is the based on the best possible scientific
adoption of electronic patient health methodology and evidence. These
records implemented or planned to be dimensions are interrelated and interde-
implemented in many countries. Although pendent. Good ethics cannot do without
these may be perceived as mostly admin- good science and developmental goals
istrative tools, they hold scientific poten- cannot be achieved without following
tial for monitoring of safety and quality ethical principles and a sound science
medicines therapy. There is already first- base.
102

20. WHO Drug Information Vol 23, No. 2, 2009 New Regulatory Challenges
The clinical pharmacologist is thus a 3. The Council for International Organizations
unique specialist and ally who can serve of Medical Sciences (CIOMS). International
the public best by ensuring that only safe Ethical Guidelines for Biomedical Research
and effective medicines are authorized for Involving Human Subjects, Geneva, 2002.
http://www.cioms.ch/
use, as well as facilitating cost effective
prescribing and improving rational use of 4. World Health Organization. Guidelines for
drugs. In order to meet the needs of good clinical practice (GCP) for trials on
various governmental services and pharmaceutical products. Technical Report
ensure that the best scientific knowledge Series, No. 850, 1995. http://www.who.int/
is used to make decisions, clinical phar- medicines/library/par/ggcp/GGCP.shtml
macology as a discipline should be
harmonized with the objectives and 5. International Conference of Harmonization
policies of governments to ensure a (ICH) E6: Good Clinical Practice: Consoli-
benefit to public health dated Guideline. http://www.ich.org/cache/
compo/276–254–1.html
Equally, governments of emerging econo- 6. Smith AJ, McGettigan P. Quality use of
mies and developing countries may medicines in the community: the Australian
benefit hugely from the expertise of experience. Br J Clin Pharmacol (2000) 50(6):
clinical pharmacologists and experience 515–519.
has shown that a qualified clinical phar-
macologist can make a great difference at 7. Wang X, Hripcsak G, Markatou M, et al.
country level. Active computerized pharmacovigilance using
natural language processing, statistics and
References electronic health records: a feasibility study. J
Am Med Inform Assoc (2009).
1. World Health Organization. WHO Policy
Perspective on Medicines No 7, “Effective 8. Lesko LJ. Paving the Critical Path: How can
Medicines Regulation: Ensuring Safety, Clinical Pharmacology Help Achieve the
Efficacy and Quality”, November 2003. http:// Vision? Clinical Pharmacology & Therapeutics
www.who.int/medicines/organization/mgt/ (2007) 81:170–177.
PolicyPerspectives.shtml
9. Massol J, Puech A, Boissel JP. How to
2. EMEA Mission Statement. http:// anticipate the assessment of the public health
www.emea.eu.int/mission.htm benefit of new medicines? Therapie. (2007)
62(5):427–35.
103

21. WHO Drug Information Vol 23, No. 2, 2009
Safety and Efficacy Issues
Etanercept: histoplasmosis Reference: Communication from Amgen. 21
April 2009 at Health Canada. http://www. hc-
and invasive fungal infections sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/
_2009/index-eng.php
Canada — The manufacturer of
etanercept (Enbrel®) has informed
healthcare professionals of the risk of Zonisamide: metabolic
invasive fungal infections, including acidosis
histoplasmosis. Etanercept is indicated
for the treatment of rheumatoid arthritis, United States of America — Following
psoriatic arthritis, juvenile idiopathic a review of updated clinical data, the
arthritis, ankylosing spondylitis and Food and Drug Administration (FDA) has
plaque psoriasis. determined that treatment with zonis-
amide can cause metabolic acidosis in
There have been reports of serious some patients. Zonisamide (Zonegran®
pulmonary and disseminated histoplas- and generics) is indicated as adjunctive
mosis, coccidioidomycosis, blastomycosis therapy in the treatment of partial sei-
infections, sometimes with fatal out- zures in adults with epilepsy.
comes, in patients taking TNF blockers,
including etanercept. Histoplasmosis and Chronic metabolic acidosis can have
other invasive fungal infections have not adverse effects on the kidneys and on
been recognized consistently in patients bones, and can retard growth in children.
taking TNF blockers. This has led to Patients with predisposing conditions or
delays in instituting appropriate treatment, therapies, including renal disease, severe
sometimes resulting in death. respiratory disorders, diarrhoea, surgery,
ketogenic diet, or certain other drugs may
For a patient taking a TNF blocker who be at greater risk for developing meta-
presents with signs and symptoms of bolic acidosis following treatment with
systemic illness, such as fever, malaise, zonisamide. The risk of zonisamide-
weight loss, sweats, cough, dyspnoea, induced metabolic acidosis appears to be
and/or pulmonary infiltrates, the health- more frequent and severe in younger
care professional should ascertain if the patients. Although not approved by the
patient has lived or worked in or travelled FDA, zonisamide is sometimes used in
to areas of endemic mycoses, and children. Metabolic acidosis increases the
appropriate empiric antifungal treatment risk for slowed growth in children and
may be initiated while a diagnostic could reduce the overall height that they
workup is being performed. As with any achieve.
serious infection, the TNF blocker should
be stopped until the infection has been The FDA recommends that healthcare
diagnosed and adequately treated. professionals measure serum bicarbo-
nate before starting treatment and peri-
Prescribers should discuss with patients odically during treatment, even in the
and their caregivers the risk for infections absence of symptoms. If metabolic
while receiving TNF blockers, including acidosis develops and persists, consid-
infections caused by viruses, fungi, or eration should be given to reducing the
bacteria including tuberculosis (TB). dose or discontinuing zonisamide (using
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22. WHO Drug Information Vol 23, No. 2, 2009 Safety and Efficacy Issues
dose tapering), and modifying the pa- ously identified an association between
tient’s antiepileptic treatment as appropri- PML and use of some monoclonal anti-
ate. If the decision is made to continue, bodies such as natalizumab (Tysabri®,
then alkali treatment should be consid- used to treat multiple sclerosis) and
ered. rituximab (MabThera®, indicated for non-
Hodgkin lymphoma and severe active
Reference: FDA Alert, 23 February 2009 at
rheumatoid arthritis). An association has
http://www.fda.gov/medwatch
also now been identified between PML
and efalizumab (Raptiva®).
Progressive multifocal
leukoencephalopathy Up to 6 January 2009, the MHRA has
received 19 suspected reports of PML, in
United Kingdom — Progressive three of which PML was listed as the fatal
multifocal leukoencephalopathy (PML) is suspected reaction.
a rare and usually fatal re-infection of the
CNS characterized by progressive Reference: Medicines and Healthcare
damage and inflammation of the white Products Regulatory Agency, Drug Safety
matter in the brain, in multiple locations. Update, Volume 2, Issue 8 March 2009 at
PML is caused by a type of human http://www.mhra.gov.uk/Safetyinformation/
polyoma virus known as the JC, or John
Cunningham virus. The JC virus is Severe adverse reactions with
widespread, with about 70–90% of adults intravenous immunoglobulin
presenting antibodies.
Australia — Intravenous immunoglobu-
The virus usually remains latent in lin, normal (human) (IVIG) is used to treat
healthy individuals, only causing disease a variety of deficiencies and disorders
when the immune system is severely with an immune (or presumed immune)
compromised. PML has been studied in aetiology. IVIG preparations, including
patients with HIV infection, where inci- Intragam P®, Sandoglobulin®, and
dence is approximately 5% of the disease Octagam®, have been available since the
population. PML also occurs in patients 1980s. Use worldwide and in Australia
with cancer and those who have has more than doubled over the past
received kidney or bone-marrow trans- decade (1) partly due to increasing use in
plants. In PML, gradual destruction of the off-label indications.
myelin sheath covering nerve axons Nausea and vomiting are most commonly
leads to impaired transmission of nerve
observed with IVIG, as are hypersensitiv-
impulses. PML causes rapidly progres- ity reactions which may include anaphy-
sive focal neurological deficits including: laxis. Those with IgA deficiency have a
higher risk of hypersensitivity to IVIG due
• cognitive and behavioural changes; to the presence of IgA antibodies. Less
• paraesthesia; common but also serious reactions are
aseptic meningitis, haemolysis and
• visual problems; transfusion-related acute lung injury —
one case has been reported in Australia
• gait abnormalities and loss of limb
coordination, and and one in Canada (2). Recently, Health
Canada highlighted an association
• hemiparesis. between IVIG and thromboembolic
events (3).
The Medicines and Healthcare Products
Regulatory Agency (MHRA) has previ- To date, the Therapeutic Goods Adminis-
tration (TGA) has received 356 reports of
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23. Safety and Efficacy Issues WHO Drug Information Vol 23, No. 2, 2009
adverse reactions associated with IVIG: Exenatide: risk of severe
IVIG was the sole suspected agent in pancreatitis and renal failure
90% of reports. Thirty-five per cent
describe serious reactions, including United Kingdom — Exenatide (Byetta®),
where the outcome was fatal due to: an incretin mimetic, is a glucagon-like-
stroke/myocardial infarction, myocardial peptide-1 analogue that stimulates insulin
infarction, convulsions, hepatic and renal release from pancreatic cells in a glucose
failure, and respiratory failure respec- dependent manner. Exenatide is indi-
tively. In fatal cases, patients generally cated for treatment of type 2 diabetes
had thrombogenic risk factors such as mellitus in combination with metformin,
hypertension, obesity, increasing age, or with or without sulphonylureas in patients
past history of stroke. who have not achieved adequate glycae-
mic control on maximally tolerated doses
The TGA has also received substantial of these oral therapies.
numbers of reports describing pyrexia
(58), chills (41), haemolysis or anaemia Exenatide should not be used in patients
(32), meningitis (20), neutropenia (12), with type 1 diabetes or for the treatment
hepatic disorders (11), and renal failure/ of diabetic ketoacidosis. It should not be
impairment (8). In some of the cases, the used in patients with type 2 diabetes
reactions — particularly those suggesting who require insulin therapy due to cell
hypersensitivity — occurred during the failure.
IVIG infusion and improved with slowing
or stopping the infusion. Suspected adverse reaction reports of
necrotizing and haemorrhagic pancreatitis
Before and during the use of IVIG, any have been received in association with
pre-existing thrombogenic risk factors exenatide. Some of these reports had a
should be assessed and all patients fatal outcome. If pancreatitis is diag-
should be monitored closely during nosed, exenatide should be permanently
infusion. A slow infusion rate of IVIG discontinued. Reports of renal impair-
should be considered for all patients with ment, including acute renal failure and
risk factors (as recommended in the PI). worsened chronic renal failure have also
Extracted from the Australian Adverse been received. Exenatide is not
Drug Reactions Bulletin, Volume 28, recommended for use in patients with
Number 2, April 2009 at http:// end-stage renal disease or severe renal
www.tga.gov.au/adr/aadrb/aadr0904.htm impairment
References Reference: Medicines and Healthcare
Products Regulatory Agency, Drug Safety
1. National Blood Authority. Criteria for the Update, Volume 2, Issue 8 March 2009 at
clinical use of intravenous immunoglobulin in http://www.mhra.gov.uk/Safetyinformation/
Australia. Australian Health Ministers’ Confer-
ence. December 2007. Benefits of methylphenidate
2. Case Presentation: Intravenous immune
continue to outweigh risks
globulin – suspected association with transfu- United Kingdom — The EMEA’s Com-
sion-related acute lung injury. Canadian mittee for Medicinal Products for Human
Adverse Reactions Newsletter Oct 2008; 18/4.
Use (CHMP) concluded that on the basis
3. Intravenous immune globulin: myocardial of currently available data, the benefits of
infarction and cerebrovascular and thrombotic methylphenidate continue to outweigh the
adverse reactions. Canadian Adverse Reac- risks when used in its licensed indication.
tions Newsletter Jan 2008; 18/1. Methylphenidate is indicated as part of a
106

24. WHO Drug Information Vol 23, No. 2, 2009 Safety and Efficacy Issues
comprehensive treatment programme for 2. Further information on brands of
attention deficit/hyperactivity disorder methylphenidate available in the UK, see
(ADHD) in children aged 6 years or older BNF, p 216 (edn 56; www.bnf.org).
and adolescents who are diagnosed
3. Information on DSM-IV criteria is at
according to DSM-IV criteria or guidelines
http://www.psychiatryonline.com/;
in ICD-10 and when remedial measures information on ICD-10 is at
alone are insufficient. http://www.cdc.gov/nchs/about/otheract/i
cd9/abticd10.htm
Treatment must be under the supervision
of a specialist in childhood behavioural 4. Medicines and Healthcare Products
disorders. Patients should be monitored Regulatory Agency, Drug Safety Update,
during treatment, which should be inter- Volume 2, Issue 8 March 2009 at http://
rupted at least once a year to determine www.mhra.gov.uk/Safetyinforma tion/
whether continuation is needed.
Chromic phosphate P32:
Contraindications—methylphenidate acute lymphocytic leukaemia
should not be used in patients with:
Canada — Information has been pro-
• Diagnosis or history of severe depres- vided on important new safety information
sion, anorexia nervosa or anorexic concerning Chromic phosphate P32
disorders, suicidal tendencies, psychotic suspension (Phosphocol® P32) which is
symptoms, mania, schizophrenia, authorized for intracavitary instillation for
severe mood disorders, or psychopathic the treatment of peritoneal or pleural
or borderline personality disorder. effusions caused by metastatic disease.
• Diagnosis or history of severe and Physicians should be vigilant for signs
episodic (type I) bipolar (affective) and symptoms of leukaemia in patients
disorder that is not well-controlled. who have received Phosphocol® P32.
• Pre-existing cerebrovascular disorders The Canadian product monograph will be
— e.g., cerebral aneurysm and vascular updated to include the following warning.
abnormalities, including vasculitis or
stroke. Leukaemia: Phosphocol® P32 may
increase the risk of leukaemia in certain
• Unless specialist cardiac advice has situations. Two children (ages 9 and 14)
been obtained, in pre-existing cardio- with haemophilia developed acute lym-
vascular disorders, including severe phocytic leukaemia approximately 10
hypertension, heart failure, arterial months after intra-articular injections.
occlusive disease, angina, haemody- Phosphocol® P32 is not indicated in the
namically significant congenital heart treatment of haemarthroses.
disease, cardiomyopathies, myocardial
infarction, potentially life-threatening In addition, the product monograph will be
arrhythmias, and dysfunction of cardiac updated to include post-marketing reports
ion channels of radiation injury (necrosis and fibrosis)
to the small bowel, caecum, and bladder
References: following peritoneal administration of
Phosphocol® P32.
1. EMEA press release at http://www.
emea.europa.eu/pdfs/human/ Reference: Health Canada, Alert dated 25
referral/methylphenidate/2231509en.pdf; March 2009. at http://www.hc-sc.gc.ca/dhp-
question-and-answer document at mps/medeff/advisories-avis/prof/_2009/index-
http://www.emea.europa.eu/pdfs/human/ eng.php
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25. Safety and Efficacy Issues WHO Drug Information Vol 23, No. 2, 2009
Warning for metoclopramide- frequently than other agents. Prescribers
containing drugs are advised to monitor all patients taking
antipsychotics for adverse metabolic
United States of America — The Food effects.
and Drug Administration (FDA) has
announced that manufacturers of meto- References
clopramide, a drug used to treat gastroin-
testinal disorders, must add a boxed 1. http://www.bpac.org.nz/magazine/2007/
february/antipsychotics.asp
warning to labelling about the risk of long-
term or high-dose use. Chronic use of 3. Prescriber Update 2009;30(2):12 at http://
metoclopramide has been linked to www.medsafe.govt.nz/profs/PUarticles.asp
tardive dyskinesia even after the drugs
are no longer taken.
Cefaclor and serum sickness-
Metoclopramide works by speeding up like reactions in children
the movement of the stomach muscles, Australia — The association between
thus increasing the rate at which the cefaclor and serum sickness-like reac-
stomach empties into the intestines. It is
tions (SSLR), particularly in children, has
used as a short-term treatment of gastro- long been recognized (1). These reac-
oesophageal reflux disease in patients tions are characterized by a variety of
who have not responded to other thera-
rashes, which include urticaria or ery-
pies, and to treat diabetic gastro-paresis. thema multiforme, with or without
It is recommended that treatment not angioedema, accompanied by arthritis/
exceed three months.
arthralgia, with or without fever.
Reference: FDA News, 26 February 2009 at
http://www.fda.gov The reactions are rare but occur more
often after a second or subsequent
Metabolic effects of course of treatment. Onset time is often a
few days after cefaclor is commenced
antipsychotics and signs and symptoms typically sub-
New Zealand — Although schizophrenia side a few days after the drug is ceased.
itself is associated with several adverse However, onset may also be delayed and
metabolic effects it is now clear that all occur 7–21 days after stopping cefaclor.
antipsychotics, and in particular some Children are more susceptible than
atypical antipsychotics, are associated adults.
with adverse effects on weight, blood
glucose, and lipid concentrations. All of The TGA continues to receive about 10
these adverse effects have long-term reports per year of cefaclor-related SSLR
consequences in terms of life expectancy. in children. If cefaclor must be prescribed
to a child, the parents/caregivers should
While the effects of antipsychotics on be advised to remain alert for the devel-
weight gain may be responsible for the opment of new or worsening symptoms
increased risk of diabetes and hyperlipi- that might indicate a hypersensitivity
daemia, a direct effect on glucose me- reaction to the drug and to contact their
tabolism may also occur. doctor immediately if there are concerns.
Not all atypical antipsychotics are associ- Extracted from the Australian Adverse
ated with the same level of risk. Clozap- Drug Reactions Bulletin, Volume 28,
ine and olanzapine are considered to Number 2, April 2009 at http://
cause adverse metabolic effects more www.tga.gov.au/adr/aadrb/aadr0904.htm
108

26. WHO Drug Information Vol 23, No. 2, 2009 Safety and Efficacy Issues
Reference: ADRAC. Cefaclor in the young • If signs or symptoms that may be
patient: arthritis and arthralgia <http:// associated with cardiac arrhythmia
www.tga.gov.au/adr/aadrb/aadr9508.htm# occur during treatment with toremifene,
cefaclor>. Aust Adv Drug React Bull 1995; 14 treatment should be stopped and an
(3).
ECG should be performed.
Toremifene: prolongation Currently, toremifene 20 mg/day and 80
of QTc interval mg/day are being studied in prostate
cancer indications.
United Kingdom/European Union —
The manufacturer of toremifene Reference: Communication from Orion
(Fareston®) has informed healthcare Pharma UK at http://www.mhra.gov.uk/
professionals of new information on Safetyinformation/
prolongation of the QTc interval related to
toremifene. The approved therapeutic Atomoxetine: risk of psychotic
indication for toremifene 60 mg/day is the or manic symptoms
first line treatment of hormone dependent
metastatic breast cancer in postmeno- United Kingdom — Atomoxetine
pausal patients. (Strattera®) is a selective noradrenaline
reuptake inhibitor, authorized since 2004
Both in preclinical investigations and in for use in the treatment of attention-
humans, changes in cardiac electro- deficit/hyperactivity disorder (ADHD) as
physiology have been observed following part of a comprehensive treatment
exposure to toremifene, in the form of QT regimen. Continued case reports of
prolongation. Consequently: possible nervous-system and psychiatric
adverse effects prompted a review of
• Toremifene is therefore contraindicated data from all sources resulting in updated
in patients with: information on the risk of new-onset or
worsening of serious psychiatric disor-
Congenital or documented acquired QT ders, including psychotic reactions,
prolongation; electrolyte disturbances, hallucinations, mania, and agitation.
particularly in uncorrected hypokalae-
mia; clinically relevant bradycardia; Product information for prescribers has
clinically relevant heart failure with been updated to reflect more fully the
reduced left-ventricular ejection fraction; emerging safety information. Atomoxetine
previous history of symptomatic arrhyth- is associated with treatment-emergent
mias. psychotic or manic symptoms in children
and adolescents without a history of such
• Toremifene should not be used concur- disorders. If such symptoms occur,
rently with other drugs that prolong the consideration should be given to a
QT interval. possible causal role of atomoxetine and
discontinuation of treatment.
• Toremifene should be used with caution
in patients with ongoing proarrhythmic Advice for healthcare professionals:
conditions (especially elderly patients)
such as acute myocardial ischaemia or • At normal doses, atomoxetine can be
QT prolongation as this may lead to an associated with emergent psychotic or
increased risk for ventricular arrhyth- manic symptoms (e.g., hallucinations,
mias (including Torsade de Pointes) and delusional thinking, mania, or agitation)
cardiac arrest. in children and adolescents without a
history of psychotic illness or mania.
109

27. Safety and Efficacy Issues WHO Drug Information Vol 23, No. 2, 2009
• If such symptoms occur, consideration In February 2008, the manufacturer
should be given to a possible causal informed healthcare professionals of very
role of atomoxetine and discontinuation rare liver injuries and serious skin reac-
of treatment. tions associated with moxifloxacin. This
was in response to a worldwide review of
• It remains possible that atomoxetine serious, including fatal cases of hepato-
might exacerbate pre-existing psychotic toxicity and bullous skin reactions such as
or manic symptoms Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN) reported
Reference: Medicines and Healthcare for moxifloxacin.
Products Regulatory Agency, Drug Safety
Update, Volume 2, Issue 8 March 2009 at To date, HSA has received 22 local
http://www.mhra.gov.uk/Safetyinformation/ spontaneous adverse drug reaction
reports associated with oral moxifloxacin.
Lignocaine with chlorhexidine Patient exposure to moxifloxacin to date
is estimated to be 230 577, according to
gel: anaphylaxis local figures provided by the manufac-
United Kingdom — Lignocaine 2% gel turer. In the interpretation of the above
with chlorhexidine 0.05% is an anaes- figures, there is a need to consider the
thetic/antiseptic/disinfectant combination significant degree of under-reporting of
used as a lubricant for urology proce- adverse reactions as is the case with all
dures and examination, and as sympto- spontaneous adverse drug reaction
matic treatment of painful urethritis. reporting programmes.
References
Since 1990, the TGA has received 19
reports of suspected adverse reactions to 1. EMEA Press Release. European Medicines
lignocaine with chlorhexidine gel. Eleven Agency recommends restricting the use of oral
of these were of anaphylaxis. Some were moxifloxacin-containing medicines. http://
life threatening, but there have been no www.emea. europa.eu/pdfs/human/press/
fatalities.
2. Direct Healthcare Professional Communica-
The MHRA warns of the potential for tion regarding moxifloxacin (Avelox®) and
serious hepatic and bullous skin reactions.
anaphylaxis or other hypersensitivity
http://www.mhra.gov.uk/
reactions with both lignocaine and chlor-
hexidine. Users of local anaesthetic 3. HSA Safety News, 19 Mar 2009 at http://
preparations should check which prod- www.hsa.gov.sg
ucts contain chlorhexidine and are
reminded of the risk of severe allergic
reactions to medicines, even when
Codeine toxicity
applied topically. in breastfed infants
Singapore — Codeine is found in many
Reference: Medicines and Healthcare
prescription and non-prescription pain
Products Regulatory Agency, http://
www.mhra.gov.uk/Safetyinforma tion/ relievers and cough syrups. Once in-
gested, codeine is metabolised by cyto-
chrome P450 2D6 (CYP2D6) to its active
Moxifloxacin safety update metabolite, morphine, which relieves pain
Singapore — Moxifloxacin (Avelox® and or cough. Limited evidence suggests that
Vigamox®) is a broad-spectrum antibac- individuals with a specific CYP2D6
terial that is available locally. genotype (otherwise known as ultra-rapid
metabolisers) may convert codeine to
110