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WHO Drug Information Vol 19, No. 1, 2005 World Health Organization

WHO Drug Information

Contents
Current Topics Regulatory Action
Pharmacogenetics: towards improving Northern hemisphere influenza vaccine
treatment with medicines 3 composition 2005/2006 30
Abnormal drug response: opportunities for Valdecoxib: severe skin reactions and
risk reduction through pharmacogenetics 3 cardiovascular risk 30
COX-2 inhibitors: review plans 30
Safety and Efficacy Issues Co-proxamol products withdrawn 31
The role of pharmacovigilance in medicines Cisapride licences voluntarily cancelled 31
safety 13 Tentative approval for generic co-packaged
National Centres discuss new safety antiretrovirals 31
monitoring methods 16 Natalizumab approved for multiple sclerosis 32
Signalling and safety problems 16 Pegaptanib for age-related macular
Third meeting of the Signal Review Panel 17 degeneration 32
COX-2 inhibitors: overview 19 Amphetamine salts suspended 32
Telithromycin and warfarin: suspected Tolcapone: return to market 33
interaction 21 Patient reporting and public access to
Penicillin: information strengthened 21 safety data 33
Linezolid and neuropathy 22 Australia and Canada agree mutual
Ceftriaxone and immune haemolytic recognition 34
anaemia in children 22 Didanosine-tenofovir interactions: safety
Ethinylestradiol/cyproterone: increased risk recommendations 34
of thrombosis 23
Influenza virus vaccine: interactions 23 Prequalification of Medicines
Rosiglitazone and pioglitazone: dangers of Improving medicines quality through
off-label use 24 prequalification 35
Naproxen and celecoxib suspended in How to participate in prequalification 36
Alzheimer prevention trial 24
Heparin contraindicated in severe renal
impairment 24
ATC/DDD Classification
Flucloxacillin: serious hepatic disorders 25 Final list 40
Bevacizumab and arterial thromboembolic Temporary list 43
events 25
Amiodarone toxicity concerns 26 The International Pharmacopoeia
Darbepoetin alfa: adverse outcomes 26 Monographs for antiretrovirals
Didanosine (final) 45
Vaccines and Biomedicines Indinavir sulfate (final) 51
Latest developments in biological Nelfinavir mesilate (final) 55
standardization 27 Ritonavir (final) 59
International Reference Standards 27 Saquinavir (final) 62
Recommendations and guidelines 27 Saquinavir mesilate (final) 65
Consolidated list of WHO recommendations
and guidelines 29 Recommended International
Nonproprietary Names:
List 53 69

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WHO Drug Information Vol 19, No. 1, 2005

Current Topics

Pharmacogenetics: towards improving

treatment with medicines

Increasingly, sponsors of new drugs are integrating pharmacogenetics into their drug development
programmes. The outcome of this integration will present challenges to the traditional paradigms for
drug development, regulatory evaluation of safety and efficacy and clinical use of drugs. Pharmacoge-
netics is still an evolving discipline and a very active area of research. It promises to revolutionize
therapeutics through ‘individually targeted therapy’. In principle, genotype-based individually targeted
prescribing ought to be more effective at improving response rates and decreasing the burden of
adverse drug reactions.

The extent to which this promise of pharmacogenetics is fulfilled remains to be seen. The experience
to date is mixed with a few successes but many frustrations. Discovering highly predictive associa-
tions during drug development and demonstrating their clinical validity and utility in clinical trials will no
doubt better define the role of pharmacogenetics in future clinical practice.

The Council for International Organizations of Medical Sciences (CIOMS) and its Working Group on
Pharmacogenetics have recently published a report entitled Pharmacogenetics: towards improving
treatment with medicines. This is the outcome of discussions among a number of senior scientists
from drug regulatory authorities, pharmaceutical companies and academia. It reflects their current
views and visions and expectations for the future. The article below is drawn from the report, which is
available from CIOMS. Details can be found on http://www.cioms.ch

Abnormal drug response:
opportunities for risk reduction
through pharmacogenetics
An adverse drug reaction (ADR) can result from a
variety of risk factors including variability in
pharmacokinetics and pharmacodynamics of a
drug due to the genetic make-up of an individual.
Other important influences are external factors
such as co-medications and co-morbidities, which
give rise to drug-drug or drug-disease interac-
tions. The net effect of these interactions is that
the prescribed dose of a drug is an inappropriate
one. Usually, clinically relevant drug interactions
result when the plasma concentration of one of
the interacting drugs increases to toxic levels.
With careful attention to prescribing information re-
garding dose, age-related adjustments and popu-
lations at risk for drug-drug and drug-disease inter-
actions, the impact of ADRs can be greatly mini-
mized. However, it is unlikely that any single ap-
proach will completely eliminate all ADRs. With avail-
able data suggesting that some ADRs might have a
monogeneic or polygeneic basis, the application of
pharmacogenetics provides an opportunity for fur-
ther reductions in both the incidence and severity
of ADRs.
The article below reviews some of the data on ab-
normal drug response related to polymorphisms in
drug metabolizing enzymes, pharmacological tar-
gets and drug transporters. It illustrates how, at least
in some areas, pharmacogenetics may offer the
prospects of minimizing the risks of drug toxicity and
therapeutic failures.
Pharmacogenetics and drug
metabolizing enzymes
A number of drug metabolizing enzymes displays
genetic polymorphisms. Candidate gene associa-
tion studies, investigating the role of these
polymorphic drug metabolizing enzymes such as
CYP2D6, CYP2C9, CYP2C19, N acetyltrans-
ferase (NAT2), thiopurine S-methyltransferase
(TPMT), UDP-glucuronosyltransferases (UGTs)

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Current Topics WHO Drug Information Vol 19, No. 1, 2005

and dihydropyrimidine dehydrogenase (DPD) products of gene expression have been consid-
have already shown that there is a genetic ered as markers for optimization of drug therapy,
predisposition to a number of ADRs. most especially in the field of oncology.

It is now generally assumed that because of this Polymorphic variation in CYP2D6

genetic predisposition, there may be a great
potential for preventing ADRs and improving the
safe and effective use of medicines through the
increasing knowledge of genetic factors that
determine drug response. Polymorphic genes and
Studies over the last two decades have shown
that any given population may be divided into two
phenotypes – extensive metabolizers (EMs) or
poor metabolizers (PMs) – depending on their
ability to mediate CYP2D6-dependent

Table 1. Clinical consequences for PM and ultrarapid EM phenotypes of CYP2D6

Clinical Consequences for the Poor Metabolizer

Increased risk of toxicity

Debrisoquine Postural hypotension and physical collapse

Sparteine Oxytocic effects
Perphenazine Extrapyramidal symptoms
Flecainide Ventricular tachyarrhythmias
Perhexiline Neuropathy and hepatotoxicity
Phenformin Lactic acidosis
Propafenone CNS toxicity and bronchoconstriction
Metoprolol Loss of cardioselectivity
Nortriptyline Hypotension and confusion
Terikalant Excessive prolongation in QT interval
Dexfenfluramine Nausea, vomiting and headache
L-tryptophan Eosinophilia-myalgia syndrome
Indoramin Sedation
Thioridazine Excessive prolongation in QT interval

Failure to respond

Codeine Poor analgesic efficacy

Tramadol Poor analgesic efficacy
Opiates Protection from oral opiate dependence

Clinical Consequences for the Ultrarapid Metabolizer

Increased risk of toxicity

Encainide Proarrhythmias
Codeine Morphine toxicity

Failure to respond

Nortriptyline Poor efficacy at normal doses

Propafenone Poor efficacy at normal doses
Tropisetron Poor efficacy at normal doses
Ondansetron Poor efficacy at normal doses

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WHO Drug Information Vol 19, No. 1, 2005
hydroxylation of the antihypertensive drug
debrisoquine. Among the EM phenotype, there
are two subgroups of particular interest at either
extreme of the EM population distribution. One
subgroup, termed the ultrarapid metabolizers
(UMs), is comprised of individuals possessing
multiple copies of the gene for normal metabolic
capacity and the other group, termed the interme-
diate metabolizers (IMs), is comprised of a
heterozygous genotype (“gene-dose effect”). UMs
metabolize drugs so avidly that they attain very
low concentrations of the parent drug and high
concentrations of rapidly accumulating metabo-
lites while IMs display a modest impairment in
drug metabolizing capacity.
CYP2D6 is responsible for the metabolism of well
over 60 drugs that include antiarrhythmics, b-
adrenoreceptor antagonists, antihypertensives,
antianginals, neuroleptics, antidepressants,
analgesics as well as a number of other miscella-
neous drugs. Candidate gene association studies
have shown that a number of ADRs to CYP2D6
substrates are related to CYP2D6 genotype
(Table 1).
One of the first reports on the clinical significance
of CYP2D6 polymorphism and its association with
serious toxicity was perhexiline-induced neuropa-
thy in patients with impaired CYP2D6 metabolism.
Although the recommended dose of perhexiline
was 100 mg three times daily, a recent study of
23 patients has shown that to maintain the
plasma concentrations of perhexiline within the
therapeutic and non-toxic range, PMs required a
dose of 10-25 mg/day while EM and ultrarapid EM
required 100-250 and 300-500 mg/day respec-
tively [1]. Other clinical consequences for individu-
als with the PM or ultrarapid phenotypes of
CYP2D6 are also shown in Table 1.
Application of pharmacogenetic principles may
also improve efficacy. There are several examples
where subjects carrying certain alleles suffer from
a lack of drug efficacy because of ultrarapid
metabolism caused by multiple genes or by
induction of gene expression. As with perhexiline,
some patients who are ultrarapid metabolizers fail
to respond to conventional doses of nortriptyline
and require ‘megadoses’ of this antidepressant.
Similarly, poor metabolizers fail to respond to
therapeutic effects mediated by metabolites. This
is illustrated by the relative loss in PMs of analge-
sic effects following administration of codeine or
tramadol or the loss of antiarrhythmic effects of
encainide.
Current Topics
Polymorphic variation in CYP2C9
Retrospective case studies have shown that the
presence of mutant CYP2C9 allele (especially
CYP2C9*3 allele) confers a significantly in-
creased risk of bleeding following treatment with
warfarin. Available data, however, indicate that
although the CYP2C9*3/ CYP2C9*3 genotype is
associated with dramatic over anticoagulation
soon after the introduction of oral anticoagulants,
overdose during the maintenance period is mostly
related to environmental factors [2, 3]. It is also
recognised that inter-individual variability in
warfarin sensitivity also originates from environ-
mental factors. In one study, age and CYP2C9
genotype accounted for 12% and 10% of the
variation in warfarin dose requirements, respec-
tively [4]. Clearly, other pharmacodynamic (such
as to an abnormality in the target enzyme vitamin
K epoxide reductase) and dietary factors also play
an important role. In a retrospective cohort study
of patients on long-term warfarin, it was found that
the mean maintenance dose varied significantly
among the six genotypes of CYP2C9. Compared
to patients with the wild type genotype, patients
with at least one variant allele required longer
time to achieve stable dosing and had a signifi-
cantly increased risk of a serious or life-threaten-
ing bleeding event, although patient numbers
were small for some genotypes in this study [5].
Similarly, to achieve a therapeutic serum concen-
tration of phenytoin, patients carrying at least one
mutant CYP2C9 allele required a mean phenytoin
dose that was about 37% lower than that in
patients with wild type genotype (199 mg/day
versus 314 mg/day) [6]. Since phenytoin has a
narrow therapeutic index and genotyping may be
carried out rapidly and at a relatively low cost,
dosage adjustment based on CYP2C9 genotype,
especially at the induction of therapy, would be of
value in order to lower the risk of concentration
dependent phenytoin toxicity in the carriers of
mutant alleles.
Polymorphic variation in CYP2C19
CYP2C19 mediates the major pathway responsi-
ble for metabolic elimination of proton pump
inhibitors. Since therapeutic activity correlates
with exposure to the parent compound, it is not
surprising that a number of studies have shown
that PMs of CYP2C19 respond better to H. pylori
eradication therapy. These preliminary findings
need to be confirmed in large prospective studies
[7]. EMs of CYP2C19 require higher doses of
these drugs.
5
Current Topics
Polymorphic variation in thiopurine S-
methyltransferase
Azathioprine and 6-mercaptopurine are metabo-
lised by thiopurine S-methyltransferase (TPMT).
The activity of TPMT is inversely related to the
risk of developing acute leucopenia associated
with the use of these drugs. A number of studies
have shown that the risk of azathioprine-induced
acute leucopenia can be greatly reduced by
basing the initial azathioprine dose on TPMT
genotype or phenotype [8, 9]. Of course, not all
azathioprine-induced toxicities have a genetic
basis. In one study of 93 patients, it was noted
that azathioprine-related gastrointestinal side
effects are independent of TPMT polymorphism
[10]. The value of genotyping for TPMT is illus-
trated by a report from Murphy and Atherton [11]
that by initiating therapy at dose levels of 2.5-3.5
mg/kg in atopic eczema patients with a normal
TPMT level, they felt confident in reducing the
frequency with which tests of bone marrow and
liver function had to be undertaken.
Polymorphic variation in UDP-
glucuronosyltransferases
Conjugation reactions such as glucuronidation
mediated by UDP-glucuronosyltransferases
(UGTs) are now also attracting increasing atten-
tion, especially in the field of oncology.
Glucuronidation is by far the most important
conjugation pathway in man. A multigene family
encodes the UGTs and a relatively small number
of human UGT enzymes catalyse the
glucuronidation of a wide range of structurally
diverse endogenous (bilirubin, steroid hormones
and biliary acids) and exogenous chemicals.
Genetic variations and single nucleotide poly-
morphisms (SNPs) within the UGT genes are
remarkably common, and lead to genetic poly-
morphisms [12, 13]. Some polymorphic UGTs
have demonstrated a significant pharmacological
impact in addition to being relevant to drug-
induced ADRs. Two major isoforms of UDP-
glucuronosyltransferase, UGT1A1 and UGT1A9,
have been shown to display genetically deter-
mined wide inter-individual variability in their
activities. Studies investigating the role of UGT1A
isoforms in the metabolism of drugs such as
irinotecan [14, 15], flavopiridol [16, 17], tranilast
[18] and atazanavir [19] have been most valuable
in explaining the safety issues (myelosuppres-
sion, diarrhoea or hyperbilirubinaemia) associated
with the use of these drugs.
A meta-analysis by Phillips et al [20] identified 131
specific drugs, 55 drug classes, and 19 therapeu-
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WHO Drug Information Vol 19, No. 1, 2005
tic drug categories as being associated with
ADRs. All except three of these drugs were
included among the top 200 selling drugs in the
United States. The therapeutic categories associ-
ated with the most common ADRs were cardio-
vascular, analgesics, psychoactive drugs and
antibiotics. This meta-analysis included 18 of 333
ADR studies and 22 of 61 variant allele review
articles. It identified 27 drugs frequently cited in
ADR studies. Among these drugs, 59% were
metabolised by at least one enzyme with a variant
allele known to cause poor metabolism. In
contrast, only 7% to 22% of randomly selected
drugs were metabolised by enzymes displaying
genetic polymorphism (p = 0.006 - < 0.001).
These data suggest that drug therapy based on
the genotype of individual patients may result in a
clinically important reduction in adverse out-
comes.
Pharmacogenetics and transporters
For the vast majority of drugs, however, the
reason for individual susceptibility to ADRs has
remained unknown and there are hardly any data
on genetic susceptibility. However, recent studies
have shown that organ-specific organic anion and
cation transporters play an important role in the
transport of drugs into the cells. These transport-
ers may account for drug-induced toxicity, hitherto
termed “idiosyncratic”.
Molecular studies have found evidence of genetic
polymorphisms of these transporters in hepato-
cytes [21, 22]. Mutations in the genes coding for
these transporters may lead to dysfunctional
polypeptides, which affect not only the pharma-
cokinetics of the drugs concerned but also the
potential hepatotoxic effects of some of these
drugs [23, 24]. Furthermore, the variant alleles
show inter-ethnic differences [22, 25] that may
possibly explain inter-ethnic differences in the
hepatotoxic potential of a drug (such as ibufenac).
Studies investigating these transporters in
patients with hepatotoxicity offer exciting pros-
pects for exploring the potential role of pharmaco-
genetics in drug-induced hepatotoxicity.
These transporters and P-glycoproteins co-
localize in organs of importance to drug
disposition (intestine, liver and kidney). The
expression of P-glycoprotein activity is under the
control of the MDR1 gene [26] and is an important
factor in the disposition of many drugs. In multi-
drug resistance (MDR), the processes involved
show considerable interindividual and inter-ethnic
variability. For example, a variant allele recently
WHO Drug Information Vol 19, No. 1, 2005
designated as MDR1*2 (resulting from three
linked SNPs) occurred in 62% of European
Americans and only 13% of African Americans
[27].
The MDR1 gene and its variants have significant
implications in terms of efficacy or development of
resistance to anticonvulsants, antineoplastic
therapy and anti-HIV drugs [28, 29].
Pharmacogenetics and
pharmacological targets
In addition to pharmacogenetic effects on drug
metabolism, therapeutically promising examples
of genetic variations in pharmacological targets
are also beginning to emerge. These targets
include receptors, transporters, enzymes, chan-
nels and intracellular coupling processes that
modulate pharmacodynamic responses. Among
the most widely studied are the pharmacological
targets related to cardiac arrhythmias, asthma,
depression and the HLA antigen genotype in
hypersensitivity reactions.
To date, the focus of pharmacogenetic studies in
the context of ADRs has been on drug metabolis-
ing enzymes. It is now becoming evident that
polymorphisms of pharmacological targets
(pharmacodynamic polymorphisms) may in fact
be even more important. In one study of 270
cancer patients given antiemetic therapy with 5-
HTR3B receptor antagonists, approximately 30%
suffered from nausea or vomiting despite these
drugs. Ultrarapid metabolism of tropisetron (and
to a lesser extent for ondansetron) was shown to
predispose patients to poor efficacy [30]. In
another study by the same group of investigators,
patients homozygous for a deletion variant of the
promotor region of 5-HTR3B gene were shown to
experience vomiting more frequently than did all
the other patients [31]. In a pharmacogenetic
study that compared paroxetine and mirtazapine
in 246 elderly patients with major depression,
discontinuations due to paroxetine-induced side
effects were strongly associated with the 5-HTR2A
C/C, rather than CYP2D6, genotype. There was a
significant linear relationship between the number
of C alleles and the probability of discontinuation.
The severity of side effects in paroxetine-treated
patients with the C/C genotype was also greater
[32]. Thus, although paroxetine is metabolised by
CYP2D6, polymorphism of 5-HTR2A is a more
important determinant of paroxetine-induced
ADRs.
Current Topics
Polymorphisms of cardiac potassium
channels
Drugs prolonging the QT interval of the surface
electrocardiogram (ECG) have attracted consider-
able attention recently. Excessive prolongation of
the QT interval, in the right setting, predisposes to
torsade de pointes (TdP), a potentially fatal
ventricular tachyarrhythmia [33]. The duration of
this interval reflects the duration of ventricular
action potential. The major determinant of the
action potential duration is the potassium current
mediated by the rapid component of the delayed
rectifier potassium channels (IKr). Many drugs
have been withdrawn as a result of their potential
to prolong the QT interval and induce TdP.
Following advances in molecular biology, genetics
and pharmacology of ion channels, it has become
evident that there is a great diversity of genes that
control the expression of these potassium
channels. Mutations of the subunits that form
these channels, including IKr, are common and
give rise to congenital long QT syndromes.
Relatively large numbers of individuals carry
variants of long QT syndrome genes that are
clinically silent. While these individuals have a
normal ECG phenotype, they nevertheless have a
diminished repolarization reserve and are highly
susceptible to drug-induced QT interval prolonga-
tion and/or TdP following normal therapeutic
doses of drugs (such as cisapride, astemizole,
terfenadine and halofantrine among others) even
in the absence of inhibitors of their metabolism
[34]. In an analysis of 341 reports of cisapride-
induced ventricular arrhythmias, there were 38
(11%) cases in whom there were no identifiable
risk factors or contraindications [35]. These
individuals may well represent a population with a
concealed genetic defect of their potassium
channels.
Polymorphisms of b2-adrenoceptors and
ALOX-5
Individuals who carry Arg16/Gly16 or Gly16/Gly16
mutations of b2-adrenoceptors have been shown
to respond much less favourably to salbutamol-
induced bronchodilatation, in contrast to those
with wild type receptor characterised by Arg16/
Arg16 genotype – the difference in FEV1 re-
sponse between Gly16/Gly16 and Arg16/Arg16
genotypes is 6.5-fold [36]. Similarly, asthmatic
patients who carry mutations of the core promoter
of 5-lipoxygenase (ALOX-5) respond poorly to
ALOX-5 inhibitors such as zileuton [37].
7
Current Topics
Kaye et al [38] have recently shown that in
individuals with cardiac failure, patients who were
homozygous for the Gln27 allele of b2-adreno-
ceptor displayed a significantly lower proportion of
good responders to carvedilol than did patients
who were homozygous or heterozygous for the
Glu27 polymorphism (26% versus 63%, p=0.003).
Polymorphisms of the serotonin trans-
porter
Genetic polymorphism in the promoter region of
the serotonin transporter (5-HTT) gene is report-
edly a determinant of response to fluvoxamine, a
selective serotonin re-uptake inhibitor. The
insertion variant of this polymorphism (long allele)
is associated with higher expression of brain 5-
HTT compared to the deletion variant (short
allele) [39]. Patients who have one or two copies
of the long variant (homozygous l/l or hetero-
zygous l/s) may show a better therapeutic
response than patients who are homozygous for
the short variant (s/s). The efficacy of fluvoxamine
in the treatment of delusional depression has
been shown to correlate with 5-HTT genotypes
[40].
Abacavir-induced hypersensitivity reac-
tions and HLA genotype
Hypersensitivity reactions (HSR) to abacavir
occur in about 5% of patients who receive the
drug for HIV-1 infection. Three independent
research groups have identified an association
between HLA-B*5701 and hypersensitivity to
abacavir in patients of Caucasian ancestry [41-
44]; the sensitivity of HLA-B*5701 ranged from
46-94%. While two groups suggest that there
may be clinical value in prospectively screening
Caucasian patients for HLA-B*5701 prior to the
use of abacavir [43, 44], in the largest, and most
ethnically diverse study, the association between
HLA-B*5701 and hypersensitivity was much
weaker in Hispanic patients and was absent in
Black patients [45]. While this is an interesting
example of the potential of pharmacogenetics,
there is legitimate risk that HLA-B*5701 screening
could unintentionally compromise the highly
successful risk management programme estab-
lished for abacavir hypersensitivity. Specifically,
physician vigilance might be reduced in patients
who do not carry markers associated with hyper-
sensitivity and marker-negative patients might be
at increased risk for experiencing serious and/or
life-threatening hypersensitivity reactions because
symptoms associated with abacavir hypersensitiv-
ity are not promptly recognised and abacavir
discontinued. Efforts to analyse thousands of
8
WHO Drug Information Vol 19, No. 1, 2005
SNPs across the genome for association to HSR
are under way to identify additional genetic
markers with sufficient predictive value to be
clinically useful [46].
Pharmacogenetics and
hepatotoxicity
Hepatotoxicity is of serious concern not only
because of the morbidity and mortality associated
with it but also because it is the leading reason for
withdrawal of drugs from the market [47]. Apart
from the role of transporters at the hepatocytes-
biliary canalicular interface, there is conclusive
evidence for the role of polymorphic drug metabo-
lism in hepatotoxicity associated with some drugs.
For isoniazid, the genetic basis for this toxicity is
well known. Individuals who have a low activity of
N-acetyltransferase (NAT2 slow acetylators) are
at a much greater risk of developing isoniazid-
induced hepatotoxicity. Slow acetylators
produce a low level of an intermediate metabolite
that is also eliminated by acetylation. Failure to
eliminate this effectively results in production of
an alternative metabolite that is hepatotoxic [48,
49].
Perhexiline-induced hepatotoxicity, a major factor
in the drug’s withdrawal from the market, is
associated with impaired CYP2D6 status [50].
The involvement of genetic factors in drug-
induced hepatotoxicity generally is strongly
suggested by the susceptibility of the female
gender. In addition, there are reports of familial or
ethnic susceptibility to hepatotoxicity associated
with some drugs such as phenytoin [51] or
ibufenac [52] respectively.
Pharmacogenetics and drug
interactions
Drug-drug interactions can be dramatically
influenced by genotypic differences. A number of
studies have shown that CYP2D6 PMs (with
alleles expressing no functional enzyme) do not
show the drug-drug interactions predicted from in
vitro studies. This is hardly surprising since there
is no functional CYP2D6 activity to inhibit or
induce. Likewise, UMs too may fail to exhibit the
expected drug-drug interaction unless the dose of
the inhibitor is (toxic) high enough. The individuals
most likely to display a drug interaction are those
who have an intermediate drug metabolising
capacity or those who have inherited CYP2D6
alleles with reduced or altered affinity for CYP2D6
substrates. At the level of CYP2D6, the depend-
ence of drug interactions on the metabolic
WHO Drug Information Vol 19, No. 1, 2005
phenotype has already been shown for a number
of its substrates, for example codeine [53],
propafenone [54, 55], mexiletine [56], encainide
[57], metoprolol [58] and desipramine [59]. The
organic ion transporters and P-glycoproteins
referred to earlier are additional sites of important
drug interactions and pharmacogenetic factors
are also likely to be important here.
Predictive genotyping: improving
drug response and minimizing ADRs
It has been estimated that predictive genotyping
(for candidate genes) will lead to benefit in 10–
20% of drug treatment by allowing prevention of
ADRs [60, 61].
If genetic markers of a greater number of ADRs
(candidate genes, SNPs or haplotypes) can be
identified and if cheap and rapid genotyping of
patients can be done routinely, then the impact of
ADRs on morbidity and mortality can be consid-
erably reduced. Veenstra et al [62] have re-
viewed cost-effectiveness of genetic tests and
have identified five primary characteristics that
will enhance the cost-effectiveness of the
application of pharmacogenetics. These are:
1. A well-established association between the
genotype and drug response.
2. The variant gene is relatively common.
3. Relatively cheap and rapid genetic test.
4. Difficulties in monitoring drug response.
5. Severe clinical or economic consequences
from not using the pharmacogenetic informa-
tion.
Similar conclusions have been reached by Rioux
[63] who has also emphasised the importance of
the frequency of the variant allele in determining
the cost-effectiveness of the application of
pharmacogenetics in therapeutics.
Other workers who have evaluated the potential
impact of pharmacogenetics have concluded that
its application in therapeutics will be cost-
effective “sometimes” and that it would be
effective primarily for chronic diseases where
unnecessary long-term therapy with an ineffec-
tive drug for many years could be avoided in
some patients [64].
Current Topics
Limitations
It is not intended to suggest that the application of
pharmacogenetics will totally eliminate the
problems of ADRs. Recently, Kirchheiner et al
have provided a preliminary guidance for a
number of drugs metabolised by CYP2D6 and
CYP2C19 with a view to introducing genotype/
phenotype-specific dose schedules [65]. Recom-
mending inappropriately high dose can easily
offset the potential benefits of pharmacogenetics.
Co-administration of a metabolic inhibitor converts
an extensive metabolizer into a poor metabolizer.
It is therefore not surprising that drug interactions
feature prominently among the causes that lead
to withdrawal of drugs from the market.
One unpublished report analysed 17 studies (with
a total of about 1,350 patients) published between
1995-2000 on antipsychotic drug therapy, investi-
gating an association between CYP2D6 genotype
and both plasma levels of the drug(s) and re-
sponse to these drugs [66]. There was a relation-
ship between genotype and plasma concentra-
tions of drugs that were predominantly metabo-
lised by CYP2D6 but a large intra-genotypic
variability obscured clinical utility of concentration
measurements.
However, there was no relationship evident
between genotype and drug response (i.e. failure
to respond beneficially). There was only a modest
positive trend between the genotype, especially
the presence of CYP2D6*10 allele in the Japa-
nese, and severity of tardive dyskinesia and
extrapyramidal syndrome. This may not alto-
gether be surprising since many neuroleptics
have active metabolites. When applying pharma-
cogenetic testing in routine clinical practice, it is
important to take note of the pharmacology of the
metabolites relative to that of the parent drug, the
fraction of the drug cleared by the polymorphic
pathway and the therapeutic index of the drug
concerned [67].
In humans, diclofenac is metabolised to 4'-
hydroxy (OH), 3'-OH and 5-OH metabolites. The
polymorphic CYP2C9 is involved in the metabo-
lism of diclofenac to 4'-OH diclofenac and 3'-OH
diclofenac. However, the CYP2C9 genotype does
not correlate with diclofenac-induced hepatotoxic-
ity or COX-1 and COX-2 inhibition [68, 69].
Similarly, in asthma, patients who are deficient in
5-lipoxygenase due to a genotypic variant in the
ALOX-5 gene are non-responsive to 5-lipoxy-
genase inhibitors. However, most of the 5-
lipoxygenase inhibitor non-responders have
9
Current Topics
normal ALOX-5 genes, and the basis of their non-
responsiveness lies in other factors, probably
related to the nature of their asthma.
However, if a genotype/phenotype relationship
can be shown, pharmacogenetics offers another
important strategy by which to reduce ADRs. The
dose schedules recommended need to be
carefully chosen and the clinical awareness of the
consequences of co-administration of interacting
drugs need to be heightened. Prior genotyping of
patients can be used to improve safe and more
effective use of specific and carefully chosen
medicines by identifying patients most likely to
respond beneficially and those most likely to
develop an ADR. This strategy would immediately
translate into great reductions in healthcare and
economic resources that are currently expended
in managing the consequences of ADRs.
Even if a correlation between genotype and
phenotype can be established, it is worth remem-
bering that drug-related problem(s) may not be
completely eliminated. This is because a number
of non-genetic external factors interact with
genotype or modulate the response to a drug. In
addition, there are a number of other factors that
complicate what may appear to be a simple
relationship.
Conclusions
This article highlights the potential contribution of
pharmacogenetics in reducing the incidence of
dose-related and idiosyncratic ADRs. In relation to
ADRs, the research aim of pharmacogenetics is
to identify a genetic profile that characterises
patients who are more likely to suffer an ADR
compared with those in whom the risk is unlikely.
Using this knowledge in the clinic, the choice of
medicine and dose can be targeted for an
individual and the overall result may be an
improvement in the safety profile of the drug.
Moreover, as a result of improved safety following
application of pharmacogenetic principles,
improved efficacy may also accrue. Many dosing
schedules are limited by appearance of side
effects. By eliminating the use of high doses in
those genotypes most at risk, it may become
possible to evaluate the additional benefits of
higher doses in the remaining genotypes.
Advances in biotechnology promise the prospects
of characterising genetic variations in individual
patients rapidly and cheaply with a view to
individualisation of therapy. Exploration of the role
of pharmacogenetics should be undertaken
10
WHO Drug Information Vol 19, No. 1, 2005
during drug development and continued well into
the post-marketing period to include the study of
rare and delayed adverse reactions. This will
make the application of pharmacogenetics in
minimising morbidity and mortality from ADRs a
realistic and worthwhile proposition.
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WHO Drug Information Vol 19, No. 1, 2005
Safety and Efficacy Issues
The role of pharmacovigilance
in medicines safety
Modern medicines have changed the way in
which diseases are managed and administered.
Despite obvious benefits, evidence continues to
accrue that adverse reactions to medicines are a
common — and often preventable — cause of
illness, disability and death. In some countries,
adverse drug reactions (ADRs) rank among the
top ten leading causes of mortality.
In order to prevent or reduce harm to patients and
thus improve public health, mechanisms for
evaluating and monitoring the safety of medicines
in clinical use must be in place. In practice, this
means having a well-organized pharmacovigi-
lance system. WHO defines pharmacovigilance
as the science and activities relating to the
detection, assessment, understanding and
prevention of adverse effects or any other medi-
cine-related problem.
Pharmacovigilance is a dynamic clinical and
scientific discipline. It plays a crucial role in
meeting the challenges posed by the ever
increasing range and potency of medicines, all of
which carry an inevitable and sometimes unpre-
dictable potential for harm. When adverse effects
and toxicity do appear – especially if previously
unknown – it is essential that these are reported,
analysed and their significance communicated
effectively to an audience that has the knowledge
to interpret the information.
For all medicines there is a trade-off between the
benefits and the potential for harm which can be
minimized by ensuring that medicines of good
quality, safety and efficacy are used rationally, and
that the expectations and concerns of the patient
are taken into account when therapeutic decisions
are made.
The aims of pharmacovigilance
Nearly 40 years of worldwide pharmacovigilance
practices have highlighted the need for effective
drug monitoring systems. The aims of pharma-
covigilance programmes are to:
• improve patient care and safety in relation to the
use of medicines, and all medical and para-
medical interventions;
• improve public health and safety in relation to
the use of medicines;
• contribute to the assessment of benefit, harm,
effectiveness and risk of medicines, encourag-
ing their safe, rational and more effective
(including cost-effective) use. Risk management
demands close and effective collaboration
between a host of key players.
• promote understanding, education and clinical
training in pharmacovigilance and effective
communication to health professionals and the
public.
With the increasing use of medicines within the
last decade, the scope of pharmacovigilance has
extended beyond the strict confines of detecting
new signals of safety concerns. Globalization,
consumerism, the resulting explosion in free trade
and communication across borders, and use of
the Internet have all contributed to a change in
the way people use medicinal products and
information about them. These changing patterns
require a shift in the approach to pharmacovigi-
lance, more specifically, towards one that is more
closely linked and responsive to the prevailing
patterns of medicines use within society.
Key elements of pharmacovigilance:
• Establishment of national pharmacovigilance
systems especially for spontaneous reporting of
adverse events, including national pharma-
covigilance centres, and, if appropriate, regional
centres.
• Development of necessary legislation/regulation
for medicine monitoring.
• Development of national policy and plans of
action (to include costing, budgeting and
financing).
• Undergraduate and continuing education of
health-care providers on safe and effective
pharmacotherapy.
13
Safety and Efficacy Issues
• Continuously providing information on adverse
reactions to professionals and consumers.
• Monitoring of the impact through process
indicators and outcome.
The provision of good quality, safe and effective
medicines and their appropriate use is the
responsibility of national governments. The
achievement of these goals requires the estab-
lishment of a national regulatory agency and a
designated centre for the monitoring and study of
adverse reactions. Multidisciplinary collaboration
is of great importance within and among govern-
ments and with other stakeholders, including the
pharmaceutical industry, universities, nongovern-
mental organizations (NGOs) and professional
associations having responsibility for education
on rational use of medicines and pharmaco-
therapy.
Reference: World Health Organization. Pharmacovigi-
lance: ensuring the safe use of medicines. WHO Policy
Perspectives on Medicines. October 2004.
WHO Programme for
International Drug Monitoring
The WHO Programme for International Drug
Monitoring was launched in 1968 as a pilot project
of ten countries with established national report-
ing systems for ADRs. Since then, many more
countries worldwide have developed national
pharmacovigilance centres for the recording of
Structure of the WHO Programme for International Drug Monitoring
Partner Role
World Health Organization Policy and
oversight
Coordination
Communication
WHO Collaborating Centre for Operational
International Drug Monitoring management
Communication
National Centres Reporting network
Communication
14
WHO Drug Information Vol 19, No. 1, 2005
ADRs and the reporting network has expanded
significantly. Currently, a total of 86 countries
participate in the International Drug Monitoring
Programme. The Programme depends on a WHO
Collaborating Centre based in Sweden (Uppsala
Monitoring Centre), which is responsible for
maintaining the global ADR database. VIGIBASE
now contains more than three million ADR
reports.
As part of its work, the WHO Collaborating Centre
analyses the reports in the database to :
• identify early warning signals of serious adverse
reactions to medicines;
• evaluate the hazard; and
• undertake research into the mechanisms of
action to aid the development of safer and more
effective medicines.
WHO also plays an important role in the provision
of expert advice through an advisory committee,
on all matters of safety of medicines. Its aim is to
facilitate consistent policies and action among
member countries and to advise those who may
be concerned about action taken in another
country.
The success of the WHO International Drug
Monitoring Programme is entirely dependent on
collaboration with national pharmacovigilance
centres. Such centres provide an essential pool of
Responsibility
Exchange of Information
Advisory Committee on Safety of Medicinal
Products
Guideline development
International training courses
Global ADR data base
Guideline development
Signal detection
Review Panel for Signal Detection
International training courses
Annual meetings
Advisory Committee for Pharmacovigilance
National data base
Signal detection
National training courses
WHO Drug Information Vol 19, No. 1, 2005
experience and competence which has been
instrumental in the continuous development of the
WHO programme. Ideally every country should
have a national pharmacovigilance system.
References
1. World Health Organization. Policy perspectives on
Medicines. Pharmacovigilance: ensuring the safe sue of
medicines. Available at http://www.who.int/medicines
2. Lazarou, J. et al. Incidence of ADR in hospitalized
patients: a meta-analysis of prospective studies. Journal
of the American Medical Association, 279:1000–1005
(1998).
3. World Health Organization. Safety monitoring of
medicinal products. The importance of pharmacovigi-
lance. Geneva, 2002.
4. World Health Organization. Guidelines for good
clinical practice (GCP) for trials on pharmaceutical
products. Annex 3. Technical Report Series, No. 850.
1995.
5. World Health Organization. Aide Memoire for a
national strategy for safe drugs and their appropriate
use. 2001. http://www.who.int/medicines/library/qsm/
aidemem_drug_safety.pdf
6. WHO Collaborating Centre for International Drug
Monitoring. Expecting the worst. Crisis management.
Uppsala, 2002. http://www.who-umc.org
WHO International Drug Monitoring Programme: membership
Full members
Associate members
Safety and Efficacy Issues
7. WHO Collaborating Centre for International Drug
Monitoring. Effective communications in pharmacovigi-
lance: the Erice Report. Uppsala, 1998. http://www.who-
umc.org
8. WHO Collaborating Centre for International Drug
Monitoring. Dialogue in pharmacovigilance – more
effective communication. Uppsala, 2002. http://
www.who-umc.org
9. World Health Organization. Safety of medicines. A
guide to detecting and reporting adverse drug reactions.
WHO/EDM/QSM/2002.2. http://www.who.int/medicines
10. The WHO Collaborating Centre for International
Drug Monitoring, Uppsala, Sweden (the Uppsala
Monitoring Centre) www.who-umc.org
11. World Health Organization. Safety monitoring of
medicines. Guidelines for setting up and running a
pharmacovigilance centre. Geneva, 2000. http://
www.who.int/medicines
12. Linquist, A.M. Seeing and observing in international
pharmacovigilance. Uppsala, WHO Collaborating
Centre for International Drug Monitoring, 2003.
13. Van Boxtel, C.J., Santoso, B., Edwards, I.R.
Medicine benefits and risks. In: International Textbook of
Clinical Pharmacology. John Wiley & Sons, Chichester,
2001.
15
Safety and Efficacy Issues
National Centres discuss new
safety monitoring methods
The Twenty-seventh meeting of National Centres
participating in the WHO Programme for Interna-
tional Drug Monitoring took place in Dublin,
Ireland, in October 2004. The meeting focused on
identification of new methods of pharmacovigi-
lance, drug monitoring and reporting with particu-
lar attention to facilitating regulatory action within
the constraints of individual country settings.
Focused surveillance methods (FSMs) provide
information concerning medicines use and
adverse drug reactions (ADRs) but are not
commonly employed in developing countries
beyond the existing spontaneous reporting
systems. However, FSMs have numerous
advantages since they provide specific types of
data (population-specific, gender-specific, etc.)
and identify specific factors needing long-term
follow-up. Additionally, non-serious or rare ADRs
can be captured. The disadvantage of FSMs is
that they tend to be resource intensive and time
consuming. The type of FSM that will work best
will therefore depend on country needs, financial
resources, support systems, and available
knowledge and expertise. Also of relevance would
be the deployment of mass treatment and
immunization programmes, local problems of
counterfeiting, or populations with special charac-
teristics such as rare and neglected diseases.
Reporting data
During the meeting, it was proposed that the
WHO Collaborating Centre for International Drug
Monitoring should develop a user friendly tem-
plate for reporting data from focused surveillance
studies which is flexible and adaptable to each
country’s needs. Additionally, a registry of all FSM
studies carried out by different countries should
be maintained and the information made available
to all national centres. Questions of data owner-
ship and confidentiality were also discussed and it
was agreed that provision and use should follow
clearly defined rules, in particular concerning data
ownership and commercial use.
The importance of registry creation
A registry is defined as a list of patients sharing
the same characteristics. These characteristics
could be a disease (disease registry) or a specific
exposure (drug registry). A registry should involve
a systematic collection of defined events in a
defined population over a defined period
16
WHO Drug Information Vol 19, No. 1, 2005
of time. They should include sufficient information
to enable a search of patient medical records or
linkages with other databases. Different types of
registries exist and may be useful in pharmaco-
epidemiological studies, data linkage analyses,
calculation of incidence rates, and to obtain
information on disease prevalence, drug usage,
off label usages and outcomes in general.
Registries can be developed on vaccine use,
prescription drug utilization data, large public
health programmes, pregnancy exposure
and outcomes including birth defects. Setting up a
registry can be resource intensive and expensive
to maintain so that countries need to be clear
about the objectives and scope of a registry
before launching, including definition of the
population to be covered and variables to be
recorded. It was suggested that a need exists for
developing a master registry as a first step in
bringing together all available registries in
different countries.
Reference: World Health Organization. Report of the
Twenty-seventh Annual Meeting of Representatives of
the National Centres. EDM/QSM/2004.3 available from
http:www.who.int/medicines/
Signalling and safety problems
One of the most important tasks of the WHO
Programme for International Drug Monitoring is to
identify signals of drug safety problems as early
as possible. The WHO database, which is
maintained by the WHO Collaborating Centre for
International Drug Monitoring in Uppsala, Sweden
holds over 3.1 million case reports making it the
largest database of spontaneous ADR reports
from health professionals in the world.
Since 1998, the Collaborating Centre has been
using the Bayesian Confidence Propagation
Neural Network (BCPNN) methodology to identify
unexpectedly strong quantitative associations
between drugs and adverse reactions. The
BCPNN uses a logarithmic measure of
disproportionality called the information compo-
nent (IC) which is based on observed to expected
ratios for the co-occurrence of a drug and ADR in
the database. Using this methodology, the
complete WHO database is screened quarterly
generating a computerized table known as the
combinations database of more than 50 000 drug-
ADR combinations reported the last quarter
(approximately 2000 associations). This compre-
hensive listing of drug-ADR combinations con-
tains no review, filtering or analysis. It is sent
WHO Drug Information Vol 19, No. 1, 2005
every quarter to the national centres (NCs) who
review its international contents for issues of
relevance to their own countries. This signal
detection work by the Collaborating Centre and its
review team is complementary to the work
performed by national centres and not a substi-
tute for local evaluation and decision-making.
Since 2001 these associations have been filtered
further using the following algorithms:
• Rapid reporting increase. The drug-ADR
combination is a new association and the IC has
increased by a set value, for example two or
more, since the previous quarter
• Serious reactions and new drugs. The drug-ADR
combination is a new association and the drug
was first entered into the database in the last
one or two years and the ADR is a WHO-ART
critical term and there are few reports on the
association and there was a fatality in at least
one case.
• Reactions of special interest. Special attention
will be put on important typically drug related
reactions such as: Stevens-Johnson or Lyells
syndrome, agranulocytosis. or rhabdomyolysis.
The filter is IC- independent.
In addition to these algorithms other factors can
be focused on, such as multinational reporting,
since a signal is more credible if the drug-ADR is
reported from several countries. Quality criteria,
such as positive re-challenge cases, can also be
added to the algorithms.
A signal is defined as: Reported information on a
possible causal relationship between an adverse
event and a drug, the relationship being unknown
or incompletely documented previously. Usually
more than a single report is required to generate
a signal, depending upon the seriousness of the
event and the quality of the information.
The filtering process known as the triage is
performed by the staff at the WHO Collaborating
Centre for International Drug Monitoring. How-
ever, the use of sophisticated computer systems
and algorithms cannot replace the unique human
qualities necessary for clinical review. The next
stage in the triage process for the retrieved drug–
ADR combinations is to check for its occurrence
in the available sources of published product
information (Martindale, Physician’s Desk Refer-
ence, Drug Dex and summaries of product
characteristics), to see what is already known and
if the combination should be passed to reviewers
Safety and Efficacy Issues
for in-depth study. For drugs where the reaction is
not found in the literature or fully described,
complete case reports are retrieved from the
WHO database.
The different topics are divided amongst the
members of the international expert review panel,
which consists of 36 consultants from 20 coun-
tries. The reviewers are asked to assess the case
reports using their clinical experience and phar-
macological knowledge. Analysis of potential
signals includes checking the available case data
and making literature searches. After assessing
the cases, including judgment on the causal
strength of the drug-ADR association, the re-
viewer drafts a short report on the assessment
indicating if it is a signal or not and if the issue is
worth notifying to national centres. After review
within the Collaborating Centre, the text of this
report may be included in the publication, SIG-
NAL, for distribution to national centres. It is the
responsibility of the national centre to take action
on the signal raised.
Although whole populations can be covered, most
often drug usage data is collected using sampling
methods and, therefore, in addition to the uncer-
tainties affecting the numerator, generalizability
also depends on the validity of the methods used
in obtaining the denominator information. There
are other reasons why results must be interpreted
cautiously, including the following:
• the numerator and denominator information is
obtained from separate sources, therefore
different biases may apply
• correlational studies refer to populations rather
than individuals, thus it is not possible to link an
exposure to occurrence of an outcome in the
same person.
A cautionary statement is included in a caveat
document which accompanies data released from
the WHO Collaborating Centre.
Third meeting of the
Signal Review Panel
On 13 and 14 December 2004, 25 members of
the Signal Review Panel met together in Uppsala,
Sweden in order to exchange experiences on
their work and to learn how to make best use of
the information in the WHO database. Discus-
sions focused on the balance needed for quickly
finding early signals and having enough quality
data to meet the criteria to determine that the
signal is important for public health.
17
Safety and Efficacy Issues
Quality of reports
The low quality of a large number of reports in the
WHO database is a problem. The BCPNN,
however, is not dependent on the quality of
reports to be able to highlight associations
standing out from the background of the data-
base. Since 2002, the WHO database has been
capable of linking to narratives, but not all national
centres provide such information. The Collaborat-
ing Centre can always ask national centres for
additional information but this may take time and
some centres do not respond. Concerning the
question of whether original reports should be
requested before each signal, some reviewers
think that each case report summary in the WHO
database is a concern and getting external data is
a waste of time since it is the national centre’s
responsibility to investigate the possible drug
safety problem presented in the signal texts.
Others think that one should always go back and
ask for original data as the hypothesis may
otherwise be based on faulty data.
Reporting from national centres
The WHO database contains different types of
reports. Approximately 50 000 new reports are
entered each quarter. The Collaborating Centre
encourages regular reporting, but less than 10
countries send reports once per month; some
countries do not send any reports at all; some
countries send reports in large batches and
nothing in between for long periods. Case reports
can be valued according to whom the sender is; a
report from a specialist is regarded differently to
that of a report from a general practitioner or a
pharmacist. Every report counts, but the reviewer
should weigh/judge them differently. Consumer
reports may be very valuable for certain types of
reactions. At the moment, consumer reports are
part of the background for BCPNN runs and
approximately 20% of all US reports are con-
sumer reports. The Collaborating Centre is
currently investigating the effects of this.
Collaboration
In order for the Collaborating Centre to obtain
high quality narratives there is a need to increase
the collaboration with both national centres and
industry. The work should be complementary to
the national centres work and therefore the
reviewers want to collaborate/work more closely
with national centres. The Collaborating Centre
should aim to involve national centres more and
encourage them to announce when they are
investigating a problem or have discovered a
signal. The closeness of the relationship/collabo-
18
WHO Drug Information Vol 19, No. 1, 2005
ration regarding signal detection with national
centres varies very much. The contact should be
on a personal level, but workload and time are
limiting factors at the national centres.
Education
The pharmacovigilance culture is weak in many
countries. Medical schools should be made aware
of the importance of pharmacovigilance. In some
countries, the deans of medicine do not discuss
drug safety problems in their country. Drugs
banned from the market are still available over-
the-counter. In order to promulgate pharmacovigi-
lance, education could be added to the agenda of
meetings of different groups such as EACPT and
IUPHAR. A clinical harm registry could be devel-
oped in order for the world to know which different
drug safety harms people are working on.
National problems with banned drugs should
always be brought to the attention of WHO.
There should be increased collaboration with
universities, medical schools, health departments,
pharmacoepidemiological groups and acadaemia.
Improving signals
There is no general solution as to how a signal
should be presented. Signals have a different
character, different amount of information and
level of evidence but all are equally important. It is
also important to describe the case reports and
determine why the finder thinks the selected drug-
ADR association should be investigated further.
Even an experienced reviewer can feel uncertain,
therefore feedback from the Collaborating Centre
on the assessments was asked for. The reviewers
were asked to always inform the Collaborating
Centre in each assessment about the level of
evidence used, and motivation for deciding if a
combination/topic is a signal or not or if it should
be included for follow-up. By always writing down
and adding the logic, the conclusion of the
reviewer will become clear and will facilitate the
work of the Collaborating Centre. Reviewers
should always inform the Collaborating Centre
about any problems they may have and if their
current workload prevents them from performing
the review task satisfactorily. If a combination
needs a major investigation, this should be left to
the national centres.
Signals with no change in the literature but
increasing report numbers should be communi-
cated via publications, directly with the national
centres or included in WHO Pharmaceutical
Newsletter. Single country signals are sometimes
important to include in the SIGNAL document
WHO Drug Information Vol 19, No. 1, 2005
since other countries need to know of the prob-
lem. For high reporting rates the responsible
national centre should be requested at an early
stage prior to signalling for a possible reason
behind increased reporting. Ideally, original case
reports should be requested before sending any
cases to reviewers but this would be too time
consuming. Therefore, it was suggested that
original data could be requested at least for
potential signals when reviewer has made first
assessment. All kinds of signals are allowed. For
brief and quick signals the importance of the
earliness due to the topic should be clearly stated.
In conclusion, the Collaborating Centre will
increase the feedback to reviewers on the written
assessments. Since signals have different
character, different amount of information and
level of evidence but all are equally important, all
kinds of signals will be allowed. The Collaborating
Centre should always be informed about the level
of evidence used in the assessment.
Wider audience of signals
Formally, the task of the Collaborating Centre and
reviewer stops when the signal reaches the
national centre, but the SIGNAL document should
not be the end of a combination. National centres
take over in a sense, but the continuation of an
investigation of a possible drug safety hazard is
important. It is the right of each national centre to
use the information in any way they see fit.
National centres could publish translated signals
in national drug bulletins. Reviewers could help by
informing the Collaborating Centre when they
think some signal is worth publishing externally.
WHO encourages the publication of signals in
order to reach a larger audience.
It is the right of each national centre to use the
information generated within the WHO Interna-
tional Drug Monitoring Programme in any way
they see fit. A larger audience could be reached
by publishing more signals. It was re-emphasized
that the three statements of the caveat document
always must be included in all external publica-
tions, i.e. the source of the information; that the
information is not homogenous, at least with
respect to origin or likelihood that the pharma-
ceuticala product caused the adverse reaction;
and that the information does not represent the
opinion of the World health organization.
Re-signalling
The panel discussed the importance of following
up signals after they have been presented in
SIGNAL as well as the importance of follow-up of
Safety and Efficacy Issues
associations of possible interest having, at the
time, too small amount of data to assess. It was
agreed that a follow-up of all previous signals
should be conducted by checking the changes in
reporting and IC to determine developments, but
literature should only be checked when there is
an increase in reporting. When re-signalling, the
reporting should ideally be linked to the usage of
the drug. All methods of promoting and publishing
signals should be explored.
COX-2 inhibitors: overview
On 30 September 2004, Merck & Co., Inc.
announced a voluntary withdrawal of rofecoxib
(Vioxx®) from the worldwide market due to safety
concerns of an increased risk of cardiovascular
events (including heart attack and stroke) in
patients on rofecoxib. Rofecoxib is a prescription
cyclooxygenase-2 (COX-2) selective, nonsteroidal
anti-inflammatory drug (NSAID) approved by the
US Food and Drug Administration (FDA) in May
1999 for the relief of the signs and symptoms of
osteoarthritis, for the management of acute pain
in adults, and for the treatment of menstrual
symptoms. It was later approved for the relief of
the signs and symptoms of rheumatoid arthritis in
adults and children.
The manufacturer withdrew rofecoxib (Vioxx®)
from the market following recommendations of the
data safety monitoring board overseeing a long-
term study in patients at risk of developing
recurrent colon polyps (1). This study was halted
following an increased risk of serious cardiovas-
cular events, including heart attacks and strokes,
among study patients taking rofecoxib compared
with patients receiving placebo.
Market withdrawal of rofecoxib comes more than
five years after its launch. More than 80 million
patients have used this medicine, with annual
sales topping US$ 2.5 billion.
The first trial to show an association of COX-2
inhibitors with cardiovascular events was the
Vioxx Gastrointestinal Outcomes Research
(VIGOR) study in 2000 in which 0.4% of the
rofecoxib group and 0.1% of the naproxen group
developed myocardial infarction (2). This result
was extended by a between-study comparison
(3). The comparison, which included celecoxib
and rofecoxib, implicated both medicines as being
associated with a significantly higher rate of
myocardial infarction than placebo. The authors
postulated that COX-2 inhibitors may have a
prothrombotic effect through inhibition of prosta-
19
Safety and Efficacy Issues
cyclin and concluded that ‘it is mandatory to
conduct a trial specifically assessing cardiovascu-
lar risk and benefit of these agents’.
Such a specific trial, however, was never con-
ducted. While the world debates whether the
rofecoxib story deserves a full congressional
review, it is timely to focus on the importance of
post-marketing adverse drug reaction (ADR)
reporting and to evaluate the ‘signal’ generating
capabilities of the WHO global ADR database
which is accessible to 86 member countries (See
pages 13–18).
The risk of cardiovascular adverse reactions and
rofecoxib was discussed in early November 2000,
at the 23rd Annual Meeting of National Centres in
the WHO Programme for International Drug
Monitoring. It was pointed out that within 10
months of its introduction in 2000, there had been
eight reports of cardiovascular problems with four
fatalities associated with rofecoxib use in the
Netherlands; all four cases occurred within four
days of commencing therapy and one case
occurred two hours after taking the first tablet. It
also came to light that there had been one report
of a fatality in Malaysia, three reports of cardiac
failure in Australia and a total of five reports with
various cardiovascular events in Portugal.
COX-2 inhibitors and cardiovascular events were
also discussed during the 25th and 27th Annual
National Centre Meetings. Data from the New
Zealand Intensive Medicines Monitoring Pro-
gramme (IMMP) database demonstrated a higher
proportion of prothrombotic events and a shorter
time to onset of death associated with the use of
COX-2 inhibitors than with comparator drugs (that
is, all other drugs in the IMMP cohorts for the
proportion of prothrombotic events and versus
omeprazole in the survival analysis). The only
identifiable difference to explain the shorter
survival was the higher rate of myocardial infarc-
tion and stroke. A cohort of 32 630 patients on
celecoxib (mean age 63 years) and 26 666 on
rofecoxib (mean age 58 years) was reviewed;
ischaemic heart disease was the fourth most
common type of event reported for celecoxib and
rofecoxib. Of note, there was no difference in rate
between the two but celecoxib had twice the rate
of cardiac dysrhythmias. Deaths were most
commonly represented in the cardiovascular
system organ classification for celecoxib and the
second most common for rofecoxib.
The WHO Collaborating Centre for International
Drug Monitoring uses the BCPNN (Bayesian
20
WHO Drug Information Vol 19, No. 1, 2005
Confidence Propagation Neural Network) data
mining method, to assess disproportionality of a
specific ADR-drug combination against the ADR
distribution for all drugs in the global ADR data-
base. Of interest is an analysis (4) using the
BCPNN method comparing the renal-related
adverse drug reactions between rofecoxib and
celecoxib, based on ADR reports in the WHO
global database at the end of the second quarter
of 2000. They concluded that rofecoxib had
greater renal toxicity than celecoxib and other
traditional NSAIDs; and that this negative renal
impact may have the potential to increase the risk
for serious cardiac and/or cerebrovascular events.
A similar analysis of the WHO global database for
celecoxib has also shown an association of
myocardial infarction with celecoxib use (5).
Results of analyses are transmitted to the parties
concerned for feedback. Sulfonamide reaction
terms were reported significantly more frequently
with celecoxib compared to rofecoxib in the WHO
database (overall sulfonamide relative reporting
rate 1.8, 95% CI 1.6-1.9) (6). Amongst these type
of reactions, fatal reactions were reported 80%
more often (relative reporting rate 1.8, 95% CI
0.9-4.0). These observations, as well as the
recent experience with rofecoxib should caution
us against dismissing the findings with celecoxib,
particularly amidst concerns that the cardiovascu-
lar effects of rofecoxib may be a class effect,
applicable to all COX-2 selective inhibitors (6, 7).
Extracted from Drugs of Current Interest, WHO
Pharmaceutical Newsletter, Number 5, 2004 on http://
www.who.int/medicines/
References
1. Merck & Co Press Release, 30 September 2004.
Available at http://www.merck.com
2. Bombardier, C., Laine, L., Reicin, A. et al. Compari-
son of upper gastrointestinal toxicity of rofecoxib and
naproxen in patients with rheumatoid arthritis. New
England Journal of Medicine, 343: 1520–1528 ( 2000).
3. Mukherjee, D., Nissen, S.E., Topol, E.J. Risk of
cardiovascular events associated with selective COX-2
inhibitors. Journal of the American Medical Association,
286: 954–959 (2001).
4. Zhao, S.Z., Reynolds, M.W., Lejkowith, J. et al. A
comparison of renal-related adverse drug reactions
between rofecoxib and celecoxib, based on the World
Health Organization/Uppsala Monitoring Centre safety
database. Clinical Therapeutics, 23(9): 1478–1491
(2001).
WHO Drug Information Vol 19, No. 1, 2005
5. ‘Signal’ 2001-09. WHO Collaborating Centre for
International Drug Monitoring at http://www.who-
umc.org.
6. Wiholm, B.E. Identification of sulfonamide-like
adverse reactions to celecoxib in the World Health
Organization database. Current Medical Research
Opinion, 17(3): 210–216 (2001).
7. Editorial. Lessons from the withdrawal of rofecoxib.
British Medical Journal, 329: 867–868 (2004).
8. Press Release. EMEA to review COX-2 inhibitors.
http://www.emea.eu.int, 22 October 2004, EMEA/
117908/2004.
Telithromycin and warfarin:
suspected interaction
Telithromycin (Ketek®) is a novel antimicrobial
that belongs to a new chemical family, the
ketolides (1). Ketolides are recent additions to the
macrolide-lincosamide streptogramin class and
are designed to treat macrolide-resistant respira-
tory tract pathogens (2, 3). The Ketek® product
monograph states that, in a study involving
healthy volunteers, there were no pharmacody-
namic or pharmacokinetic effects on racemic
warfarin (1).
From 29 May 2003 (the date of marketing in
Canada) to 15 September 2004, Health Canada
received 25 reports of suspected adverse reac-
tions involving telithromycin. Telithromycin is
metabolized by cytochrome P450 3A4 (CYP3A4)
and to a lesser extent by cytochrome P450 1A
(CYP1A) (1). Warfarin exists as a racemic mixture
of R- and S-warfarin. The S-isomer, metabolized
by CYP2C9, is primarily responsible for the
hypoprothrombinaemic activity. The R-isomer,
metabolized by CYP1A2 or CYP3A4, is less
pharmacologically active than the S-isomer, but
significant drug interactions have resulted from
inhibition of its metabolism (2, 4). Telithromycin is
a substrate and inhibitor of CYP3A4. Its concen-
trations may be increased with concomitant
administration of CYP3A4 inhibitors (e.g., ketoco-
nazole), and telithromycin will increase the
concentrations of other drugs metabolized by
CYP3A4 (5). Antibiotics have been reported to
decrease the intestinal flora that produce vitamin
K, reduced concentrations of which impair
prothrombin production. Also, genetics, age, diet
(e.g., vegetables rich in vitamin K), fever, stress
and concomitant medication could modify the
metabolism of warfarin and affect the intensity of
the resulting interaction (6).
Safety and Efficacy Issues
Although it has been stated that telithromycin
does not interact with warfarin, (1, 7) the pro-
thrombin time and INR should be monitored
closely, (2) especially in elderly patients, as
should be the case whenever a new drug is
started in a patient taking warfarin.
Extracted from Canadian Adverse Reaction
Newsletter, Volume 15, Issue 1, January 2005.
References
1. Ketek (telithromycin) [product monograph]. Laval:
Aventis Pharma Inc.; 2003.
2. Kolilekas, L., Anagnostopoulos, G.K., Lampaditis, I. et
al. Potential interaction between telithromycin and
warfarin. Annals of Pharmacotherapy, 38(9):1424–
1427(2004)
3. Zuckerman, J.M. Macrolides and ketolides: azithro-
mycin, clarithromycin, telithromycin. Infectious Diseases
Clinics of North America, 18(3 ): 621–649 (2004).
4. Michalets, E.L. Update: clinically significant cyto-
chrome P-450 drug interactions. Pharmacotherapy,
18(1): 84–112 (1998).
5. Bearden, D.T., Neuhauser, M.M., Garey, K.W.
Telithromycin: an oral ketolide for respiratory infections.
Pharmacotherapy, 21(10): 1204–1222 (2001).
6. Lauzon, M. Place aux questions: Quels antibiotiques
devraient-on éviter lors de la prise de la warfarine?
Québec Pharmacie, 51(4): 302–304 (2004).
7. Fish, D.N. Telithromycin: a viewpoint by Douglas N.
Fish. Drugs, 64(15):1695–1696 (2004).
Penicillin: information strengthened
The manufacturer of penicillin G benzathine and
penicillin G procaine (Bicillin®) products has
advised of important labelling changes to ensure
that these products are used and administered
appropriately.
Penicillin G benzathine injectable suspension is
the only currently approved penicillin G benza-
thine product indicated for use in sexually trans-
mitted infections, including syphilis. Conversely,
penicillin G benzathine and penicillin G procaine
injectable suspension, which consists of a
combination of penicillin G benzathine and
penicillin G procaine in an injectable suspension,
should not be used for the treatment of syphilis.
The Centers for Disease Control (CDC) 2002
Sexually Transmitted Diseases Treatment
21
Safety and Efficacy Issues
Guidelines (1) recommend penicillin G benzathine
for the treatment of syphilis infection. However,
postmarketing reports from multiple STD clinics in
the US show that Bicillin® C-R has been inappro-
priately used to treat patients infected with
syphilis. Bicillin® L-A is the only currently ap-
proved penicillin G benzathine product indicated
for the treatment of syphilis
Reference: Communication from King Pharmaceuticals,
Inc. December 10, 2004 available at http://www.fda.gov/
medwatch
Linezolid and neuropathy
Linezolid (Zyvoxam®), a synthetic antibacterial
agent in a new class of antibiotics, the oxa-
zolidinones, has been marketed in Canada since
2001 (1). Linezolid is active against methicillin-
and vancomycin-resistant Gram-positive micro-
organisms (2).
The safety and efficacy of linezolid given for
longer than 28 days has not been evaluated in
controlled clinical trials (1). Dosage and adminis-
tration guidelines recommend that treatment lasts
no more than 28 consecutive days (1) but in view
of its activity against resistant organisms, linezolid
has been used in clinical practice for longer than
the recommended treatment course (2). The long-
term use of linezolid has been associated with
severe peripheral and optic neuropathy (2–4). In
most cases, the optic neuropathy resolved after
stopping the drug, but the peripheral neuropathy
did not (4).
Neuropathy (peripheral or optic) has rarely been
reported in patients treated with linezolid and has
primarily occurred in patients treated for more
than the maximum recommended duration of 28
days. Myelosuppression including anaemia is
listed in the product monograph under warnings
and postmarketing experience (1). Pure red-cell
aplasia is not listed in the product monograph.
Health care professionals should be aware of the
potential for adverse reactions when linezolid is
used beyond its recommended duration (2).
Extracted from Canadian Adverse Reaction
Newsletter, Volume 15, Issue 1, January 2005.
References
1. Zyvoxam (linezolid) [product monograph].
Mississauga (ON): Pharmacia Canada Inc; 2002.
2. Rho, J.P., Sia, I.G., Crum, B.A. et al. Linezolid-
associated peripheral neuropathy. Mayo Clinic Proceed-
ings, 79(7): 927–930 (2004).
22
WHO Drug Information Vol 19, No. 1, 2005
3. Lee, E., Burger, S., Shah, J. et al. Linezolid-associ-
ated toxic optic neuropathy: a report of 2 cases. Clinical
Infectious Disease, 37(10): 1389–1391 (2003).
4. Bressler, A.M., Zimmer, S.M., Gilmore, J.L. et al.
Peripheral neuropathy associated with prolonged use of
linezolid. Lancet Infectious Diseases, 4(8): 528–531
(2004).
Ceftriaxone and immune
haemolytic anaemia in children
Ceftriaxone (Rocephin®), marketed in Canada
since 31 December 1987, is a third-generation
cefalosporin indicated for the treatment of suscep-
tible strains of bacteria, as well as for prophylaxis
against infections in patients undergoing hyster-
ectomy, coronary artery bypass surgery or biliary
tract surgery (1). Immune haemolytic anaemia
(IHA) is a hypersensitivity adverse reaction (AR)
known to occur in adults and children. The
Rocephin® product monograph describes
autoimmune haemolytic anaemia as a rare AR (<
0.1% of cases), (1) but does not mention IHA.
Ceftriaxone antibodies appear to be induced by
an immune complex mechanism during a sen-
sitization phase after initial exposure to the drug
(2). Intravascular haemolysis may be triggered
after subsequent re-exposure. The signs and
symptoms of drug-induced IHA include severe
haemolytic anaemia, haemoglobinuria, hypoten-
sion, acute renal failure, fever and back pain (3).
Health Canada has received 1 report of acute
haemolysis suspected of being associated with
ceftriaxone. A young child with sickle cell disease
had been given a single dose of ceftriaxone (80
mg/kg body weight) intravenously for fever and
cough, and within 30 minutes developed a rash,
pallor and decreased level of consciousness.
Laboratory examination showed a positive direct
Coomb’s test result, a haemoglobin level of 7 g/L
(the pre-infusion level was 110 g/L) and haemo-
lysed red blood cells. The following day, the
patient died despite resuscitation attempts. The
only concomitant medication was a single oral
dose of erythromycin. The patient had been
exposed to ceftriaxone in the past.
Nine paediatric cases of IHA associated with
exposure to ceftriaxone were identified in the
literature, 6 of which were fatal (4–12). One child
with sickle cell anaemia received ceftriaxone on
several occasions and experienced 6 episodes of
unexplained transient haemoglobinuria before the
onset of the IHA (10).
WHO Drug Information Vol 19, No. 1, 2005
Drug-induced IHA is associated with a high
mortality rate (3). Other than supportive care and
red blood cell transfusion, there are few effective
treatment options. Reintroduction of the drug is
contraindicated because of the high risk of
recurrence of haemolysis, which is often more
severe (3).
IHA associated with ceftriaxone is rare and has
been reported to occur with repetitive, intermittent
use of this drug. Children with underlying condi-
tions such as haemoglobinopathies and immuno-
deficiencies are likely to require frequent treat-
ment or prophylaxis with ceftriaxone, which may
place them at increased risk of IHA. The develop-
ment of signs and symptoms of IHA, including
haemoglobinuria or unexplained anaemia, should
prompt health care professionals to consider this
diagnosis and the discontinuation of the suspect
drug (3).
Extracted from Canadian Adverse Reaction
Newsletter, Volume 15, Issue 1, January 2005.
References
1. Rocephin (ceftriaxone) [product monograph].
Mississauga (ON): Hoffman-La Roche Limited; 1997.
2. Arndt, P.A., Leger R.M., Garratty, G. Serology of
antibodies to second- and third-generation cefalosporin
associated with immune haemolytic anaemia and/or
positive direct antiglobulin tests. Transfusion, 39(11–12):
1239–1246 (1999).
3. Solal-Celigny, P. Abnormal hematologic values. In:
Benichou C, editor. Adverse drug reactions. A practical
guide to diagnosis and management. Chichester: John
Wiley and Sons Ltd.; 1994. pp. 13-30.
4. Mattis, L.E., Saavedra, J.M., Shan, H. et al. Life-
threatening ceftriaxone-induced immune hemolytic
anemia in a child with Crohn’s disease. Clinical
Pediatrics (Phila), 43(2): 175–178 (2004).
5. Citak, A., Garratty, G., Ucsel, R. et al. Ceftriaxone-
induced haemolytic anaemia in a child with no immune
deficiency or haematological disease. Journal of
Paediatric Child Health, 38(2): 209–210 (2002).
6. Viner, Y., Hashkes, P.J., Yakubova, R. et al. Severe
hemolysis induced by ceftriaxone in a child with sickle-
cell anemia. Pediatric Infectious Diseases Journal,
19(1): 83–85 (2000).
7. Meyer, O., Hackstein, H., Hoppe, B. et al. Fatal
immune haemolysis due to a degradation product of
ceftriaxone. British Journal of Haematology, 105(4):
1084–1085 (1999).
Safety and Efficacy Issues
8. Scimeca, P.G., Weinblatt, M.E., Boxer, R. Hemolysis
after treatment with ceftriaxone. Journal of Pediatrics,
128(1): 163 (1996).
9. Moallem HJ, Garratty G, Wakeham M, Dial S,
Oligario A, Gondi A, et al. Ceftriaxone-related fatal
hemolysis in an adolescent with perinatally acquired
human immunodeficiency virus infection. Journal of
Pediatrics, 133(2): 279–281 (1998).
10. Bernini, J.C., Mustafa, M.M., Sutor, L.J. et al. Fatal
hemolysis induced by ceftriaxone in a child with sickle
cell anemia. Journal of Pediatrics, 126(5 Pt 1): 813–815
(1995).
11. Lascari, A.D., Amyot, K. Fatal hemolysis caused by
ceftriaxone. Journal of Pediatrics, 126(5 Pt 1): 816–817
(1995).
12. Borgna-Pignatti, C., Bezzi, T.M., Reverberi, R. Fatal
ceftriaxone-induced hemolysis in a child with acquired
immunodeficiency syndrome. Pediatric Infectious
Diseases Journal, 14(12): 1116–1117 (1995).
Ethinylestradiol/cyproterone:
increased risk of thrombosis
The Norwegian Medicines Control Agency
(NMCA) has issued a reminder that ethinylestra-
diol/cyproterone (Diane®) is associated with an
increased risk of thrombosis. The NMCA has
received 26 reports of adverse reactions associ-
ated with ethinylestradiol/ cyproterone, including
15 of venous thrombosis, two of which were fatal.
They note that ethinylestradiol/ cyproterone
should be used with the same caution as oral
contraceptives, and should not be used in women
with known risk factors for thrombosis, such as
smoking, obesity and a personal or family history
of thrombosis.
Reference: Nytt om Legemidler, 11 August 2004.
Available at http://www. legemiddelverket.no
Influenza virus vaccine: interactions
Prescribers are advised to be alert for signs of
toxicity following influenza vaccination in patients
receiving anti-epileptic drugs or warfarin.
Medsafe, New Zealand, notes that, in addition to
published reports of warfarin, phenytoin and
theophylline toxicity following influenza vaccina-
tion, a report of carbamazepine toxicity has been
received by the Australian Adverse Drug Reac-
tions Advisory Committee, and a report of
elevated international normalized ratio (INR) in a
patient receiving warfarin has been received by
the Centre for Adverse Reactions Monitoring,
both following influenza vaccination. It is sug-
23
Safety and Efficacy Issues
gested that inhibition of cytochrome P450 3A4
may be involved in these interactions, and
prescribers are advised to watch for toxicity in
patients receiving drugs metabolized by this
enzyme.
Reference: Prescriber Update 25(2), November 2004.
Rosiglitazone and pioglitazone:
dangers of off-label use
Rosiglitazone and pioglitazone are contraindi-
cated in combination with insulin and in patients
with cardiac failure or a history of cardiac failure
Evidence from United Kingdom reports and usage
data indicate that rosiglitazone and pioglitazone
are being prescribed in combination with insulin,
despite this being a contraindication for both
products.
These data also indicate that thiazolidinediones
are being prescribed in patients with cardiac
failure, which is a contraindication with rosigli-
tazone and pioglitazone. This off-label use of
glitazones may be causing or aggravating cardiac
failure.
Diabetes is in itself a strong risk factor for conges-
tive heart failure (CHF) (1). Since 2000, approxi-
mately 120 000 patients have received a prescrip-
tion for rosiglitazone and 33 000 patients for
pioglitazone in the United Kingdom (2). Seven
spontaneous reports of cardiac failure or oedema
or both in patients receiving either rosiglitazone or
pioglitazone in combination with insulin have been
received. In addition, 12 reports of aggravated
cardiac failure in association with the use of these
agents have been received. Due to higher levels
of patient exposure, rosiglitazone has been
associated with the greatest number of spontane-
ous reports.
Prescribers are reminded that rosiglitazone and
pioglitazone should not be used:
• In patients with cardiac failure or a history of
cardiac failure (NYHA stages I to IV).
• In combination with insulin.
Extracted from: Committee on Safety of Medi-
cines, Current Problems in Pharmacovigilance,
Volume 30, October 2004.
References:
1. Nesto, R.W. Circulation, 2941–2948 (2003).
2. DIN-LINK, CompuFile Ltd, May 2004.
24
WHO Drug Information Vol 19, No. 1, 2005
Naproxen and celecoxib suspended
in Alzheimer prevention trial
The National Institutes of Health (NIH) has
announced that investigators have suspended the
use of two drugs, naproxen (220 mg twice a day)
and celecoxib (200 mg twice a day), in a large,
three-arm, national Alzheimer disease prevention
trial sponsored by the National Institute on Aging
(NIA), a part of the NIH. The trial, called the
Alzheimer Disease Anti-Inflammatory Prevention
Trial (or ADAPT) was designed to assess the
potential benefit of long-term use of nonsteroidal
anti-inflammatory drugs (NSAIDs) — naproxen
(Aleve®) and the COX-2 inhibitor celecoxib
(Celebrex® ) in decreasing the risk of developing
Alzheimer disease in people 70 years of age or
older who were considered to be at increased risk
because of family history, but did not have
symptoms of the disease.
Approximately 2400 volunteer participants were
randomly assigned to receive naproxen,
celecoxib, or placebo for periods of time up to
three years. Although no significant increase in
risk for celecoxib was found in this trial, the use of
these drugs in the study was suspended in part
because of findings reported last week from a
National Cancer Institute (NCI) trial to test the
effectiveness of celecoxib in preventing colon
cancer. In addition, however, data from the
ADAPT trial indicated an apparent increase in
cardiovascular and cerebrovascular events
among the participants taking naproxen when
compared with those on placebo.
The ADAPT trial began in 2001 and was con-
ducted at six sites across the USA. Investigators
and NIH scientists will continue to review this and
other studies. The cancer prevention trials and
the ADAPT study are among the first long-term,
clinical trials to test these classes of drugs. These
studies are examining these compounds for uses
very different from the uses for which these
medications are currently approved.
Reference: NIH News, 20 December 2004. http://
www.nih.gov
Heparin contraindicated in
severe renal impairment
Monitoring anti-factor Xa activity may be helpful in
patients receiving low molecular weight heparins
(LMWH) who are at risk of bleeding or are actively
bleeding.
WHO Drug Information Vol 19, No. 1, 2005
Bemiparin, certoparin, dalteparin, enoxaparin,
reviparin and tinzaparin are LMWHs. Some are
indicated for the prevention of venous throm-
boembolism and some are indicated for the
treatment of deep venous thrombosis, pulmonary
embolism, unstable coronary artery disease and
for the prevention of clotting in extracorporeal
circuits.
Prescribers are reminded of the need to refer to
individual product information regarding indica-
tions, cautions, appropriate dose-adjustment and
contraindications in patients with risk factors for
bleeding, such as renal or hepatic impairment.
Severe renal impairment is a contraindication for
use of reviparin and certoparin, whereas caution
is advised for dalteparin and bemiparin and dose
reduction should be considered for tinzaparin.
The Marketing Authorization holder for enoxaparin
has issued new prescribing advice on dose
reduction in severe renal failure. Careful clinical
monitoring is advised for mild/moderate renal
impairment. Anti-Factor Xa monitoring is not
normally required, but may be considered in those
patients treated with LMWH who also have either
an increased risk of bleeding (such as those with
renal impairment, elderly and extremes of weight)
or are actively bleeding.
Reference: Committee on Safety of Medicines. Current
Problems in Pharmacovigilance, 30. 10 (2004).
Flucloxacillin: serious hepatic
disorders
Flucloxacillin treatment is very rarely associated
with an increased risk of hepatic disorders,
namely, hepatitis and cholestatic jaundice. In
some patients, almost always those with serious
underlying disease, these adverse reactions have
been fatal.
The United Kingdom Committee on Safety of
Medicines (CSM) has previously advised that:
• The onset of hepatic reactions may be delayed
for several weeks (up to 2 months) after treat-
ment with flucloxacillin has stopped.
• These reactions are related neither to the dose
nor to the route of administration of flucloxacillin.
• Risk factors include treatment for more than two
weeks and increasing age.
Prescribers are reminded that:
Safety and Efficacy Issues
• Flucloxacillin should not be used in patients with
a history of flucloxacillin-associated jaundice or
hepatic dysfunction.
• Flucloxacillin should be used with caution in
patients with evidence of hepatic dysfunction.
• Careful enquiry should be made concerning
previous hypersensitivity reactions to ß-lactams.
Extracted from: Committee on Safety of Medi-
cines, Current Problems in Pharmacovigilance,
Volume 30, October 2004.
Reference
1. Committee on Safety of Medicines Current Problems
in Pharmacovigilance, 35: 2. (1992).
Bevacizumab and arterial
thromboembolic events
The manufacturer of bevacizumab (Avastin®) has
drawn attention to an increased risk of arterial
thromboembolic events associated with the use of
bevacizumab in combination with chemotherapy.
These events included cerebral infarction,
transient ischemic attacks (TIAs), myocardial
infarctions (MI), angina, and a variety of other
arterial thromboembolic events. Some of these
events were fatal.
The risk of these events should be viewed in the
context of bevacizumab’s ability to improve over-
all survival in patients with metastatic colorectal
cancer (median survival 20.3 vs.15.6 months).
Bevacizumab should be discontinued in patients
developing severe arterial thromboembolic events
during treatment.
In randomized, active-controlled studies, the
overall incidence of arterial thromboembolic
events was increased with the use of beva-
cizumab in combination with chemotherapy. The
incidences of both cerebrovascular arterial events
and cardiovascular arterial events were in-
creased. In addition, there was a correlation
between age (65 years and over) and the in-
crease in risk of thromboembolic events.
The clinical benefit of bevacizumab, as measured
by survival in the two principal arms, was seen in
all subgroups tested. The subgroups examined
were based on age, sex, race, ECOG perform-
ance status, location of primary tumour, prior
adjuvant therapy, number of metastatic sites, and
tumour burden.
25
Safety and Efficacy Issues
Reference: Communication from Genentech on http://
www..fda.gov/medwatch/ 5 January 2005.
Amiodarone toxicity concerns
The US Food and Drug Administration (FDA) has
required pharmacists and other health care
professionals who dispense medication to
distribute Medication Guides to patients for
certain products, including amiodarone tablets.
Amiodarone HCl (Cordarone®) is intended for use
only in patients with indicated life-threatening
arrhythmias because its use is accompanied by
substantial toxicity. Amiodarone has several
potentially fatal toxicities, the most important of
which is pulmonary toxicity (hypersensitivity
pneumonitis or interstitial/alveolar pneumonitis)
that has resulted in clinically manifest disease at
rates as high as 10 to 17% in some series of
patients with ventricular arrhythmias given doses
around 400 mg/day, and as abnormal diffusion
capacity without symptoms in a much higher
percentage of patients. Pulmonary toxicity has
been fatal about 10% of the time.
Liver injury is common with amiodarone, but is
usually mild and evidenced only by abnormal liver
enzymes. Overt liver disease can occur, however,
and has been fatal in a few cases. Like other
antiarrhythmics, amiodarone can exacerbate the
arrhythmia. Although the frequency of such
proarrhythmic events does not appear greater
than with many other agents used in this popula-
tion, the effects are prolonged when they occur.
Even in patients at high risk of arrhythmic death,
in whom the toxicity of amiodarone is an accept-
able risk, amiodarone poses major management
problems that could be life-threatening in a
population at risk.
Patients with the indicated arrhythmias must be
hospitalized while the loading dose of amiodarone
is given, and a response generally requires at
least one week, usually two or more. Because
absorption and elimination are variable, mainte-
Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and unex-
pected adverse drug reactions. A signal is defined as "reported information on a possible causal
relationship between an adverse event and a drug, the relationship being unknown or incompletely
documented previously. Usually, more than a single report is required to generate a signal, depend-
ing upon the seriousness of the event and the quality of the information". All signals must be vali-
dated before any regulatory decision can be made.
26
WHO Drug Information Vol 19, No. 1, 2005
nance-dose selection is difficult, and it is not
unusual to require dosage decrease or discon-
tinuation of treatment. Attempts to substitute other
antiarrhythmic agents when amiodarone must be
stopped will be made difficult by the gradually, but
unpredictably, changing amiodarone body burden.
A similar problem exists when amiodarone is not
effective; it still poses the risk of an interaction
with whatever subsequent treatment is tried.
Reference: Communication from Wyeth dated 30
December 2004 on http://www.wyeth.com. and http://
www..fda.gov/medwatch/
Darbepoetin alfa:
adverse outcomes
Darbepoetin alfa (Aranesp®) is indicated for the
treatment of chemotherapy-induced anaemia in
patients with nonmyeloid malignancies. The
manufacturer has updated the safety information
to reflect results from two recent investigational
studies with other erythropoietic products, epoetin
alfa and epoetin beta conducted outside the USA,
where patients with cancer were treated to higher
haemoglobin target levels beyond the correction
of anaemia in those patients. These studies
permitted or required dosing to achieve haemo-
globin levels of greater than 12 grams per
deciliter. An increased frequency of adverse
patient outcomes, including increased mortality
and thrombotic vascular events were reported in
these studies.
The prescribing information of darbepoetin alfa
has been revised to include a warning for throm-
botic events and increased mortality and the
precautions to include tumour growth factor
potential. The manufacturer continues to recom-
mend that target haemoglobin should not exceed
12 grams per deciliter in men or women as
indicated in the prescribing information.
Reference: Communication from Amgen on http://
www.amgen.com and the Medwatch website at http://
www.fda.gov/medwatch. 11 January 2005.
WHO Drug Information Vol 19, No. 1, 2005
Vaccines and Biomedicines
Latest developments in
biological standardization
The WHO Expert Committee on Biological
Standardization met in Geneva from 15 to 18
November 2004 to establish biological reference
standards (International Standards), guidance on
production and quality control of biological
products, and to develop international scientific
consensus on quality, safety and efficacy issues.
The following summary provides an overview of
the decisions made by the Committee. A full
report of the meeting is in preparation and will be
published in the WHO Technical Report Series. In
the meantime, pre-publication versions of the
documents have been posted onto the WHO
website to provide early notice of their content
(www.who.int/biologicals).
International Reference Standards
A list of new or replacement reference standards
is given in Table 1 overleaf.
Recommendations and guidelines
The Committee recommended establishment of
the following two documents:
Guidelines on the production and quality
control of candidate live tetravalent
attenuated dengue vaccines
The guidelines were developed in response to
interest from many countries. The scope of the
guideline covers candidate live attenuated
tetravalent dengue vaccines with active clinical
trials in progress. Extensive testing has been
conducted to define the attenuation phenotype for
each of the vaccine candidates. Vaccine formula-
tions are being developed based on the optimal
degree of attenuation and immunogenicity.
Another type of vaccine candidate has been
generated from molecular clones of each of the
four dengue virus serotypes. In addition, chimeric
vaccine candidates are being prepared for clinical
development. A combination tetravalent vaccine
is currently under development which will have all
four dengue serotypes, represented as chimeric
dengue-yellow fever vaccines.
Issues that were considered included specifica-
tions for:
• Vaccines developed in Vero cells, in primary dog
kidney cells and in fetal rhesus lung diploid
cells.
• Plaque or focus-forming assay specified for
infectivity determinations in a tetravalent
mixture. Since candidate titration standards do
not exist at present, WHO was advised to
consider developing such reagents and their
subsequent characterization by international
collaborative study.
• Stability study programmes to determine the
thermal stability of the tetravalent final freeze-
dried product and the stability of the liquid
vaccine after reconstitution. It was noted that in
some countries stability testing of intermediates
is required. WHO was requested to develop
further guidance on this issue.
• An accelerated degradation test to each new
batch of vaccine to show the consistency of
manufacture of the final stabilized formulation.
• Vectored vaccines where reference to general
WHO principles for vaccines for human use
derived by molecular methods, that are under
development, should be considered.
• Nonclinical testing of candidate dengue vaccines
where in addition to the conventional proce-
dures the issue of antibody-mediated disease
enhancement should be addressed.
During discussion, the Committee emphasized
that these guidelines cover only candidate
vaccines since, so far, no vaccine has been
licensed.
Recommendations for the preparation,
characterization and establishment
of international and other biological
reference standards (revision)
Biological reference standards form the basis of
regulation and clinical dosing for biological
medicines, and also for regulation of in vitro
diagnostic devices. The process whereby such
27
Vaccines and Biomedicines WHO Drug Information Vol 19, No. 1, 2005

international biological reference standards are
established and the technical specifications to
which they comply are set out in a written stand-
ard, which is intended to be scientific and advi-
sory in nature.
WHO has worked with the scientific community,
national regulatory authorities, other standards
setting bodies and users through a series of
consultations to review the scientific basis of
characterization of biological reference materials.
As a result, the concepts used by WHO for
biological standardization have been re-affirmed
as appropriate to ensure the continued usefulness
of this class of reference materials. During the
consultation process it was recognized that
improved clarity in explaining the rationale for the
principles used by WHO in biological standardiza-

Table 1. New or Replacement Standards established by the Committee.

Additions

Antigens and related substances

Poliomyelitis vaccine, oral
7.51 log10 TCID50/ml poliovirus Second International Standard
type 1 2004
6.51 log10 TCID50/ml poliovirus
type 2
6.87 log10 TCID50/ml poliovirus
type 3
7.66 log10 TCID50/ml total
poliovirus content

Pertussis serotype 2, No assigned value First Reference Reagent 2004

typing serum
Pertussis serotype 3, No assigned value First Reference Reagent 2004
typing serum

Blood products and related substances

Anti-D blood grouping No assigned value First International Standard
reagents (monoclonal)
2004
Factor V Leiden, human No assigned value First International Genetic
Reference Panel 2004
Factor XIII, plasma, human 0.91 IU/ampoule First International Standard
2004
Immunoglobulin, intravenous:
anti-D positive control No assigned value First Reference Reagent
2004
anti-D negative control No assigned value First Reference Reagent 2004

These substances are held and distributed by the International Laboratory for Biological Standards,
National Institute for Biological Standards and Control, Potters Bar, Herts. EN6 3QG, England

Disestablishment

Antigens and related substances

Hepatitis B vaccine, plasma No assigned value First International Reference
derived Reagent

28
WHO Drug Information Vol 19, No. 1, 2005
tion would be of benefit. Accordingly a revised
version of the 1990 WHO guidance was prepared.
In addition the consultative process has revealed
a need for continued scientific and capacity
building work in the area of biological standards.
Thus the Committee also recommended that
WHO considers starting or continuing work
specifically on:
• predicting and monitoring the stability of biologi-
cals;
• developing specific training modules for biologi-
cal standardization, with the collaboration of the
WHO Global Training Network; and
• developing a manual to describe in detail
calibration procedures for secondary standards.
Vaccines and Biomedicines
Consolidated list of WHO
Recommendations and Guidelines
Recommendations and guidelines published by
WHO are scientific and advisory in nature, but
they may be adopted by a national regulatory
authority as national requirements, and are also
intended to provide guidance to those responsible
for the production of biologicals or those who may
have to decide upon appropriate methods of
testing, assay and control in order to ensure the
quality, safety and efficacy of products.
A consolidated list of WHO Recommendations
and Guidelines, together with a list of a variety of
other documents produced by the WHO biological
standardization programme has now been
reviewed and is available on the WHO website at:
www.who.int/biologicals
29

Regulatory Action
Northern hemisphere influenza
vaccine composition 2005/2006
World Health Organization — The following
influenza virus vaccine composition has been
recommended for the forthcoming winter in the
northern hemisphere.
• an A/New Caledonia/20/99(H1N1)-like virus;
• an A/California/7/2004(H3N2)-like virus;
• a B/Shanghai/361/2002-like virus (currently used
vaccine viruses include B/Shanghai/361/2002,
B/Jilin/20/2003 and B/Jiangsu/10/2003).
As in previous years, the national control authori-
ties should approve the specific vaccine viruses
used in each country. National public health
authorities are responsible for recommendations
regarding the use of the vaccine.
Reference: Weekly Epidemiological Record, 80: 71–75
(2005).
Valdecoxib: severe skin reactions
and cardiovascular risk
United States of America — The Food and Drug
Administration (FDA) has announced important
new information on side effects associated with
the use of valdecoxib (Bextra®), a COX-2 selec-
tive nonsteroidal anti-inflammatory drug (NSAID)
which is indicated for the treatment of osteoarthri-
tis, rheumatoid arthritis and dysmenorrhoea
(menstrual pain). A boxed warning, strengthening
previous warnings about the risk of life-threaten-
ing skin reactions and a new bolded warning
contraindicating the use of valdecoxib in patients
undergoing coronary artery bypass graft (CABG)
surgery will be added to the label.
Serious skin reactions
Patients taking valdecoxib have reported serious,
potentially fatal skin reactions, including Steven-
Johnson Syndrome and toxic epidermal necro-
lysis. These skin reactions are most likely to occur
in the first 2 weeks of treatment, but can occur
any time during therapy. In a few cases, these
reactions have resulted in death. The labelling
30
WHO Drug Information Vol 19, No. 1, 2005
advises that valdecoxib should be discontinued at
the first appearance of a skin rash, mucosal
lesions (such as sores on the inside of the
mouth), or any other sign of allergic reactions.
Valdecoxib contains sulfa, and patients with a
history of allergic reactions to sulfa may be at a
greater risk of skin reactions.
As of November 2004, FDA has received reports
of a total of 87 cases in the USA of severe skin
reactions in association with valdecoxib.
Cardiovascular risks
In addition to highlighting serious skin reactions,
the strengthened label warnings also highlight
new data about cardiovascular risks. A recently-
completed study conducted by the manufacturer,
which included over 1500 patients treated after
CABG, showed an increased cardiovascular risk
in patients treated with valdecoxib compared to
placebo.
Reference: FDA Talk Paper, T04-56 . 9 December 2004
http://www.fda.gov/medwatch/index.html .
COX- 2 inhibitors: review plans
European Union — Following the worldwide
withdrawal of rofecoxib (Vioxx), the European
Medicines Agency (EMEA) has been asked by the
European Commission to conduct a review of all
cyclo-oxygenase-2 (COX-2) inhibitor medicines.
The Agency’s scientific committee responsible for
human medicines (CHMP) will look at newly
available data on all aspects of cardiovascular
safety of the COX-2 inhibitors celecoxib, etori-
coxib, lumiracoxib, parecoxib and valdecoxib,
including thrombotic events (heart attack and
stroke) and cardiorenal events (e.g. hypertension,
oedema and cardiac failure).
The objective of this review is to assess
whether there is a need to make changes to
existing marketing authorizations including
labelling throughout the whole of the
European Union and whether additional
studies are needed. When completed, the
outcome of the review will be posted on the
Agency’s website. In the meantime the agency
WHO Drug Information Vol 19, No. 1, 2005
reminds that the earlier warnings, issued on 6
October 2004, remain valid:
• Rofecoxib has been withdrawn due to serious
thrombotic events. Patients on rofecoxib should
be reviewed and alternative treatment consid-
ered. When considering treatment with other
COX- 2 inhibitors, prescribers should consult
the latest version of the summary of product
characteristics, particularly for cardiovascular
events.
• Patients who were taking rofecoxib should
consult their doctor at the next available oppor-
tunity to discuss their treatment options.
Reference: EMEA Press Release, EMEA/117908/2004.
Available at: http://www.emea.eu.int
Co-proxamol products withdrawn
United Kingdom — The Committee on Safety of
Medicines (CSM) has recently reviewed the risks
and benefits of co-proxamol (paracetamol/
dextropropoxyphene). The efficacy of co-prox-
amol is poorly established and the risk of toxicity
in overdose, both accidental and deliberate, is
now considered to be unacceptable. Co-proxamol
contains a dose of paracetamol (325 mg) that
would, on its own, be considered sub-therapeutic,
and dextropropoxyphene (32.5 mg) is a weak
opioid analgesic that is known to be toxic in
overdose. Each year there are 300–400 fatalities
following deliberate or accidental drug overdose
involving co-proxamol in England and Wales
alone.
CSM has therefore advised that:
• In relation to safety, there is evidence that fatal
toxicity may occur with a small multiple of the
normal therapeutic dose and a proportion of
fatalities are caused by inadvertent overdose.
Pharmacokinetic and pharmacodynamic
interactions with alcohol further reduce the
threshold for fatal toxicity.
• There is no robust evidence that efficacy of this
combination product is superior to full strength
paracetamol alone in either acute or chronic
use.
• It has not been possible to identify any patient
group in whom the risk-benefit may be positive.
• Co-proxamol products should be withdrawn
altogether over the next 6–12 months.
Regulatory Action
• During the withdrawal phase, interim restrictions
and warnings regarding the use of co-proxamol
should be introduced to the product information.
Reference: Committee on Safety of Medicines. CEM/
CMO/2005/2, 31 January 2005 at http://medicines.
mhra.gov.uk/aboutagency/regframework/csm/
csmhome.htm
Cisapride licences
voluntarily cancelled
United Kingdom — The marketing authorizations
for cisapride-containing products were suspended
in July 2000, following advice from the Committee
on Safety of Medicines (CSM), due to the risk of
cardiac side effects. CSM advised that the
balance of risks and benefits was no longer
favourable. This advice was communicated to UK
health professionals (1).
Following this suspension, a Europe-wide review
of the risks and benefits of cisapride took place
under the auspices of the Committee for Propri-
etary Medicinal Products (CPMP). On the advice
of the CPMP, the European Commission decided
that cisapride-containing products should be
maintained within Europe but with restricted
indications in adults and children after failure of
other treatment options. A condition was that all
patients treated with cisapride should be enrolled
in either a clinical safety study/registry or a clinical
trial to evaluate efficacy.
The UK marketing authorizations remained
suspended until October 2003, when the licence
holder voluntarily decided not to implement the
EU decision in the UK. Instead they have decided
to cancel all existing UK marketing authorizations.
References
1. Committee on Safety of Medicines. Current Problems
in Pharmacovigilance, 26: 9 (2000).
2. Committee on Safety of Medicines, Current Problems
in Pharmacovigilance, 30: (2004).
Tentative approval for generic
co-packaged antiretrovirals
United States of America — The Food and Drug
Administration (FDA) has announced the tentative
approval of a co-packaged antiretroviral drug
regimen manufactured in South Africa for the
treatment of HIV-1 infection in adults. The agen-
cy’s tentative approval means that although
31
Regulatory Action
existing patents and/or exclusivity prevent US
marketing of this product, it meets FDA’s quality,
safety and efficacy standards for US marketing.
This action is the first tentative approval of an HIV
drug regimen manufactured by a non-US-based
generic pharmaceutical company. Once the
marketing application was made on 13 January
2005, FDA completed its review within two weeks.
The tentatively approved regimen consists of co-
packaged lamivudine/zidovudine fixed-dose
combination tablets and nevirapine tablets.
Lamivudine/zidovudine fixed dose combination
tablets are a version of the already approved
Combivir® tablets and Viramune® tablets. The
new co-packaged product consists of two tablets
(lamivudine/zidovudine and nevirapine) each to
be taken twice daily, after the initial two-week
initiation phase of a nevirapine regimen.
More information on HIV and AIDS is available
online at FDA’s website: http://www.fda.gov/oashi/
aids/hiv.html.
Reference: FDA News, P05-02. 25 January 2005
Natalizumab approved
for multiple sclerosis
United States of America — The Food and Drug
Administration (FDA) has licensed a new biologic
approach to treat patients with relapsing forms of
multiple sclerosis (MS) to reduce the frequency of
symptom flare-ups or exacerbations of the
disease. Natalizumab (Tysabri®) is a monoclonal
antibody bioengineered from part of a mouse
antibody to closely resemble a human antibody.
Although the cause of MS is unknown, it is widely
considered to be an autoimmune disease in which
the person’s immune system attacks the brain
and/or spinal cord. Natalizumab appears to work
by binding to these immune system cells, thus
preventing them from travelling to the brain where
they can cause damage.
The approval is based on positive results seen in
patients after one year of treatment. This product
received accelerated approval because it appears
to provide substantial benefit for patients with a
serious disease. As part of that approval, the
manufacturer has committed to continuing its
trials of this product for another year.
The most frequently reported serious adverse
reactions in clinical trials were infections, includ-
32
WHO Drug Information Vol 19, No. 1, 2005
ing pneumonia, temporary hypersensitivity
reactions (such as rash, fever, low blood pres-
sure, and chest pain), depression, and gallstones.
These serious adverse reactions were uncom-
mon. Common adverse reactions were generally
mild and included non-serious infections (such as
urinary tract, lower respiratory tract, GI system,
and vaginal infections), headache, depression,
joint pains, and menstrual disorders.
Reference: FDA News, P04-107. November 2004
Pegaptanib for age-related
macular degeneration
United States of America — The Food and Drug
Administration (FDA) has approved pegaptanib
sodium injection (Macugen®), a new therapy to
slow vision loss in people with the eye disease
neovascular (wet) age-related macular degenera-
tion (AMD). Pegaptanib is a selective vascular
endothelial growth factor (VEGF) antagonist.
AMD, a retinal disease causing severe and
irreversible vision loss, is a major cause of
blindness in individuals older than 55 years.
Untreated, the majority of eyes affected with wet
AMD may become functionally blind. Wet AMD,
which makes up approximately 10 percent of
AMD, is caused by the growth of abnormal leaky
blood vessels that eventually damage the area of
the eye responsible for central vision, which is
essential for most fine detail visual activities,
including reading, driving, and recognizing faces.
The safety and efficacy of pegaptanib was studied
in two trials in patients with wet AMD for two
years. Patients exhibited a significant decrease in
vision loss in both trials. Serious adverse events
related to the injection procedure included
infections, retinal detachment, and traumatic
cataract. Other frequently reported adverse
events in patients treated with pegaptanib were
eye irritation, eye pain, haemorrhage under the
outer membrane of the eye (conjunctiva), and
blurred vision.
Reference: FDA News, P04-110. 20 December 2004
Amphetamine salts suspended
Canada — Health Canada has suspended
marketing of amphetamine salts (Adderall XR®)
for attention deficit hyperactivity disorder (ADHD)
with effect 9 February 2005.
WHO Drug Information Vol 19, No. 1, 2005
The decision to withdraw amphetamine salts is
founded on very rare, international, spontaneous
reports of sudden deaths in paediatric and adult
patients. Reports for death include those for
patients taking usual recommended doses,
including recommended starting doses. In a
minority of cases, the events occurred on the first
day of dosing or shortly after an increase in dose
or a switch from another drug in the structural
class. Deaths were reported for patients both
naïve or chronically exposed to amphetamine-
related central nervous system stimulants. The
decision was not based on reported deaths that
were associated with overdose, misuse or abuse.
Of the 20 reported deaths, there were cases that
occurred in patients without a documented history
of structural or other cardiac abnormalities/
disease. In a few cases, other drugs, including
antidepressants, clonidine and/or anti-psychotics,
were concomitant medications. Exercise was an
associated event in some of the reports of death.
None of the reported deaths occurred in Canada.
Health Canada has requested manufacturers of
other stimulants approved for the treatment of
ADHD to provide a thorough review of their
worldwide safety data. Information updates will be
provided as they become available.
Reference: Communication dated 9 February 2005
from Health Canada at http://www.hc-sc.gc.ca
Tolcapone: return to market
United Kingdom —Tolcapone (Tasmar®) is a
catechol-O-methyltransferase (COMT) inhibitor
medicine developed for use in Parkinson disease.
In February 1999, the Committee on Safety of
Medicines reported the withdrawal of tolcapone
following serious hepatic reactions and neurolep-
tic malignant syndrome (NMS) (1). At its April
2004 meeting, the European Committee for
Proprietary Medicinal Products recommended
lifting the suspension of the marketing authoriza-
tion for tolcapone. This followed review of the
available clinical evidence including evidence of
increased efficacy for tolcapone over entacapone
in the control of motor fluctuations in patients with
advanced Parkinson disease.
Tolcapone will be made available with the re-
stricted indication in patients “who failed to
respond to or are intolerant of other COMT
inhibitors”.
Regulatory Action
The following conditions will be applied to use of
tolcapone :
• More frequent liver function monitoring and
closer attention to the monitoring of possible
signs and symptoms of underlying liver disease.
• Contraindication in patients with severe dyski-
nesia or with a previous history of NMS.
• Restriction on prescribing to physicians experi-
enced in the management of advanced Parkin-
son’s disease.
The safety of tolcapone will be closely monitored.
1. Committee on Safety of Medicines, Current Problems
in Pharmacovigilance, 25: 2 (1999).
Patient reporting and
public access to safety data
United Kingdom — Patients and researchers will
be able to access data on the safety of different
medicines as a move to further improve the drug
side effect reporting system — the Yellow Card
Scheme — used to monitor the safety of medi-
cines in the United Kingdom.
The Medicines and Healthcare products Regula-
tory Agency (MHRA) will publish anonymous data
on suspected adverse drug reactions on their
website. Researchers will also be able to access
more detailed data and measures will be put in
place to prevent potential abuse of the informa-
tion. Every request will be reviewed by an inde-
pendent committee to make sure it is ethically and
scientifically sound and protects patient confiden-
tiality.
A first pilot phase of a project for patient reporting
of unexpected effects of drugs to the regulator
were also launched. Forms to report unexpected
drug reactions will be available in 4000 physician
surgeries across the UK and patients will also be
able to make reports online.
The Yellow Card System is recognized as one of
the best spontaneous reporting schemes for
adverse drug reactions in the world. Expansion of
the scheme nationally is planned for later in the
year.
The new measures are key recommendations
made by experts who reviewed the yellow card
scheme last year and a public consultation.
33
Regulatory Action WHO Drug Information Vol 19, No. 1, 2005

Reference: Medicines and Healthcare products
Regulatory Agency. 2005/0015. 17 January 2005. http://
www.yellowcard. gov.uk
Australia and Canada agree
mutual recognition
The Governments of Australia and Canada have
signed a Mutual Recognition Agreement (MRA)
that enables both countries to accept each other’s
good manufacturing practice (GMP) audits and
inspection of the makers of prescription and over
the counter medicines. GMP regulation is the
cornerstone of ensuring that medicines on the
market have been manufactured to the highest
standards of safety and efficacy. The agreement
will enable access to the latest products assessed
to best regulatory standards in as short a
timeframe as possible. The MRA will allow the
manufacturer’s batch certifications to be recog-
nized by the other party without re-analysis at the
point of import.
The Therapeutic Goods Administration (TGA) of
Australia has signed a number of multi-sectoral
MRAs over the past few years, including with the
European Community, the European Free Trade
Association and Singapore. The TGA also has a
cooperative arrangement with the US Food and
Drug Administration on GMP inspections, recalls,
adverse product trends, health hazard evaluations
and alert system information.
The MRA reflects the significant growth in phar-
maceutical exports. The total trade between
Australia and Canada in regulated medicines for
human use was more than $67 million in 2004.
Australian imports from Canada amounted to
more than $17 million in 2004 while in the same
year Australian exports to Canada were some
$50 million. By reducing regulatory costs and
duplication, the MRA will significantly speed up
the process of getting life saving drugs onto the
market of both countries.
Reference: TGA Press statement. CP013/05. 16 March
2005. http://www.tga.gov.au
Didanosine-tenofovir
interaction: safety concerns
France — The Agency for Health Products Safety
(AFSSAPS), in collaboration with the European
Medicines Agency (EMEA), has carried out a
review of available data with regard to reporting of
increased reactions and lack of efficacy following
concomitant use of two antiretrovirals, didanosine
(Videx®) and tenofovir (Viread®).
EMEA has issued the following recommendations:
• Concomitant administration of didanosine and
tenofovir is not recommended, in particular
among those patients with high viral load and
low CD4 cell count.
• rare, sometimes fatal, cases of pancreatitis and
lactic acidosis have been reported with co-
administration of tenofovir and didanosine.
• If co-administration is considered unavoidable,
patients should be closely monitored for efficacy
and signs of intolerance or adverse reactions.
References:
1. AFSSAPS Press release. 3 March 2005. http://
www.agmed.sante.gouv.fr/htm/10/filltrpsc/indlp3.htm
2. European Medicines Agency. EMEA/62331/2005. 3
March 2005.

The International Pharmacopoeia available on CD-ROM

The International Pharmacopoeia comprises a collection of recommended procedures for analysis
and specifications for the determination of pharmaceutical substances, excipients, and dosage
forms that are intended to serve as source material for reference or adaptation and to establish
pharmacopoeial requirements.
The collection of Volumes to 5 have now been grouped on a single CD-ROM.
Available from: Marketing and Dissemination, World Health Organization,
1211 Geneva 27, Switzerland or by e-mail: publications@who.int

34
WHO Drug Information Vol 19, No. 1, 2005
Prequalification of Medicines
Improving medicines quality
through prequalification
WHO, UNICEF and other organizations are
involved in the procurement of pharmaceutical
products for use in public health programmes,
such as those to combat HIV/AIDS, malaria and
tuberculosis. Because low-cost pharmaceutical
products of assured quality offer the greatest
potential for maximizing the impact of efforts to
combat such diseases, the quality of pharmaceu-
tical products has become a major concern at
both international and country level. Efforts to
accelerate access to pharmaceutical products
used in the treatment of these major impact
diseases through price negotiation and generic
competition have highlighted the fundamental
importance of developing a robust quality assur-
ance system for pharmaceutical products and
diagnostics. Without a quality assurance system,
public health agencies risk sourcing substandard,
counterfeit and contaminated pharmaceutical
products leading to product complaints and
recalls, waste of money and health risk to pa-
tients.
WHO Prequalification Project
The prequalification project, set up in 2001, is a
service provided by the World Health Organiza-
tion to facilitate access to medicines for HIV/
AIDS, malaria and tuberculosis that meet interna-
tional standards of quality, safety and efficacy.
From the outset, the project was established by
WHO, UNAIDS, UNICEF, UNFPA, with the
support of the World Bank, as a concrete contri-
bution to the United Nations priority goal of
addressing widespread diseases in countries with
limited access to quality medicines.
Prequalification by WHO involves assessing data
provided by the manufacturer and inspecting sites
involved in manufacturing, clinical or bioequiva-
lence testing for compliance with WHO require-
ments. The coordination of the project, including
dossier assessments and site inspections are
impartial. Neither the external assessors and
inspectors nor the WHO prequalification team are
engaged in product procurement, supply, distribu-
tion, or policy-making. The manufacturer is
responsible for the development of the products
and must ensure that a product dossier is submit-
ted and that any sites involved in manufacturing
and clinical testing comply with good manufactur-
ing pactice (GMP), good clinical practice (GCP)
and good laboratory practice (GLP). In the event
that compliance is not confirmed, the manufac-
turer will be expected to take corrective action
and generate new data as required. If the correc-
tive actions are confirmed as satisfactory by
WHO, the product – as manufactured at a
particular site — will be included in the WHO list
of prequalified products (1).
Achievements and challenges
In May 2004, the World Health Assembly re-
quested measures to strengthen the Prequalifica-
tion Project and to ensure that the prequalification
review process and results of inspections and
assessment reports of listed products are made
publicly available (2). The Prequalification Project
has optimized its resources to avoid any backlog
in its pipeline. It now takes around 3–4 months
from submission of a dossier to prequalification of
the product, provided the dossier is complete at
the time of submission and the sites comply with
WHO requirements. By regulatory standards this
is a very short turnaround.
The time taken to produce and submit data
however depends on a number of factors, many
of which are unrelated to the prequalification
process, such as the manufacturer’s own re-
sources and prioritizations, time schedules of any
partners involved, the time needed to write anyt
reports, etc. WHO is not in control of these factors
and cannot make decisions in this regard on
behalf of the manufacturer. In other words, any
time delays are intimately linked to the manufac-
turer’s willingness and ability to take prompt and
appropriate action in order to become compliant
or to complement deficient dossiers with a
minimum of delay.
The prequalification team has been strengthened
and additional resources made available. This will
enable WHO to convene additional expert
assessment meetings in 2005 and thus handle
more products and possibly reduce timelines
even further. However, quality cannot be as-
35
Prequalification of Medicines
sessed, tested or inspected in the final product. It
must be built in. This process is fully in the hands
of manufacturers. In order to prepare manufactur-
ers from developing countries to apply for pre-
qualification successfully, appropriate training is
needed. WHO has unique experience obtained in
assessing a great number of generic products
from different countries. During 2005, two work-
shops for local manufacturers and national
regulators have been held focusing on GMP and
the quality and bioequivalence requirements for
the product dossier. The workshop in Malaysia
focused on drugs to treat tuberculosis and the
other in China on antiretrovirals. Other workshops
will follow to satisfy needs. These efforts will
develop understanding of what is required to
improve the quality, safety and efficacy of prod-
ucts and ensure that only good quality products
are supplied. Manufacturers will also gain insight
into which areas need improvement and how to
comply with international regulatory requirements.
The importance of prequalification has been
underscored by different parties (3, 4) and is
supported by the international regulatory commu-
nity as reflected in recent recommendations from
the Tenth and Eleventh International Conferences
of Drug Regulatory Authorities (5). Indeed, without
the contribution and collaboration of over 40
national regulatory authorities that provide
expertise in the form of assessors and inspectors,
WHO would not be able to maintain such a high
level of technical capability.
Immediate outcomes of WHO prequalification
include the list of prequalified products for treating
priority diseases (see prequalification website at:
http://mednet3.who.int/prequal/), harmonization of
quality requirements for international procurement
and strengthening of collaboration between WHO,
other UN agencies, related organizations and
drug regulatory authorities. Collaboration and
coordination is improved through joint inspections,
assessment of product dossiers, training of
inspectors and assessors, and making informa-
tion on prequalification inspections available on
the prequalification website (6). Meanwhile,
ongoing monitoring, review and updating of
quality-related systems and programmes, and
more effective networking and information
exchange on drug regulatory and drug quality
issues are constantly under development.
How to participate in prequalification
Products identified as being of public health
significance are listed on the prequalification
website under an “invitation for expression of
36
WHO Drug Information Vol 19, No. 1, 2005
interest”. Products are selected from the respec-
tive WHO treatment guidelines and are largely
consistent with the WHO Model List of Essential
Medicines. Any manufacturer or supplier of such a
product is eligible for assessment in the prequalifi-
cation project and can apply by submitting a
product dossier together with the site master file
and a sample of the product (7). Products submit-
ted for prequalification should meet WHO require-
ments as set out below.
Data and information: generic products
For multisource (generic) products, dossiers
should meet the specifications as summarized in
the guideline for the preparation of a product
dossier. Multisource (generic) products must
satisfy the same quality standards as those of the
originator product. In addition, assurance must be
provided that they are clinically interchangeable
with the originator products as shown by bio-
equivalence or relevant clinical data. Information
is required as follows (7):
• Details of the product.
• Registration in other countries.
• Active pharmaceutical ingredient(s) – API
- Properties of the API(s)
- Sites of manufacture
- Route of synthesis
- Specification
API described in a pharmacopoeia
API not described in a pharmacopoeia
- Stability testing
• Finished product.
- Formulation
- Sites of manufacture
- Manufacturing procedure
- Specifications for excipients (in addition
to API)
- Specifications for finished product
- Container/closure system(s) and other
packaging
- Stability testing
- Container labelling
- Product information
- Patient information and package inserts
- Justification for any differences to the
product if different to the product
authorized in the country of origin.
• Interchangeability.
- Bio-equivalence study (or other relevant
clinical studies).
• Summary of pharmacology, toxicology and
efficacy of the product if applicable.
WHO Drug Information Vol 19, No. 1, 2005 Prequalification of Medicines

Data and information: innovator products tion Cooperation Scheme (PIC/S) countries, a
For innovator products licensed in the USA, WHO representative (with experience and training
European Union or Japan (ICH countries) or as a GMP inspector), and an inspector(s) from the
country with similarly requirements: drug regulatory authority of the country in which
the manufacturing site is located.
• A WHO-type Certificate of a Pharmaceutical
Product issued by the regulatory authority, If inspection has already been carried out by a
together with the summary of product character- stringent regulatory authority, the reports should
istics (SPC). be submitted to WHO. If these are satisfactory, an
inspection may not be necessary. In cases where
• Assessment report(s) issued by the regulatory a manufacturing site was inspected by a stringent
authority. regulatory authority, compliance is acceptable on
the basis of documentary evidence, which should
• WHO-type batch certificate from the manufac- also include a WHO-type Certificate of a Pharma-
turer. ceutical Product as
issued by the national
• Stability testing data, if drug regulatory author-
the packaging of the WHO prequalification ity. However, in the
product is different requirements: event that the product is
from that approved by licensed and manufac-
the drug regulatory au- • Product dossier assessment (including qual- tured for export pur-
thority. ity and bioequivalence parts). poses only, an inspec-
tion by WHO may be
• Arguments and/or data • Inspection of manufacturing site of finished required.
to support the applica- pharmaceutical product for compliance with
bility of the WHO GMP requirements. Inspections normally
certificate(s) in the take a minimum of three
event that the formula- • Assessment of drug master file and inspec- consecutive days and
tion, strength, or speci- tion of API manufacturing site for compliance involve verification of all
fications are different with WHO GMP requirements. aspects of GMP
from the product for including premises,
which the WHO-type • Inspection of the CRO used by the applicant equipment, materials,
Certificate of a Phar- for clinical (bioequivalence) studies for com- documentation, valida-
maceutical Product pliance with WHO GCP and GLP require- tion, personnel, produc-
was issued. ments. tion, quality control,
HVAC (heating, ventila-
Assessment of • Completion of WHOPAR and WHOPIR. tion, and air condition-
dossiers ing), water systems,
Following submission of utilities, and production
documentation, a team and control.
of WHO appointed assessors drawn from national
regulatory authorities will assess the product data. WHO Public Assessment Reports
Teams are drawn from both developed and devel- In May 2004, the World Health Assembly requested
oping authorities, offering a unique opportunity to WHO to “ensure that the prequalification review
benefit from each other’s expertise and experience. process and the results of inspection and assess-
Manufacturers are informed of the outcome of the ment reports of the listed products, aside from pro-
evaluation and given the opportunity to submit ad- prietary and confidential information, are made pub-
ditional information if required. Samples are evalu- licly available” (2). WHO Public Assessment Reports
ated and may be sent for independent testing at (WHOPAR) are summaries of the assessment of
quality control laboratories. the product data and information as submitted by
the manufacturer.
Inspection and monitoring
Products cannot be prequalified before the Documents supporting a WHOPAR are requested
manufacturing site has been inspected by a team as part of the initial submission for prequalifica-
appointed by WHO and generally includes an tion. These include package leaflets, summary of
inspector from one of the Pharmaceutical Inspec- product characteristics, labelling and in certain

37
Prequalification of Medicines WHO Drug Information Vol 19, No. 1, 2005

cases a separate summary of the product’s
quality, safety and efficacy data. A draft guideline
with detailed information to manufacturers on how
to submit information for the WHOPAR is avail-
able on the prequalification website (6).
WHO Public Inspection Report
A WHO Public Inspection Report (WHOPIR) is a
summary of the inspection report covering either
a manufacturing site for an active pharmaceutical
ingredient (API), a manufacturing site for a
finished product (FP), or an organization such as
a contract research organization where a
bioequivalence or other clinical study has been
performed
The WHOPIR is a summary of the findings of
inspection, and excludes confidential and propri-
etary information. It is important to note that the
observations contained in the WHOPIRs reflect
general findings, and that generally any “non-
compliance” will have been corrected. Verification
of corrective action is conducted by WHO through
a documentation review or a follow-up inspection.
Public inspection reports are published on the
WHO Prequalification web page. Requests for
copies of the complete inspection reports should
be made to individual manufacturers.
Re-qualification process
Manufacturers are required to apply for re-
qualification of their products three years after
prequalification. Re-qualification involves re-
assessment of the product data and information
as provided in the original product dossier, and re-
inspection of the relevant site(s) for compliance
with WHO requirements. The following is needed
for re-qualification:
Generic (multisource) products
• submission of fully updated information to WHO

List of documents which should be available at the CRO

No Document

1 Organizational chart
2 Job descriptions
3 Updated and signed CVs of responsible persons
4 Training records and course certificates of responsible persons
5 List of persons who have access to archives
6 List of persons who have access to computer database
7 Specification of data protection methods (virus testing, backup copies)
8 List of clinical laboratory normal ranges
9 Accreditation certificate of clinical laboratory
10 Sample contract forms for investigators
11 Application form for ethics committee approval
12 Adverse event registration form
13 Serious adverse event registration form
14 SOP for monitoring, data verification check-lists for monitor
15 SOP for designing CRF, standard CRF modules
16 Record for biological sample collection times
17 SOP for labelling of samples
18 Record for storage of biological samples (temperature log)
19 List of persons who have access to investigational drugs
20 Drug accountability forms (receipt, storage, randomization, dispensing, administration to subjects,
destruction or return to sponsor of remaining medication)
21 SOP for data entry and data validation procedure
22 Documentation (validation) of the pharmacokinetic computer program
23 Documentation (validation) of the statistical computer program
24 Trial report template
25 SOP’s for calibration and quality control of the apparatus. (Depends on apparatus0
26 SOP’s for analytical method validation
27 Procedures for raw data handling, archiving and labelling
28 SOP for laboratory QA audit
29 List of signatures of responsible persons (including any delegations).
30 Raw data
31 Case Report Forms
32 Informed consent forms
33 Proof of independent ethical review of the study undertaken.

38
WHO Drug Information Vol 19, No. 1, 2005
including mention of any changes that could
impact the safety, efficacy or quality of the
product, such as changes relating to sourcing of
the active pharmaceutical ingredient (API),
formulation, manufacturing method, manufactur-
ing equipment or manufacturing site or new
clinical data or changes in the safety profile of
the product.
• request for a WHO inspection of the manufactur-
ing sites and the CRO or other site used for the
bioequivalence study.
• a sample of the product and its commercial
presentations.
Innovator products
• submission of a fully updated dossier for each
product with a covering letter summarizing any
changes since the previously submitted data
and information on the products. For example,
information on changes to API sourcing,
formulation, manufacturing method, equipment
or site or new clinical data/changes to safety
profile. When there are no changes, a letter
confirming this will suffice.
• in some cases, latest inspection reports by the
competent drug regulatory authority may be
required.
Guidelines for organizations
conducting bioequivalence studies
Products submitted for prequalification are often
multisource (generic) products. In such cases,
therapeutic equivalence is generally demon-
strated by performing a bioequivalence study
carried out by an independent organization,
company, or academic institution, a research
organization, or laboratory.
Recently, certain contract research organizations
(CROs) were found to be deficient with discrepan-
cies in bioequivalence data and non-compliance
with WHO good clinical practices (GCP) or good
laboratory practices (GLP) requirements. As a
consequence, it is now a prerequisite for prequali-
fication of medicinal products that the CRO used
by the sponsor for bioequivalence or other clinical
studies is also inspected.
Draft guidelines for organizations involved in the
conduct of in vivo bioequivalence studies are now
in the final stages of consultation. The guidelines
cover general recommendations for conducting
bioequivalence studies; analysis of clinical trial
Prequalification of Medicines
samples; facilities and equipment; and documents
and records. The guideline also provides informa-
tion on organization and management; clinical
phases, bio-analysis; pharmacokinetic and
statistical analysis; and study report. The guide-
line does not replace existing WHO GCP or GLP
guidelines, but may be useful as an additional
guidance for organizations to help them conduct
bioequivalence studies properly.
Monitoring programme
Random samples are taken for quality control
analysis from batches of products supplied by UN
procurement agencies as part of an ongoing
monitoring programme. Comparative dissolution
testing is also conducted as appropriate. In
addition, inspections are performed of manufac-
turing sites supplying batches of products. During
these inspections, compliance with the specifica-
tions as approved by prequalification is verified.
Batch manufacturing records are reviewed and
assessed, and compared against master specifi-
cations, dossier information, validation protocols,
reports, records and data. This is part of an
ongoing quality assurance programme to ensure
that batches contain the API listed in the product
dossier, as well as the same product formula,
manufacturing method, process and equipment.
This procedure verifies that the products supplied
are the same as those described in the product
dossier and tested in the bioequivalence study,
ensuring batch-to-batch consistency.
References
1. Participation in prequalification. http://mednet3.who.
int/prequal/
2. World Health Assembly. Resolutions and Decisions.
WHA57.14. Scaling up treatment and care within a
coordinated and comprehensive response to HIV/AIDS.
http://www.who.int/governance/en/
3. The important world of drug prequalification (Edito-
rial). Lancet, 364, (2004).
4. M. Weinberg. Generic HIV Drugs — Enlightened
Policy for Global Health (Perspective). New England
Journal of Medicine, 352, (2005).
5. 10th and 1tth International Conference of Drug
Regulatory Authorities. http://www.who.int/medicines/
icdra.shtml
6. WHOPAR and WHOPIR. http://mednet3.who.int/
prequal/
7. World Health Organization. Marketing Authorization of
Pharmaceutical Products with Special Reference to
Multisource (Generic) Products: a Manual for a Drug
Regulatory Authority, WHO/DMP/RGS/98.5 at: http://
www.who.int/medicines
39
 WHO Drug Information Vol 19, No. 1, 2005

ATC/DDD Classification (Final)

The following final anatomical therapeutic chemical (ATC) classifications and defined daily doses
(DDDs) were agreed at a meeting of the WHO International Working Group for Drug Statistics
Methodology which took place in March 2004. They came into force on 1 September 2004 and will
be included in the January 2005 issue of the ATC index. The inclusion of a substance in the lists
does not imply any recommendation of use in medicine or pharmacy. The WHO Collaborating
Centre for Drug Statistics Methodology can be contacted through e-mail: whocc@nmd.no.

ATC level INN/Common name ATC code

New ATC level codes (other than 5th level):

First-generation cefalosporins J01DB
Second-generation cefalosporins J01DC
Third-generation cefalosporins J01DD
Fourth-generation cefalosporins J01DE
New ATC 5th level codes:
anecortave S01XA16
atorvastatin, combinations C10AA55
bevacizumab L01XC07
cefoperazone, combinations J01DD62
cromoglicic acid D11AX17
darifenacin G04BD10
eplerenone C03DA04
hydroxybutyric acid N07XX04
insulin detemir A10AE05
mecobalamin B03BA05
melatonin N05CM17
olmesartan medoxomil & diuretics C09DA08
pemetrexed L01BA04
pravastatin, combinations C10AA53
rasagiline N04BD02
sulfamerazine and trimethoprim J01EE07
typhoid - hepatitis A J07CA10
ziconotide N02BG08

ATC code changes:

INN/common name Previous ATC New ATC

cefacetrile J01DA34 J01DB10

cefaclor J01DA08 J01DC04
cefadroxil J01DA09 J01DB05
cefalexin J01DA01 J01DB01
cefaloridine J01DA02 J01DB02
cefalotin J01DA03 J01DB03
cefamandole J01DA07 J01DC03
cefapirin J01DA30 J01DB08

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WHO Drug Information Vol 19, No. 1, 2005 ATC/DDD Classification

ATC code changes (continued):

INN/common name Previous ATC New ATC

cefatrizine J01DA21 J01DB07

cefazedone J01DA15 J01DB06
cefazolin J01DA04 J01DB04
cefdinir J01DA42 J01DD15
cefepime J01DA24 J01DE01
cefetamet J01DA26 J01DD10
cefixime J01DA23 J01DD08
cefmenoxime J01DA16 J01DD05
cefmetazole J01DA40 J01DC09
cefodizime J01DA25 J01DD09
cefonicide J01DA17 J01DC06
cefoperazone J01DA32 J01DD12
cefotaxime J01DA10 J01DD01
cefotetan J01DA14 J01DC05
cefotiam J01DA19 J01DC07
cefoxitin J01DA05 J01DC01
cefpiramide J01DA27 J01DD11
cefpirome J01DA37 J01DE02
cefpodoxime J01DA33 J01DD13
cefprozil J01DA41 J01DC10
cefradine J01DA31 J01DB09
cefroxadine J01DA35 J01DB11
cefsulodin J01DA12 J01DD03
ceftazidime J01DA11 J01DD02
ceftezole J01DA36 J01DB12
ceftibuten J01DA39 J01DD14
ceftizoxime J01DA22 J01DD07
ceftriaxone J01DA13 J01DD04
ceftriaxone, combinations J01DA63 J01DD54
cefuroxime J01DA06 J01DC02
latamoxef J01DA18 J01DD06
loracarbef J01DA38 J01DC08

ATC name changes

Level name ATC code

Previous: Morbilli vaccines
New: Measles vaccines J07BD
Previous: Morbilli, combinations with parotitis & rubella, live attenuated
New: Measles, combinations with mumps & rubella, live attenuated J07BD52
Previous: Morbilli, combinations with parotitis, live attenuated
New: Measles, combinations with mumps, live attenuated J07BD51
Previous: Morbilli, combinations with rubella, live attenuated
New: Measles, combinations with rubella, live attenuated J07BD53
Previous: Morbilli, live attenuated
New: Measles, live attenuated J07BD01
Previous: Parotitis vaccines
New: Mumps vaccines J07BE
Previous: Parotitis, live attenuated
New: Mumps, live attenuated J07BE01
Previous: Rubella, combinations with parotitis, live attenuated
New: Rubella, combinations with mumps, live attenuated J07BJ51

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ATC/DDD Classification WHO Drug Information Vol 19, No. 1, 2005

New DDDs:

INN/common name DDD Unit Adm.R ATC code

aprepitant 95 mg O A04AD12
aripiprazole 15 mg O N05AX12
atomoxetine 80 mg O N06BA09
abenzathine benzylpenicillin 3.6 g P J01CE08
benzathine phenoxy metylpenicillin 2 g O J01CE10
brodimoprim 0.2 g O J01EA02
buprenorphine 1.2 mg TD N02AE02
cefmenoxime 2 g P J01DD05
ceftezole 6 g P J01DB12
cloperastine 60 mg O R05DB21
clotiapine 80 mg O,P N05AX09
flumequine 1.2 g O J01MB07
flurithromycin 0.75 g O J01FA14
levosulpiride 0.4 g O N05AL07
methotrexate 2.5 mg O L04AX03
nesiritide 1.5 mg P C01DX19
rufloxacin 0.2 g O J01MA10
sodium folinate 60 mg P V03AF06
solifenacin 5 mg O G04DB08
sulfamazone 1.5 g O,R J01ED09

Change of DDDs:

INN/common name DDD Unit Adm.R ATC code

Previous: alosetron 2 mg O
New: 1 mg O A03AE01
Previous: amoxicillin & enzyme inhibitor 1 g P
New: 3 g P J01CR02
Previous: esomeprazole 20 mg O
New: 30 mg O A02BC05
Previous: fentanyl 0.6 mg TD
New: 1.2 mg TD N02AB03
Previous: levetiracetam 2 g O
New: 1.5 g O N03AX14

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WHO Drug Information Vol 19, No. 1, 2005

ATC/DDD Classification (temporary)

The following anatomical therapeutic chemical (ATC) classifications and defined daily doses (DDDs)
were agreed at a meeting of the WHO International Working Group for Drug Statistics Methodology
which took place on 28 October 2004. Comments or objections to the decisions from the meeting
should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology, e-mail:
whocc@nmd.no. They will be included in the January 2006 issue of the ATC index. The inclusion of
a substance in the lists does not imply any recommendation of use in medicine or pharmacy.

ATC level INN/Common name ATC code

New ATC level codes (other than 5th level):

Other anti-parathyroid agents H05BX
New ATC 5th level codes:
abetimus L04AA22
acetyl dihydrocodeine R05DA12
alglucosidase alfa A16AB07
anidulafungin J02AX06
atazanavir J05AE08
brivudine J05AB15
cefditoren J01DD16
ceforanide J01DC11
cinacalcet H05BX01
dimethoxanate R05DB28
duloxetine N06AX21
erlotinib L01XX34
fenetylline N06BA10
gadoxetic acid V08CA10
gatifloxacin S01AX21
histamine dihydrochloride L03AX14
ibritumomab tiuxetan [90Y] V10XX02
iodoform D09AA13
ivabradine C01EB17
measles, combinations with mumps,
rubella & varicella, live attenuated J07BD54
natalizumab L04AA23
pregabalin N03AX16
prulifloxacin J01MA17
risedronic acid and calcium M05BB02
roflumilast R03DX07
spiramycin, combinations with
other antibacterials J01RA04
sulfamerazine D06BA06
sulfanilamide D06BA05
treprostinil B01AC21
ATC code changes:
(implementation January 2006)
Previous: piribedil C04AX13
New: piribedil N04BC08

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ATC/DDD Classification WHO Drug Information Vol 19, No. 1, 2005

ATC name changes

ATC level ATC code

Previous: Histamine
New: Histamine phosphate V04CG03
Previous: Ointment dressings with antiinfectives
New: Medicated dressings with antiinfectives D09AA
Previous: Antiparathyroid hormones
New: Antiparathyroid agents H05B

New DDDs:

INN/common name DDD Unit Adm.R ATC code

atazanavir 0.3 g O J05AE08

azithromycin 0.5 g P J01FA10
brivudine 0.125 g O J05AB15
ceforanide 4 g P J01DC11
emtricitabine 0.2 g O J05AF09
esomeprazole 30 mg P A02BC05
fosamprenavir 1.4 g O J05AE07
ibandronic acid 2.5 mg O M05BA06
iloprost 0.15 mg inhal B01AC11
levodopa, decarboxylase inhibitor 0.45 g* O N04BA03
and COMT-inhibitor
melagatran 6 mg P B01AE04
moxifloxacin 0.4 g P J01MA14
nncotine 30 mg SL N07BA01
omalizumab 16 mg P R03DX05
oxybutynin 3.9 mg TD G04BD04
pregabalin 0.3 g O N03AX16
trospium 40 mg O G04BD09
ximelagatran 48 mg O B01AE05
zonisamide 0.2 g O N03AX15

* as levodopa

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WHO Drug Information Vol 19, No. 1, 2005

The International Pharmacopoeia

Monographs for antiretrovirals
Within the framework of the Procurement, Quality and Sourcing Project for HIV, Tuberculosis and Malaria
(http://www.who.int/prequal), The International Pharmacopoeia is collaborating with manufacturers, inde-
pendent analytical drug quality control laboratories, national and regional pharmacopoeial bodies, re-
search, governments, and regulatory bodies to provide specifications and monographs for the following
antiretroviral agents: abacavir, didanosine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine, ritona-
vir, saquinavir, stavudine, zidovudine. The final text for didanosine is provided below.

Didanosinum (final)
Didanosine

C10H12N4O3

Relative Molecular Mass. 236.2

Chemical name. 9-[(2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1,9-dihydro-6H-purin-6-one; 9-

(2,3-dideoxy-ß-D-glycero-pentofuranosyl)-1,9-dihydro-6H-purin-6-one; 2',3'-dideoxyinosine (DDI); CAS
Reg. No. 69655-05-6.

Description. A white to almost white powder.

Solubility. Sparingly soluble in water; slightly soluble in methanol R and ethanol (95 per cent) R

Category. Antiretroviral (nucleoside reverse transcriptase inhibitor).

Storage. Didanosine should be kept in a tightly closed container.

* Refers to The International Pharmacopoeia

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The International Pharmacopoeia WHO Drug Information Vol 19, No. 1, 2005

REQUIREMENTS

Didanosine contains not less than 98.5% and not more than 101.0% of C10H12N4O3, calculated with
reference to the dried substance.

Identity test

Either tests A and B, or test C may be applied.

A. Carry out test A.1. or , where UV detection is not available , test A.2.

A.1. Carry out the test as described under ‘‘Thin-layer chromatography’’ (Vol. 1, p. 83*), using silica gel
R6 as the coating substance and a mixture of 67 volumes of dichloromethane R, 20 volumes of
acetonitrile R, 10 volumes of methanol R and 3 volumes of ammonia (~260 g/l) TS as the mobile
phase. Apply separately to the plate 5 µl of each of 2 solutions in methanol containing (A) 1 mg of the
test substance per ml and (B) 1 mg of didanosine RS per ml. After removing the plate from the chro-
matographic chamber, allow it to dry exhaustively in air or in a current of cool air. Examine the chroma-
togram in ultraviolet light (254 nm).

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that
obtained with solution B.

A.2. Carry out the test as described under ‘‘Thin-layer chromatography’’ (Vol. 1, p. 83), using silica gel
R5 as the coating substance and a mixture of 67 volumes of dichloromethane R, 20 volumes of
acetonitrile R, 10 volumes of methanol R and 3 volumes of ammonia (~260 g/l) TS as the mobile
phase. Apply separately to the plate 5 µl of each of 2 solutions in methanol containing (A) 1 mg of the
test substance per ml and (B) 1 mg of didanosine RS per ml. After removing the plate from the chro-
matographic chamber, allow it to dry exhaustively in air or in a current of cool air. Spray with vanillin/
sulfuric acid TS1. Heat the plate for a few minutes at 120 ˚C. Examine the chromatogram in daylight.

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that
obtained with solution B.

B. The absorption spectrum of a 10 µg/ml solution in methanol R, when observed between 210 nm and
300 nm, exhibits one maximum at about 250 nm; the specific absorbance (A 1%1cm) is between 435 to
485.

C. Carry out the examination as described under “Spectrophotometry in the infrared region” (Vol. 1, p.
40*). The infrared absorption spectrum is concordant with the spectrum obtained from didanosine RS
or with the reference spectrum of didanosine.

If the spectra are not concordant, use didanosine RS. Dissolve the sample in a small amount of
methanol R, evaporate to dryness and carry out the IR spectrum with the residue as mentioned above.
Treat didanosine RS in the same way. The infrared absorption spectrum is concordant with the spec-
trum obtained from didanosine RS.

Specific optical rotation. Use a 10 mg/ml solution and calculate with reference to the dried sub-
stance; [α ]D20˚C –24˚ to –28˚.

Heavy metals. Use 1.0 g for the preparation of the test solution as described under “Limit test for
heavy metals”, Procedure 3 (Vol. 1, p. 118*); determine the heavy metals content according to Method
A (Vol. 1, p. 119*); not more than 20 µg/g.

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Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry for 4 hours at 105 ˚C; it loses not more than 5.0 mg/g.

Related substances

Note: Prepare fresh solutions and perform the tests without delay

Carry out the test as described under “High-performance liquid chromatography” (Vol. 5, p. 257*), using
a stainless steel column (25cm x 4.6mm), packed with octadecylsilyl base-deactivated silica gel for
chromatography R (5µm) (hypersil BDS is suitable).

Maintain the column temperature at 20 – 25 ˚C.

The mobile phases for gradient elution consist of a mixture of aqueous phase (Mobile phase A) and
methanol (Mobile phase B), using the following conditions :

Mobile phase A: A 0.05 M solution of ammonium acetate R adjusted to pH 8.0 using ammonia (~260
g/l) TS.

Mobile phase B: Methanol R.

Time (min) Mobile phase A (% v/v) Mobile phase B (% v/v)

0 92 8
18 92 8
25 70 30
45 70 30
50 92 8
60 92 8

Prepare the following solutions in a mixture of 92 volumes of mobile phase A and 8 volumes of mobile
phase B (dissolution solvent).

For solution (1) dissolve 5.0 mg of hypoxanthine R in the dissolution solvent and dilute to 100.0 ml with
the same solvent. Dilute 1.0 ml to 20.0 ml with the same solvent. For solution (2) dissolve 5 mg of
didanosine for system suitability RS (containing impurities A to F) in the dissolution solvent and dilute to
10 ml with the same solvent. For solution (3) dissolve 25 mg of the test substance in the dissolution
solvent and dilute to 50.0 ml with the same solvent. For solution (4) dilute 5.0 ml of solution (3) to 50.0
ml with the dissolution solvent. Then dilute 5.0 ml of this solution to 50.0 ml with the same solvent.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at
a wavelength of about 254 nm.

Use the chromatogram supplied with didanosine for system suitability RS and the chromatogram
obtained with solution (2) to identify the peaks due to impurities A to F.

Inject 20 µl of solution (2). The test is not valid unless the resolution factor between the peaks due to
impurity (C) (2'-deoxyinosine) and impurity D (3'-deoxyinosine) is greater than 2.5, if necessary reduce
the amount of methanol in the mobile phase and adjust the proportion of aqueous phase pH 8.0
accordingly.

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The International Pharmacopoeia WHO Drug Information Vol 19, No. 1, 2005

Inject separately 20 µl of solution (4) in replicate injections in the chromatographic system. The relative
standard deviation for peak areas of didanosine in replicate injections of solution (4) is not more than
5.0%.

Inject separately 20 µl each of solutions (1) and (3) and 20 µl of dissolution solvent in the chromato-
graphic system. Examine the mobile phase chromatogram for any extraneous peaks and disregard the
corresponding peaks observed in the chromatogram obtained with solution (3).

In the chromatogram obtained with solution (3), the following peaks are eluted at the following retention
times ratio with reference to didanosine (retention time = about 13-15 min): impurity A = about 0.3;
impurity B = about 0.4; impurity C = about 0.44; impurity D = about 0.48; impurity E = about 0.5;
impurity F = about 0.8; impurity I = about 1.4; impurity G = about 1.6; impurity H = about 2.0.

Measure the areas of the peak responses obtained in the chromatograms from solutions (1), (3) and
(4), and calculate the content of related substances as a percentage.

In the chromatogram obtained with solution (3) the area of any peak corresponding to impurity A
(hypoxanthine) is not greater than the area of the principal peak obtained with solution (1) (0.5%). The
area of any individual peak corresponding to impurities B, C, D, E, F or G is not greater than 0.2 times
the area of the principal peak obtained with solution (4) ( 0.2%). The area of any other impurity peak is
not greater than 0.1 times the area of the principal peak obtained with solution (4) (0.1%). The sum of
the areas of all peaks, other than the principal peak, is not greater than the area of the principal peak
obtained with solution (4) (1.0%). Disregard any peak with an area less than 0.05 times the area of the
principal peak obtained with solution (4) (0.05%).

Assay

Dissolve about 0.200 g, accurately weighed, in 50 ml of glacial acetic acid R1 and titrate with perchloric
acid (0.1 mol/l) VS as described under “Non-aqueous titration”; Method A (Vol. 1, p.131*) determining
the end point potentiometrically.

Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 23.62 mg of C10H12N4O3.

Impurities

The following list of known and potential impurities that have been shown to be controlled by the tests
in this monograph is given for information.

A. 1,7-dihydro-6H-purin-6-one (hypoxanthine)

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B. R1 = R2 = OH, R3 = H
9-ß-D-ribofuranosyl-1,9-dihydro-6H-purin-6-one (inosine)

C. R1 = R3 = H, R2 = OH
9-(2-deoxy- ß-D-erythro-pentofuranosyl)-1,9-dihydro-6H-purin-6-one (2'-deoxyinosine)

D. R1 = OH, R2 = R3 = H
9-(3-deoxy-ß-D-erythro-pentofuranosyl)-1,9-dihydro-6H-purin-6-one (3'-deoxyinosine)

E. R1 + R2 = O, R3 = H
9-(2,3-anhydro-ß-D-ribofuranosyl)-1,9-dihydro-6H-purin-6-one (2',3'-anhydroinosine)

F. R=H
9-(2,3-dideoxy-ß-D-glycero-pent-2-enofuranosyl]-1,9-dihydro-6H-purin-6-one; (2',3'-didehydro-2',3'-
dideoxyinosine)

G. R = OH
9-(2,3-dideoxy-ß-D-glycero-pentofuranosyl)-9H-purin-6-amine (2',3'-dideoxyadenosine)

H. R=H
9-(2,3,5-trideoxy-ß-D-glycero-pentofuranosyl)-9H-purin-6-amine (2',3',5'-trideoxyadenosine)

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The International Pharmacopoeia WHO Drug Information Vol 19, No. 1, 2005

I. 9-(2,3-dideoxy-ß-D-glycero-pent-2-enofuranosyl)-9H-purin-6-amine (2',3'-dideoxy-2',3'-
didehydroadenosine)

J. structure as shown for impurities B to E where R1= R2 = H, R3 = CO-CH3

9-(5-O-acetyl-2,3-dideoxy-ß-D-glycero-pentofuranosyl)-1,9-dihydro-6H-purin-6-one (didanosine acetate)

K. structure as shown for impurity F where R = CO-CH3

9-(5-O-acetyl-2,3-dideoxy-ß-D-glycero-pent-2-enofuranosyl)-1,9-dihydro-6H-purin-6-one (2',3'-
didehydrodidanosine acetate)

L.9-[2,3-O-[(1RS)-1-methoxyethylene]-ß-D-ribofuranosyl]-1,9-dihydro-6H-purin-6-one (2',3'-O-(1-
methoxyethylidene)inosine; (“dioxalane”)

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M. mixture of 9-(3,5-di-O-acetyl-2-bromo-2-deoxy-ß-D-arabinofuranosyl)-1,9-dihydro-6H-purin-6-one
and 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-ß-D-xylofuranosyl)-1,9-dihydro-6H-purin-6-one
(“bromoesters”)

Reagents

Hypoxanthine R. 1,7-dihydro-6H-purin-6-one; C5H4N4O.

A commercially available reagent of suitable grade.
Description. A white, crystalline powder.
Solubility. Very slightly soluble in water, sparingly soluble in boiling water, soluble in dilute acids
and in dilute alkali hydroxide solutions.
Melting point. Decomposes without melting at about 150 ˚C.
Thin-Layer Chromatography. Examine as prescribed in the monograph on Mercaptopurine (Vol.
4, p.77-79*); the chromatogram shows only one principal spot.

Silica gel for chromatography, octadecylsilyl, base-deactivated

A very finely divided silica gel, pretreated before the bonding of octadecylsilyl groups to mini
mize the interaction with basic components.

Monographs for antiretrovirals

Within the framework of the Procurement, Quality and Sourcing Project for HIV, Tuberculosis and Malaria
(http://www.who.int/prequal), The International Pharmacopoeia is collaborating with manufacturers, in-
dependent analytical drug quality control laboratories, national and regional pharmacopoeial bodies,
research, governments, and regulatory bodies to provide specifications and monographs for the follow-
ing antiretroviral agents: abacavir, didanosine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine,
ritonavir, saquinavir, stavudine, zidovudine. The final text for Indinavir sulfate is provided below.

Indinaviri sulfas (final)

Indinavir sulfate

C36H47N5O4,H2O4S

Relative molecular mass. 711.9

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Chemical name. (2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-

yl]amino]-5-oxopentyl]-N-(1,1-dimethylethyl)-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide sulfate;
CAS Reg. No. 157810-81-6.

Description. A white or almost white powder.

Solubility. Freely soluble in water, soluble in methanol.

Category. Antiretroviral (protease inhibitor).

Storage. Indinavir sulfate should be kept in a tightly closed container, protected from light.

Additional information. Indinavir sulfate occurs as the monoethanolate which is hygroscopic. It

converts to the hydrate upon loss of ethanol and exposure to moist air.

REQUIREMENTS

Indinavir sulfate contains not less than 98.5% and not more than 101.0% of C36H47N5O4,H2O4S calcu-
lated on anhydrous, ethanol free basis.

Identity tests

Either tests A, B and D, or tests C and D may be applied.

A. Carry out test A.1. or, where UV detection is not available, test A.2.

A.1. Carry out the test as described under ‘‘Thin-layer chromatography’’ (Vol. 1, p. 83*), using silica gel
R6 as the coating substance and a mixture of 8 volumes of dichloromethane R and 2 volumes of 2-
propanol as the mobile phase. Apply separately to the plate 10 µl of each of 2 solutions in methanol
containing (A) 1 mg of the test substance per ml and (B) 1 mg of indinavir sulfate RS per ml. After
removing the plate from the chromatographic chamber, allow it to dry exhaustively in a current of cool
air. Examine the chromatogram in ultraviolet light (254 nm).

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that
obtained with solution B.

A.2. Carry out the test as described under ‘‘Thin-layer chromatography’’ (Vol. 1, p. 83*), using silica gel
R5 as the coating substance and a mixture of 8 volumes of dichloromethane R and 2 volumes of 2-
propanol as the mobile phase. Apply separately to the plate 10 µl of each of 2 solutions in methanol
containing (A) 1 mg of the test substance per ml and (B) 1 mg of indinavir sulfate RS per ml. After
removing the plate from the chromatographic chamber, allow it to dry exhaustively in a current of cool
air. Spray with vanillin/sulfuric acid TS1. Heat the plate for a few minutes at 120˚C. Examine the
chromatogram in daylight.

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that
obtained with solution B.

B. The absorption spectrum of a 0.100 mg/ml solution, when observed between 220 nm and 280 nm,
exhibits one maximum at about 260 nm; the specific absorbance (A 1%1cm) is between 56 and 65.

C. Carry out the examination as described under ‘‘Spectrophotometry in the infrared region’’ (Vol. 1, p.
40*). The infrared absorption spectrum is concordant with the spectrum obtained from indinavir sulfate
RS or with the reference spectrum of indinavir sulfate.

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D. A 20 mg/ml solution yields reaction A described under “General identification tests” as characteristic
of sulfates (Vol. 1, p. 115*).

Specific optical rotation. Use a 10.0 mg/ml solution and calculate with reference to the anhydrous
and ethanol free substance; [a ]D20˚C = +27˚ to +31˚.

Heavy metals. Use 1.0 g for the preparation of the test solution as described under “Limit test for
heavy metals”, Procedure 1 (Vol. 1, p. 118*); determine the heavy metals content according to Method
A (Vol. 1, p. 119*); not more than 10 µg/g.

Sulfated ash.Not more than 1.0 mg/g.

Water. Determine as described under ‘‘Determination of water by the Karl Fischer method’’, Method A
(Vol. 1, p. 135*), using 0.5 g of the substance; the water content is not more than 15 mg/g.

pH value. pH of a 10 mg/ml solution in carbon-dioxide-free water R, 2.8-3.2.

Ethanol content. Determine by “Gas chromatography with static head-space injection”. Use a fused-
silica capillary or wide bore column 30 m long and 0.32 mm or 0.53 mm in internal diameter coated
with macrogol 20 000 R (film thickness: 0.25 µm).

As detector use a flame ionization detector.

Use nitrogen for chromatography R or helium for chromatography R as the carrier gas at an appropri-
ate pressure and a split ratio 1:5 with a linear velocity of about 35 cm/sec.

The following head-space injection conditions may be used:

Equilibration temperature (˚C) 80

Equilibration time (min) 60
Transfer line temperature (˚C) 85
Pressurization time (s) 30
Injection volume (ml) 1

Maintain the temperature of the column at 30 ˚C for 7 min, then raise the temperature at a rate of
35 ˚C per min to 180˚C and maintain for 10 min, maintaining the temperature of the injection port at
140 ˚C and that of the flame ionization detector at 250 ˚C.
Test solution. Dissolve 0.200 g of the test substance in purified water and dilute to 20.0 ml with the
same solvent. Introduce 5.0 ml of this solution and 1.0 ml of purified water into a headspace vial.
Prepare two more vials.
Reference solutions. Add 0.200 g of ethanol R to purified water and dilute to 200.0 ml with the same
solvent. Transfer respectively 2.0 ml, 3.0 ml and 4.0 ml in separate headspace injection vials and bring
the volume to 6.0 ml with purified water.
Blank solution. Introduce 6.0 ml of purified water into a headspace vial.
Analyse the blank solution and then alternatively three times the test solution and the three reference
solutions.
The test is not valid unless the relative standard deviation on the areas of the peaks obtained from the
test solutions is not more than 5%.
Calculate the ethanol content by using the results obtained with the test solution and with the reference
solutions; the ethanol content is not less than 50 mg/g and not more than 80 mg/g.

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Related substances. Carry out the test as described under “High–performance liquid chromatogra-
phy” (Vol. 5, p. 257*), using a stainless steel column (25 cm x 4.6 mm) packed with base-deactivated
octadecylsilyl silica gel for chromatography R (5µm).

Use the following conditions for gradient elution:

Mobile phase A: 30 volumes of acetonitrile R, 5 volumes of phosphate buffer pH 7.5 and

65 volumes of purified water.

Mobile phase B: 70 volumes of acetonitrile R, 5 volumes of phosphate buffer pH 7.5 and

25 volumes of purified water.

Prepare the phosphate buffer pH 7.5 by dissolving 1.4 g of anhydrous disodium hydrogen phosphate in
50 ml of purified water, adjust the pH to 7.5 by adding phosphoric acid (105 g/l) and dilute it to 100 ml
with purified water.

Time (min) Mobile phase A (% v/v) Mobile phase B (% v/v) Comments

0–5 93 7 Isocratic
5–25 93 to 20 7 to 80 Linear gradient
25–30 20 80 Isocratic
30–35 20 to 93 80 to 7 Return to the initial conditions
35–45 93 7 Isocratic re-equilibration

Prepare the following solutions. For solution (1) use 2.0 mg of the test substance per ml. For solution
(2) dilute a suitable volume of solution (1) to obtain a concentration equivalent to 2 µg of indinavir
sulfate per ml.

For the system suitability test: prepare solution (3) using 2 ml of solution (1) and 2 ml of sulfuric acid
(190 g/l), heat carefully in a water bath at 80˚C for 60 minutes.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at
a wavelength of 220 nm.

Maintain the column temperature at 40 ˚C, using, for example, a water-bath.

Inject 20 µl of solution (3). The test is not valid unless the resolution factor between the two major
peaks, with a retention time between 15 and 20 min, is not less than 3.5. If necessary adjust the
amount of acetonitrile in mobile phase A, or adjust the gradient programme.

Inject alternatively 20 µl each of solutions (1) and (2).

Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2). In
the chromatograms obtained with solution (1), the area of any peak, other than the principal peak, is
not greater than the area of the principal peak obtained with solution (2) (0.1 %). The sum of the areas
of all peaks, other than the principal peak, is not greater than five times the area of the principal peak
obtained with solution (2) (0.5 %). Disregard any peak with an area less than 0.5 times the area of the
principal peak in the chromatogram obtained with solution (2) (0.05%).

Assay. Dissolve 0.300 g, accurately weighed, in 50 ml of water and titrate with sodium hydroxide (0.1
mol/l) VS, determine the end point potentiometrically. Each ml of sodium hydroxide (0.1 mol/l) VS is
equivalent to 35.59 mg of C36H47N5O4,H2O4S; calculate with reference to the anhydrous and ethanol
free substance.

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Impurities Note: A list of known and potential impurities that have been shown to be controlled by the
tests in this monograph will be included for information, if and when the relevant information is
available.

Reagents

Silica gel for chromatography, octadecylsilyl, base deactivated

A very finely divided silica gel, pretreated before the bonding of octadecylsilyl groups to mini
mize the interaction with basic compounds.

Macrogol 20 000 R. Polyethyleneglycol 20 000

Description. White or almost white solid with a waxy or paraffin-like appearance.

Solubility. Very soluble in water and dichloromethane R. Practically insoluble in alcohol and in
fatty oils and mineral oils.

Nitrogen for chromatography.

Contains not less than 99.95% v/v of N2.

Helium for chromatography.

Contains not less than 99.995% v/v of He.

Monographs for antiretrovirals

Within the framework of the Procurement, Quality and Sourcing Project for HIV, Tuberculosis and Ma-
laria (http://www.who.int/prequal), The International Pharmacopoeia is collaborating with manufacturers,
independent analytical drug quality control laboratories, national and regional pharmacopoeial bodies,
research, governments, and regulatory bodies to provide specifications and monographs for the follow-
ing antiretroviral agents: abacavir, didanosine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine,
ritonavir, saquinavir, stavudine, zidovudine. The final text for nelfinavir mesilate is provided below.

Nelfinaviri mesilas (final)

Nelfinavir mesilate

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The International Pharmacopoeia WHO Drug Information Vol 19, No. 1, 2005

C32H45N3O4S,CH4O3S

Relative molecular mass. 663.9

Chemical name. (3S,4aS,8aS)-N-(1,1-dimethylethyl)-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-

methylbenzoyl)amino]-4-(phenylsulfanyl)butyl]decahydroisoquinoline-3-carboxamide methanesul-
fonate; CAS reg. No. 159989-65-8.

Description. A white or almost white powder.

Solubility. Practically insoluble in water and soluble in methanol R.

Category. Antiretroviral (Protease Inhibitor).

Storage. Nelfinavir mesilate should be kept in a tightly closed container, protected from light.

Additional information. Nelfinavir mesilate is hygroscopic.

REQUIREMENTS

Nelfinavir mesilate contains not less than 98.5% and not more than 101.0% of C32H45N3O4S,CH4O3S,
calculated with reference to the dried substance.

Identity tests

Either tests A and B or test C may be applied.

A. Carry out test A.1. or, where UV detection is not available, test A.2.

A.1. Carry out the test as described under ‘‘Thin-layer chromatography’’ (Vol. 1, p. 83*), using silica gel
R6 as the coating substance and a mixture of 67 volumes of dichloromethane R, 20 volumes of
acetonitrile R, 10 volumes of methanol R and 3 volumes of ammonia (~260 g/l) TS as the mobile
phase. Apply separately to the plate 5 µl of each of 2 solutions in methanol containing (A) 1 mg of the
test substance per ml and (B) 1 mg of nelfinavir mesilate RS per ml. After removing the plate from the
chromatographic chamber, allow it to dry exhaustively in a current of cool air. Examine the chromato-
gram in ultraviolet light (254 nm).

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that
obtained with solution B.

A.2. Carry out the test as described under ‘‘Thin-layer chromatography’’ (Vol. 1, p. 83*), using silica gel
R5 as the coating substance and a mixture of 67 volumes of dichloromethane R, 20 volumes of
acetonitrile R, 10 volumes of methanol R and 3 volumes of ammonia (~260 g/l) TS as the mobile
phase. Apply separately to the plate 5 µl of each of 2 solutions in methanol containing(A) 1 mg of the
test substance per ml and (B) 1 mg of nelfinavir mesilate RS per ml. After removing the plate from the
chromatographic chamber, allow it to dry exhaustively in a current of cool air. Spray with basic potas-
sium permanganate (5 g/l) TS. Examine the chromatogram in daylight.

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that
obtained with solution B.

B. The absorption spectrum of a 40 µg/ml solution in methanol R, when observed between 220 nm
and 280 nm, exhibits a maximum at about 253 nm; the specific absorbance (A 1% 1cm) is 124 to136.

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C. Carry out the examination as described under ‘‘Spectrophotometry in the infrared region’’ (Vol. 1, p.
40*). The infrared absorption spectrum is concordant with the spectrum obtained from nelfinavir
mesilate RS or with the reference spectrum of nelfinavir mesilate.

Specific optical rotation. Use a 10.0 mg/ml solution in methanol R and calculate with reference to
the dried substance; [a ]D20 ˚C = -105˚ to -125 ˚.

Heavy metals. Use 1.0 g in 30 ml of methanol R for the preparation of the test solution as described
under ‘‘Limit test for heavy metals’’, Procedure 2, (Vol. 1, p.118*); determine the heavy metals content
according to Method A (Vol. 1, p.119*); not more than 20 µg/g.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant mass at 100 ˚C; it loses not more than 30 mg/g.

Related substances. Carry out the test as described under “High–performance liquid chromatogra-
phy” (Vol. 5, p. 257*), using a stainless steel column (25 cm x 4.6 mm) packed with base-deactivated
octadecylsilyl silica gel for chromatography R (5µm) (hypersil BDS C18 is suitable). Use the following
conditions for gradient elution:

Mobile phase A: 27 volumes of acetonitrile R, 20 volumes of methanol R, 28 volumes of phosphate

buffer pH 3.4 and 25 volumes of purified water.

Mobile phase B: 41 volumes of acetonitrile R, 31 volumes of methanol R and 28 volumes of phosphate

buffer pH 3.4.

Prepare the phosphate buffer pH 3.4 by dissolving 4.88 g of anhydrous sodium dihydrogen phosphate
in 800 ml of purified water, adjust the pH to 3.4 by adding phosphoric acid (105 g/l) and dilute it to
1000 ml with purified water.

Time(min) Mobile phase A (% v/v) Mobile phase B (% v/v) Comments

0–27 100 0 Isocratic

27–60 100 to 0 0 to 100 Linear gradient
60–75 0 100 Isocratic
75–80 0 to 100 100 to 0 Return to the initial conditions
80–90 100 0 Isocratic re-equilibration

Prepare the following solutions using mobile phase A as diluent. For solution (1) use 2.0 mg of the test
substance per ml. For solution (2) dilute a suitable volume of solution (1) to obtain a concentration
equivalent to 10.0 µg of Nelfinavir mesilate per ml. For solution (3) use 100 µg of methanesulfonic acid
R per ml.

For the system suitability test: prepare solution (4) using 2 ml of solution (1) and 5 ml of sulfuric acid
(475 g/l), heat carefully in a boiling water bath for 30 minutes.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at
a wavelength of about 225 nm.

Maintain the column at 35 ˚C using, for example, a water-bath.

Inject 20 µl of solution (4). The test is not valid unless the resolution factor between the principal peak
(retention time = about 27 minutes) and the peak with a retention time relative to the principal peak of

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about 0.2 is not less than 15. The test is also not valid unless the resolution factor between the last two
peaks out of three peaks, which increase during the decomposition process, is not less than 4.0. The
ratio of the retention times of these two peaks relative to the principal peak is about 1.8 and 1.9
respectively. If necessary adjust the amount of acetonitrile R in both mobile phases A and B, or adjust
the gradient program.

Inject 20 µl of solution (3).

Inject alternatively 20 µl each of solutions (1) and (2).

Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2)
and calculate the content of related substances as a percentage. In the chromatograms obtained with
solution (1), the area of any peak, other than the principal peak, is not greater than that obtained with
solution (2) (0.5 %). The sum of the areas of all peaks, other than the principal peak, is not greater than
twice the area of the principal peak obtained with solution (2) (1.0 %). Disregard any peak with an area
less than 0.1 times the area of the principal peak in the chromatogram obtained with solution (2)
(0.05%) and any peak due to methanesulfonic acid, corresponding to the principal peak in the chroma-
togram obtained with solution (3).

Assay. Dissolve about 0.50 g, accurately weighed, in 50 ml of methanol R and titrate with sodium
hydroxide (0.1 mol/l) VS, determine the end point potentiometrically. Perform a blank determination
and make the necessary correction. Each ml of sodium hydroxide (0.1 mol/l) VS is equivalent to 66.39
mg of C32H45N3O4S.CH4O3S.

Impurities Note: A list of known and potential impurities that have been shown to be controlled by the
tests in this monograph will be included for information, if and when the relevant information is avail-
able.

Reagents

Silica gel for chromatography, octadecylsilyl, base-deactivated

A very finely divided silica gel, pre-treated before the bonding of octadecylsilyl groups to
minimize the interaction with basic compounds.

Methanesulfonic acid R
Molecular formula. CH4O3S
Description. Colourless and corrosive liquid, strong irritant.
Solubility. Miscible with water.
Density (d). ~1.48.
Melting point. About 20 ˚C.

Potassium permanganate, basic (5 g/l) TS

A solution of potassium permanganate R containing about 5 g of KMnO4 per litre of sodium
hydroxide (1 mol/l).

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Monographs for antiretrovirals

Within the framework of the Procurement, Quality and Sourcing Project for HIV, Tuberculosis and
Malaria (http://www.who.int/prequal), The International Pharmacopoeia is collaborating with manufac-
turers, independent analytical drug quality control laboratories, national and regional pharmacopoeial
bodies, research, governments, and regulatory bodies to provide specifications and monographs for
the following antiretroviral agents: abacavir, didanosine, efavirenz, indinavir, lamivudine, nelfinavir,
nevirapine, ritonavir, saquinavir, stavudine, zidovudine. The final text for ritonavir is provided below.

Ritonavirum (final)
Ritonavir

C37H48N6O5S2

Relative molecular mass. 721.0

Chemical name. thiazol-5-ylmethyl [(1S,2S,4S)-1-benzyl-2-hydroxy-4-[[(2S)-3-methyl-2-[[methyl[[2-(1-

methylethyl)thiazol-4-yl]methyl]carbamoyl]amino]butanoyl]amino]-5-phenylpentyl]carbamate; CAS Reg.
NO.155213-67-5.

Description. A white or almost white powder.

Solubility. Practically insoluble in water, freely soluble in methanol R, sparingly soluble in acetone R
and very slightly soluble in acetonitrile R.

Category. Antiretroviral (Protease Inhibitor).

Storage. Ritonavir should be kept in a well-closed container, protected from light.

Additional information. Ritonavir may exhibit polymorphism.

REQUIREMENTS

Ritonavir contains not less than 98.5 % and not more than 101.0 % of C37H48N6O5S2, calculated with
reference to the dried substance.

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Identity tests

Either tests A and B or test C may be applied.

A. Note: TLC to be added before publication in 4th Edition*; meanwhile use test C.

B. The absorption spectrum of a 40 µg/ml solution in methanol R, when observed between 220 nm and
280 nm, exhibits one maximum at about 240 nm; the specific absorbance (A 1% 1cm) is 116 to128.

C. Carry out the examination as described under ‘‘Spectrophotometry in the infrared region’’ (Vol. 1, p.
40*). The infrared absorption spectrum is concordant with the spectrum obtained from ritonavir RS or
with the reference spectrum of ritonavir.

If the spectra obtained in the solid-state show differences, dissolve the test substance and the refer-
ence substance separately in a minimal amount of methanol R, crystallise by adding just enough water
drop by drop, filter and dry for about one hour and record the spectra again.

Specific optical rotation. Use a 20.0 mg/ml solution in methanol R; [α ]D20 ˚C = +7˚ to +10.5˚.

Heavy metals. Use 1.0 g in 30 ml of methanol R for the preparation of the test solution as described
under ‘‘Limit test for heavy metals’’, Procedure 2, (Vol. 1, p. 118*); determine the heavy metals content
according to method A (Vol. 1, p. 119*); not more than 20 µg/g.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry for 2 hours at 105 ˚C; it loses not more than 5 mg/g.

Related substances. Carry out the test as described under “High–performance liquid chromatogra-
phy” (Vol. 5, p. 257*), using a stainless steel column (25 cm x 4.6 mm) packed with base-deactivated
octadecylsilyl silica gel for chromatography R (5 µm).

Use the following conditions for gradient elution:

Mobile phase A: 35 volumes of acetonitrile R, 28 volumes sodium phosphate buffer pH 4.0 and 37
volumes of purified water.

Mobile phase B: 70 volumes of acetonitrile R, 28 volumes sodium phosphate buffer pH 4.0 and 2
volumes of purified water.
Prepare the sodium phosphate buffer pH 4.0 by dissolving 7.8 g of sodium dihydrogen phosphate
dihydrate and 1.88 g of sodium hexanesulfonate R in 800 ml of purified water, adjust the pH to 4.0 by
adding phosphoric acid (105 g/l) and dilute to 1000 ml with purified water.

Time (min) Mobile phase A (% v/v) Mobile phase B (% v/v) Comments

0–20 70 30 Isocratic
20–30 70 to 0 30 to 100 Linear gradient
30–40 0 100 Isocratic
40–45 0 to 70 100 to 30 Linear gradient
45–50 70 30 Isocratic re-equilibration

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Prepare the following solutions using mobile phase A as diluent. For solution (1) use 0.5 mg of the test
substance per ml. For solution (2) dilute a suitable volume of solution (1) to obtain a concentration
equivalent to 0.5 µg of ritonavir per ml.

For the system suitability test: prepare solution (3) using 5 ml of solution (1) and 1 ml of sulfuric acid
(475 g/l), heat in a boiling water bath for 20 minutes.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at
a wavelength of 240 nm.

Maintain the column temperature at 35˚ C using, for example, a water-bath.

Inject 20 µl of solution (3). The test is not valid unless the resolution between the principal peak (reten-
tion time = about 22 minutes) and the peak with a retention time relative to the principal peak of about
0.8 is not less than 3.5. The test is also not valid unless the resolution between the principal peak and
the peak with a retention time relative to the principal peak of about 1.5 is not less than 9.0. If neces-
sary adjust the amount of acetonitrile in both mobile phases A and B, or adjust the gradient programme.

Inject alternatively 20 µl each of solutions (1) and (2).

Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2). In
the chromatograms obtained with solution (1), the area of any peak, other than the principal peak, is not
greater than three times the area of the principal peak obtained with solution (2) (0.3%). In the
chromatograms obtained with solution (1), the areas of not more than two peaks, other than the
principal peak, are greater than twice the area of the principal peak obtained with solution (2) (0.2%)
and the areas of not more than four such peaks are greater than the area of the principal peak obtained
with solution (2) (0.1%). The sum of the areas of all peaks, other than the principal peak, is not greater
than ten times the area of the principal peak obtained with solution (2) (1.0%). Disregard any peak with
an area less than 0.5 times the area of the principal peak in the chromatogram obtained with solution
(2) (0.05%).

Assay. Dissolve 0.25 g, accurately weighed, in 30 ml of glacial acetic acid R1 and titrate with perchloric
acid (0.1 mol/l) VS, determine the end point potentiometrically as described under ‘‘Non aqueous
titration’’ Method A (Vol. 1, p. 131*). Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 36.05 mg
of C37H48N6O5S2.

Impurities. Note: A list of known and potential impurities that have been shown to be controlled by the
tests in this monograph will be included for information, if and when the relevant information is avail-
able.

Reagents

Silica gel for chromatography, octadecylsilyl, base deactivated

A very finely divided silica gel, pre-treated before the bonding of octadecylsilyl groups to mini
mise the interaction with basic compounds.

Sodium dihydrogen phosphate dihydrate

[Sodium biphosphate]; sodium phosphate, monobasic; NaH2 PO4, 2 H2O

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The International Pharmacopoeia WHO Drug Information Vol 19, No. 1, 2005

Monographs for antiretrovirals

Within the framework of the Procurement, Quality and Sourcing Project for HIV, Tuberculosis and
Malaria (http://www.who.int/prequal), The International Pharmacopoeia is collaborating with manufac-
turers, independent analytical drug quality control laboratories, national and regional pharmacopoeial
bodies, research, governments, and regulatory bodies to provide specifications and monographs for
the following antiretroviral agents: abacavir, didanosine, efavirenz, indinavir, lamivudine, nelfinavir,
nevirapine, ritonavir, saquinavir, stavudine, zidovudine. The final text for saquinavir is provided below.

Saquinaviri (final)

Saquinavir

C38H50N6O5

Relative molecular mass. 670.8

Chemical name. (2S)-N1-[(1S,2R)-1-benzyl-3-[(3S,4aS,8aS)-3-[(1,1 dimethylethyl)carbamoyl]

octahydroisoquinolin-2(1H)-yl]-2-hydroxypropyl]-2-[(quinolin-2-ylcarbonyl)amino]butanediamide;
CAS Reg. NO.127779-20-8.

Description. A white or almost white powder.

Solubility. Practically insoluble in water and soluble in methanol.

Category. Antiretroviral (Protease Inhibitor).

Storage. Saquinavir should be kept at 2–8 ˚C in a tightly-closed container, protected from light.

Additional information. Saquinavir is slightly hygroscopic.

REQUIREMENTS

Saquinavir contains not less than 98.5 % and not more than 101.0 % of C38H50N6O5, calculated with
reference to the dried substance.

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WHO Drug Information Vol 19, No. 1, 2005 The International Pharmacopoeia

Identity tests

Either tests A and B or test C may be applied.

A. Carry out test A.1. or, where UV detection is not available, test A.2.

A.1. Carry out the test as described under ‘‘Thin-layer chromatography’’ (Vol. 1, p. 83*), using silica gel
R6 as the coating substance and a mixture of 8 volumes of dichloromethane R and 2 volumes of 2-
propanol R as the mobile phase. Apply separately to the plate 5 µl of each of 2 solutions in methanol R
containing (A) 1 mg of the test substance per ml and (B) 1 mg of saquinavir RS per ml. After removing
the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of cool air.
Examine the chromatogram in ultraviolet light (254 nm).

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that
obtained with solution B.

A.2. Carry out the test as described under ‘‘Thin-layer chromatography’’ (Vol. 1, p. 83*), using silica gel
R5 as the coating substance and a mixture of 8 volumes of dichloromethane R and 2 volumes of 2-
propanol R as the mobile phase. Apply separately to the plate 5 µl of each of 2 solutions in methanol R
containing (A) 1 mg of the test substance per ml and (B) 1 mg of saquinavir RS per ml. After removing
the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of cool air.
Dip the plate in dilute basic potassium permanganate (1 g/l) TS. Examine the chromatogram in
daylight.

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that
obtained with solution B.

B. The absorption spectrum of a 20 µg/ml solution in methanol R, when observed between 220 nm and
280 nm, exhibits one maximum at about 238 nm; the specific absorbance (A 1% 1cm) is 670 to 730.

C. Carry out the examination as described under ‘‘Spectrophotometry in the infrared region’’ (Vol. 1, p.
40*). The infrared absorption spectrum is concordant with the spectrum obtained from saquinavir RS or
with the reference spectrum of saquinavir.

Specific optical rotation. Use a 5.0 mg/ml solution in methanol R; [α ]D20 ˚C = - 50 ˚ to - 56 ˚

Heavy metals. Use 1.0 g in 30 ml of methanol R for the preparation of the test solution as described
under ‘‘ Limit test for heavy metals’’, Procedure 2, (Vol. 1, p. 118*); determine the heavy metals content
according to Method A (Vol. 1, p. 119*); not more than 10 µg/g.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry for 5 hours at 105 ˚C; it loses not more than 20 mg/g.

Related substances. Carry out the test as described under “High–performance liquid chromatography”
(Vol. 5, p. 257*), using a stainless steel column (25 cm x 4.6 mm) packed with base-deactivated
octadecylsilyl silica gel for chromatography R (5 µm).

Use the following conditions for gradient elution:

Mobile phase A: 50 volumes of a mixture of 5 parts of acetonitrile R and 2 parts methanol R, 15

volumes of phosphate buffer pH 3.4 and 35 volumes of purified water.

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Mobile phase B: 70 volumes of acetonitrile R, 15 volumes of phosphate buffer pH 3.4 and 15 volumes
of purified water.

Prepare the phosphate buffer pH 3.4 by dissolving 4.88 g of anhydrous sodium dihydrogen phosphate
in 800 ml of purified water, adjust the pH to 3.4 by adding phosphoric acid (105 g/l) and dilute to 1000
ml with purified water.

Time (min) Mobile phase A (%v/v) Mobile phase B (%v/v) Comments

0–5 100 0 Isocratic

25–45 100 to 45 0 to 55 Linear gradient
45–55 45 55 Isocratic
55–60 45 to 100 55 to 0 Linear gradient
60–70 100 0 Isocratic re-equilibration

Prepare the following solutions using mobile phase A as diluent. For solution (1) use 0.5 mg of the test
substance per ml. For solution (2) dilute a suitable volume of solution (1) to obtain a concentration
equivalent to 0.5 µg of saquinavir per ml.

For the system suitability test: prepare solution (3) using 2 ml of solution (1) and 5 ml of sulfuric acid
(475 g/l), heat carefully in a boiling water-bath for 30 minutes.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at
a wavelength of 220 nm.

Maintain the column temperature at 30 ˚C using, for example, a water-bath.

Inject 20 µl of solution (3). The test is not valid unless the resolution between the peak due to saquina-
vir (retention time = about 21 minutes) and the peak of similar size with a retention time of about 0.45
relative to the saquinavir peak is not less than 14. The test is also not valid unless the resolution
between two smaller peaks of similar size, eluted after the saquinavir peak and which increase during
decomposition, is not less than 4.0. The ratio of the retention times of these two peaks relative to the
saquinavir peak is about 1.8 and 1.9 respectively. If necessary adjust the amount of acetonitrile in both
mobile phases A and B, or adjust the gradient program.

Inject alternatively 20 µl each of solutions (1) and (2).

Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2). In
the chromatograms obtained with solution (1), the area of any peak, other than the principal peak, is
not greater than twice the area of the principal peak obtained with solution (2) (0.2%) and the area of
not more than one such peak is greater than the area of the principal peak obtained with solution (2)
(0.1 %). The sum of the areas of all peaks, other than the principal peak, is not greater than five times
the area of the principal peak obtained with solution (2) (0.5 %). Disregard any peak with an area less
than 0.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%).

Assay. Dissolve 0.300 g, accurately weighed, in 50 ml of glacial acetic acid R1 and titrate with perchlo-
ric acid (0.1 mol/l) VS, determine the end point potentiometrically as described under ‘‘Non aqueous
titration’’ method A (Vol.1, p. 131). Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 33.54 mg of
C38H50N6O5; calculate with reference to the dried substance.

Impurities
Note: A list of known and potential impurities that have been shown to be controlled by the tests in this
monograph will be included for information, if and when the relevant information is available.

* Refers to The International Pharmacopoeia

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WHO Drug Information Vol 19, No. 1, 2005 The International Pharmacopoeia

Reagents

Silica gel for chromatography, octadecylsilyl, base deactivated

A very finely divided silica gel, pre-treated before the bonding of octadecylsilyl groups to
minimize the interaction with basic compounds.

Potassium permanganate, basic, dilute (1 g/l) TS

A solution of potassium permanganate R containing about 1 g of KMnO4 per litre of sodium
hydroxide (1 mol/l).

Monographs for antiretrovirals

Within the framework of the Procurement, Quality and Sourcing Project for HIV, Tuberculosis and
Malaria (http://www.who.int/prequal), The International Pharmacopoeia is collaborating with manufac-
turers, independent analytical drug quality control laboratories, national and regional pharmacopoeial
bodies, research, governments, and regulatory bodies to provide specifications and monographs for
the following antiretroviral agents: abacavir, didanosine, efavirenz, indinavir, lamivudine, nelfinavir,
nevirapine, ritonavir, saquinavir, stavudine, zidovudine. The final text for saquinavir mesilate is provided
below.

Saquinaviri mesilas (final)

Saquinavir mesilate

C38H50N6O5.CH4O3S

Relative molecular mass. 767.0

Chemical name. (2S)-N1-[(1S,2R)-1-benzyl-3-[(3S,4aS,8aS)-3-[(1,1-

dimethylethyl)carbamoyl]octahydroisoquinolin-2(1H)-yl]-2-hydroxypropyl]-2-[(quinolin-2-
ylcarbonyl)amino]butanediamide methanesulfonate; CAS Reg. No. 149845-06-7.

Description. A white or almost white powder.

Solubility. Very slightly soluble in water and sparingly soluble in methanol R.

* Refers to The International Pharmacopoeia

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The International Pharmacopoeia WHO Drug Information Vol 19, No. 1, 2005

Category. Antiretroviral (Protease Inhibitor).

Storage. Saquinavir mesilate should be kept in a tightly-closed container, protected from light.

Additional information. Saquinavir mesilate is slightly hygroscopic.

REQUIREMENTS

Saquinavir mesilate contains not less than 98.5 % and not more than 101.0 % of C38H50N6O5.CH4O3S
calculated with reference to the dried substance.

Identity tests

Either tests A and B or test C may be applied.

A. Carry out test A.1. or, where UV detection is not available, test A.2.

A.1. Carry out the test as described under ‘‘Thin-layer chromatography’’ (Vol. 1, p. 83*), using silica gel
R6 as the coating substance and a mixture of 8 volumes of dichloromethane R and 2 volumes of 2-
propanol R as the mobile phase. Apply separately to the plate 5 µl of each of the following 2 solutions
in methanol (A) 1 mg of the test substance per ml and (B) 1 mg of saquinavir mesilate RS per ml. After
removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current
of cool air. Examine the chromatogram in ultraviolet light (254 nm).

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that
obtained with solution B.

A.2. Carry out the test as described under ‘‘Thin-layer chromatography’’ (Vol. 1, p. 83*), using silica gel
R5 as the coating substance and a mixture of 8 volumes of dichloromethane R and 2 volumes of 2-
propanol R as the mobile phase. Apply separately to the plate 5 µl of each of the following 2 solutions
in methanol (A) 1 mg of the test substance per ml and (B) 1 mg of saquinavir mesilate RS per ml. After
removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current
of cool air. Dip the plate in dilute basic potassium permanganate (1 g/l) TS. Examine the chromato-
gram in daylight.

The principal spot obtained with solution A corresponds in position, appearance, and intensity with that
obtained with solution B.

B. The absorption spectrum of a 10 µg/ml solution in methanol R, when observed between

220 nm and 280 nm, exhibits one maximum at about 239 nm; the specific absorbance
(A 1%1cm) is 580 to 640.

C. Carry out the examination as described under ‘‘Spectrophotometry in the infrared region’’
(Vol. 1, p. 40*). The infrared absorption spectrum is concordant with the spectrum obtained
from saquinavir mesilate RS or with the reference spectrum of saquinavir mesilate.

Specific optical rotation. Use a 5.0 mg/ml solution in methanol R and calculate with reference to the
dried substance; [α ]D20 ˚C = - 33 ˚ to - 39 ˚.

Heavy metals. Use 0.5 g in 30 ml of methanol R for the preparation of the test solution as described
under ‘‘Limit test for heavy metals’’, Procedure 2, (Vol. 1, p. 118*); determine the heavy metals content
according to Method A (Vol. 1, p. 119*); not more than 20 µg/g.

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WHO Drug Information Vol 19, No. 1, 2005 The International Pharmacopoeia

Sulfated ash.Not more than 1.0 mg/g.

Loss on drying. Dry for 5 hours at 105 ˚C; it loses not more than 10 mg/g.

Related substances. Carry out the test as described under “High–performance liquid chromatogra-
phy” (Vol. 5, p. 257*), using a stainless steel column (25 cm x 4.6 mm) packed with base-deactivated
octadecylsilyl silica gel for chromatography R (5 µm).

Use the following conditions for gradient elution:

Mobile phase A: 50 volumes of a mixture of 5 parts of acetonitrile R and 2 parts of methanol R, 15

volumes of phosphate buffer pH 3.4 and 35 volumes of purified water.

Mobile phase B: 70 volumes of acetonitrile R, 15 volumes of phosphate buffer pH 3.4 and 15 volumes
of purified water.

Prepare the phosphate buffer pH 3.4 by dissolving 4.88 g of anhydrous sodium dihydrogen phosphate
in 800 ml of purified water, adjust the pH to 3.4 by adding phosphoric acid (105 g/l) and dilute to 1000
ml with purified water.

Time (min) Mobile phase A (%) Mobile phase B (%) Comments

0–25 100 0 Isocratic

25–45 100 to 45 0 to 55 Linear gradient
45–55 45 55 Isocratic
55–60 45 to 100 55 to 0 Linear gradient
60–70 100 0 Isocratic re-equilibration

Prepare the following solutions using mobile phase A as diluent. For solution (1) use 0.5 mg of the test
substance per ml. For solution (2) dilute a suitable volume of solution (1) to obtain a concentration
equivalent to 0.5 µg of saquinavir per ml.

For the system suitability test: prepare solution (3) using 2 ml of solution (1) and 5 ml of sulfuric acid
(475 g/l), heat carefully in a boiling water-bath for 30 minutes.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at
a wavelength of 220 nm.

Maintain the column temperature at 30 ˚C using, for example, a water-bath.

Inject 20 µl of solution (3). The test is not valid unless the resolution between the peak due to saquina-
vir (retention time = about 21 minutes) and the peak of similar size with a retention time of about 0.45
relative to the saquinavir peak is not less than 14. The test is also not valid unless the resolution
between two smaller peaks of similar size, eluted after the saquinavir peak and which increase during
decomposition, is not less than 4.0. The ratio of the retention times of these two peaks relative to the
saquinavir peak is about 1.8 and 1.9 respectively. If necessary adjust the amount of acetonitrile in both
mobile phases A and B, or adjust the gradient programme. Inject alternatively 20 µl each of solutions
(1) and (2).

Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2). In
the chromatograms obtained with solution (1), the area of any peak, other than the principal peak, is
not greater than the area of the principal peak obtained with solution (2) (0.1 %). The sum of the areas

* Refers to The International Pharmacopoeia

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The International Pharmacopoeia WHO Drug Information Vol 19, No. 1, 2005

of all such peaks is not greater than five times the area of the principal peak obtained with solution (2)
(0.5 %). Disregard any peak with an area less than 0.5 times the area of the principal peak in the
chromatogram obtained with solution (2) (0.05 %).

Assay. Dissolve about 0.500 g, accurately weighed, in 70 ml of methanol R and titrate with sodium
hydroxide (0.1 mol/l) VS determining the end point potentiometrically. Perform a blank determination
and make the necessary correction. Each ml of sodium hydroxide (0.1 mol/l) VS is equivalent to 76.70
mg of C38H50N6O5.CH4O3S; calculate with reference to the dried substance.

Impurities Note: A list of known and potential impurities that have been shown to be controlled by the
tests in this monograph will be included for information, if and when the relevant information is avail-
able.

Reagents

Silica gel for chromatography, octadecylsilyl, base deactivated

A very finely divided silica gel, pre-treated before the bonding of octadecylsilyl groups to
minimize the interaction with basic compounds.

Potassium permanganate, basic, dilute (1 g/l) TS

A solution of potassium permanganate R containing about 1 g of KMnO4 per litre of sodium
hydroxide (1 mol/l).

* Refers to The International Pharmacopoeia

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WHO Drug Information, Vol. 19, No. 1, 2005 Recommended INN: List 53

International Nonproprietary Names for

Pharmaceutical Substances (INN)
RECOMMENDED International Nonproprietary Names:
List 53
Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended
International Nonproprietary Names for Pharmaceutical Substances [Off. Rec. Wld Health Org., 1955, 60, 3 (Resolution
EB15.R7); 1969, 173, 10 (Resolution EB43.R9)], the following names are selected as Recommended International
Nonproprietary Names. The inclusion of a name in the lists of Recommended International Nonproprietary Names does not
imply any recommendation of the use of the substance in medicine or pharmacy.
Lists of Proposed (1–91) and Recommended (1–52) International Nonproprietary Names can be found in Cumulative List
No. 11, 2004 (available in CD-ROM only).

Dénominations communes internationales

des Substances pharmaceutiques (DCI)
Dénominations communes internationales RECOMMANDÉES:
Liste 53
Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de
Dénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org. mond.
Santé, 1955, 60, 3 (résolution EB15.R7); 1969, 173, 10 (résolution EB43.R9)] les dénominations ci-dessous sont choisies
par l’Organisation mondiale de la Santé en tant que dénominations communes internationales recommandées. L’inclusion
d’une dénomination dans les listes de DCI recommandées n’implique aucune recommandation en vue de l’utilisation de la
substance correspondante en médecine ou en pharmacie.
On trouvera d’autres listes de Dénominations communes internationales proposées (1–91) et recommandées (1–52) dans
la Liste récapitulative No. 11, 2004 (disponible sur CD-ROM seulement).

Denominaciones Comunes Internacionales

para las Sustancias Farmacéuticas (DCI)
Denominaciones Comunes Internacionales RECOMENDADAS:
Lista 53
De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones Comunes
Internacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (Resolución
EB15.R7); 1969, 173, 10 (Resolución EB43.R9)], se comunica por el presente anuncio que las denominaciones que a
continuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas. La
inclusión de una denominación en las listas de las Denominaciones Comunes Recomendadas no supone recomendación
alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia.
Las listas de Denominaciones Comunes Internacionales Propuestas (1–91) y Recomendadas (1–52) se encuentran
reunidas en Cumulative List No. 11, 2004 (disponible sólo en CD-ROM).

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Recommended INN: List 53 WHO Drug Information, Vol. 19, No. 1, 2005

Latin, English, French, Spanish:

Recommended INN Chemical name or description; Molecular formula; Graphic formula

DCI Recommandée Nom chimique ou description; Formule brute; Formule développée

DCI Recomendada Nombre químico o descripción; Fórmula empírica; Fórmula desarrollada

abataceptum
abatacept 1-25-oncostatin M (human precursor) fusion protein with CTLA-4
(antigen) (human) fusion protein with immunoglobulin G1 (human
heavy chain fragment), bimolecular (146→146')-disulfide

abatacept (146→146')-disulfure bimoléculaire de

151 156 162 165 174
[Gln ,Ser ,Ser ,Ser ,Ser ] (protéine de fusion entre le
précurseur de l'oncostatine M humaine-(1-25)-peptide (séquence
signal), la protéine 4 cytotoxique du lymphocyte-T humaine-[2-126]-
peptide (partie extracellulaire de l'antigène CD152) et le peptide de
233 résidus fragment C-terminal de la chaîne lourde de
l'immunoglobuline G1 humaine)

abatacept 1-25-oncostatina M (precursor humano) proteína da fusión con

CTLA-4 (antígeno) (humano) proteína da fusión con
inmunoglobulina G1 (fragmento humano de la pesada cadena),
bimolecular (146→146')-disulfido

C3750H5872N982O1154S38

MGVLLTQRTL LSLVLALLFP SMASMAMHVA QPAVVLASSR

GIASFVCEYA SPGKATEVRV TVLRQADSQV TEVCAATYMM
GNELTFLDDS ICTGTSSGNQ *
VNLTIQGLRA MDTGLYICKV
ELMYPPPYYL *
GIGNGTQIYV IDPEPCPDSD QEPKSSDKTH
TSPPSPAPEL LGGSSVFLFP PKPKDTLMIS RTPEVTCVVV
DVSHEDPEVK FNWYVDGVEV HNAKTKPREE *
QYNSTYRVVS
VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR
EPQVYTLPPS RDELTKNQVS LTCLVKGFYP SDIAVEWESN
GQPENNYKTT PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS
CSVMHEALHN HYTQKSLSLS PGK
2

* glycosylation site
* sites de glycosylation
* posiciones de glicosilación

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WHO Drug Information, Vol. 19, No. 1, 2005 Recommended INN: List 53

acotiamidum
acotiamide N-[2-[bis(1-methylethyl)amino]ethyl]-2-[(2-hydroxy-
4,5-dimethoxybenzoyl)amino]thiazol-4-carboxamide

acotiamide N-[2-[bis(1-méthyléthyl)amino]éthyl]-2-[(2-hydroxy-
4,5-diméthoxybenzoyl)amino]thiazol-4-carboxamide

acotiamida N-[2-[bis(1-metiletil)amino]etil]-2-[(2-hidroxi-
4,5-dimetoxibenzoil)amino]tiazol-4-carboxamida

C21H30N4O5S

O
NH
CH3
O N
N
H3CO CH3
N S H 3C
H CH3
H3CO OH

alagebrium chloridum
alagebrium chloride 4,5-dimethyl-3-(2-oxo-2-phenylethyl)thiazolium chloride

chlorure d'alagébrium chlorure de 4,5-diméthyl-3-(2-oxo-2-phényléthyl)thiazolium

cloruro de alagebrio cloruro de 4,5-dimetil-3-(2-fenil-2-oxoetil)tiazolio

C13H14ClNOS

S O
H3C N+
Cl-
H3C

alglucosidasum alfa
alglucosidase alfa human lysosomal prepro-α-glucosidase-(57-952)-peptide
199-arginine-223-histidine variant

alglucosidase alfa 199-arginine-223-histidine variant du (57-952)-peptide de la prépro-

α-glucosidase lysosomale humaine

alglucosidasa alfa 199-arginina-223-histidina variante del (57-952)-peptido de la

prepro-α-glucosidasa lysosómica humana

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Recommended INN: List 53 WHO Drug Information, Vol. 19, No. 1, 2005

C4490H6823N1197O1298S32

QQGASRPGPR DAQAHPGRPR AVPTQCDVPP NSRFDCAPDK

AITQEQCEAR GCCYIPAKQG LQGAQMGQPW CFFPPSYPSY
*
KLENLSSSEM GYTATLTRTT PTFFPKDILT LRLDVMMETE
NRLHFTIKDP ANRRYEVPLE TPRVHSRAPS PLYSVEFSEE
*
PFGVIVHRQL DGRVLLNTTV APLFFADQFL QLSTSLPSQY
ITGLAEHLSP LMLSTSWTRI TLWNRDLAPT PGANLYGSHP
FYLALEDGGS AHGVFLLNSN AMDVVLQPSP ALSWRSTGGI
LDVYIFLGPE PKSVVQQYLD VVGYPFMPPY WGLGFHLCRW
*
GYSSTAITRQ VVENMTRAHF PLDVQWNDLD YMDSRRDFTF
NKDGFRDFPA MVQELHQGGR RYMMIVDPAI SSSGPAGSYR
*
PYDEGLRRGV FITNETGQPL IGKVWPGSTA FPDFTNPTAL
AWWEDMVAEF HDQVPFDGMW IDMNEPSNFI RGSEDGCPNN
ELENPPYVPG VVGGTLQAAT ICASSHQFLS THYNLHNLYG
LTEAIASHRA LVKARGTRPF VISRSTFAGH GRYAGHWTGD
*
VWSSWEQLAS SVPEILQFNL LGVPLVGADV CGFLGNTSEE
LCVRWTQLGA FYPFMRNHNS LLSLPQEPYS FSEPAQQAMR
KALTLRYALL PHLYTLFHQA HVAGETVARP LFLEFPKDSS
TWTVDHQLLW GEALLITPVL QAGKAEVTGY FPLGTWYDLQ
TVPIEALGSL PPPPAAPREP AIHSEGQWVT LPAPLDTINV
HLRAGYIIPL QGPGLTTTES RQQPMALAVA LTKGGEARGE
LFWDDGESLE VLERGAYTQV *
IFLARNNTIV NELVRVTSEG
*
AGLQLQKVTV LGVATAPQQV LSNGVPVSNF TYSPDTKVLD
ICVSLLMGEQ FLVSWC
* glycosylation sites
* sites de glycosylation
* posiciones de glicosilación

armodafinilum
armodafinil 2-[(R)-(diphenylmethyl)sulfinyl]acetamide

armodafinil (-)-2-[(R)-(diphénylméthyl)sulfinyl]acétamide

armodafinilo (-)-2-[(R)-(difenilmetil)sulfinil]acetamida

C15H15NO2S

O O
S
NH2

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bamirastinum
bamirastine 2-[6-({3-[4-(diphenylmethoxy)piperidin-1-yl]propyl}amino)imidazo=
[1,2-b]pyridazin-2-yl]-2-methylpropanoic acid

bamirastine acide 2-[6-[[3-[4-(diphénylméthoxy)pipéridin-1-yl]propyl]amino]=

imidazo[1,2-b]pyridazin-2-yl]-2-méthylpropanoïque

bamirastina ácido 2-[6-[[3-[4-(difenilmetoxi)piperidin-1-il]propil]amino]imidazo=

[1,2-b]piridazin-2-il]-2-metilpropanoico

C31H37N5O3

N CO2H

N CH3
N N N CH3
H
O

befetupitantum
befetupitant 2-[3,5-bis(trifluomethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-
6-(morpholin-4-yl)pyridin-3-yl]propanamide

béfétupitant 2-[3,5-bis(trifluométhyl)phényl]-N,2-diméthyl-N-[4-(2-méthylphényl)-
6-(morpholin-4-yl)pyridin-3-yl]propanamide

befetupitant 2-[3,5-bis(trifluometil)fenil]-N,2-dimetil-N-[4-(2-metilfenil)-6-(morfolin-
4-il)piridin-3-il]propanamida

C29H29F6N3O2

O CF3
N N
O

N CF3
CH3
H3C CH3 CH3

belotecanum
belotecan (4S)-4-ethyl-4-hydroxy-11-[2-(isopropylamino)ethyl]-1,12-dihydro-
14H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione

bélotécan (4S)-4-éthyl-4-hydroxy-11-[2-[(1-méthyléthyl)amino]éthyl]-
1,12-dihydro-14H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoléine-
3,14(4H)-dione

belotecán (4S)-4-etil-4-hidroxi-11-[2-(isopropilamino)etil]-1,12-dihidro-
14H-pirano[3’,4’:6,7]indolizino[1,2-b]quinolina-3,14(4H)-diona

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Recommended INN: List 53 WHO Drug Information, Vol. 19, No. 1, 2005

C25H27N3O4

H3C O
NH
H3C N O

O
N HO CH3

carmoterolum
carmoterol 8-hydroxy-5-[(1R)-1-hydroxy-2-{[(1R)-2-(4-methoxyphenyl)-
1-methylethyl]amino}ethyl]quinolin-2(1H)-one

carmotérol 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-méthoxyphényl)-
1-méthyléthyl]amino]éthyl]quinoléin-2(1H)-one

carmoterol 8-hidroxi-5-[(1R)-1-hidroxi-2-[[(1R)-2-(4-metoxifenil)-propan-
2-il]amino]etil]quinolin-2(1H)-ona

C21H24N2O4

H OH H
N

H CH3
HO OCH3
HN

cetilistatum
cetilistat 2-(hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one

cétilistat 2-(hexadécyloxy)-6-méthyl-4H-3,1-benzoxazin-4-one

cetilistat 2-(hexadeciloxi)-6-metil-4H-3,1-benzoxazin-4-ona

C25H39NO3

N O CH3

O
H3C
O

dasantafilum
dasantafil 7-(3-bromo-4-methoxyphenylmethyl)-1-ethyl-8-{[(1R,2R)-
2-hydroxycyclopropyl]amino}-3-(2-hydroxyethyl)-3,7-dihydro-
1H-purine-2,6-dione

dasantafil 7-(3-bromo-4-méthoxybenzyl)-1-éthyl-8-[[(1R,2R)-
2-hydroxycyclopentyl]amino]-3-(2-hydroxyéthyl)-3,7-dihydro-
1H-purine-2,6-dione

dasantafilo 7-(3-bromo-4-metoxibencil)-1-etil-8-[[(1R,2R)-2-hidroxiciclopentil]=
amino]-3-(2-hidroxietil)-3,7-dihidro-1H-purina-2,6-diona

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WHO Drug Information, Vol. 19, No. 1, 2005 Recommended INN: List 53

C22H28BrN5O5

Br

O
OCH3
N
H3C N
NH H
O N N H
OH OH

deluceminum
delucemine 3,3-bis(3-fluorophenyl)-N-methylpropan-1-amine

délucémine 3,3-bis(3-fluorophényl)-N-méthylpropan-1-amine

delucemina 3,3-bis(3-fluorofenil)-N-metilpropan-1-amina

C18H27N5O21P4

H
N
F CH3

denufosolum
denufosol 2'-deoxycytidine(5')tetraphospho(5')uridine

dénufosol 2'-désoxycytidine(5')tétraphospho(5')uridine

denufosol 2'-desoxicitidina(5')tetrafosfo(5')uridina

C18H27N5O21P4

HO O H
P O N O
O O
P O O N
O
OH
P O
O HO OH
OH
O P O N NH2
O
HO
O N

HO

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Recommended INN: List 53 WHO Drug Information, Vol. 19, No. 1, 2005

depelestatum
depelestat human recombinant neutrophil elastase inhibitor, homologue of the
second Kunitz domain of Inter-alpha-trypsin inhibitor light chain:
285 297 300 301 302
[Glu ,Ile ,Phe ,Pro ,Arg ]AMBP protein
precursor-(285-340)-peptide (human)
285 297 300 301 302
dépélestat [Glu ,Ile ,Phe ,Pro ,Arg ]précurseur de la protéine AMBP
humaine-(285-340)-peptide, homologue du second domaine Kunitz
de la chaîne légère de l’inhibiteur de l’Inter-alpha-trypsine, inhibiteur
de l’élastase neutrophile
285 297 300 301 302
depelestat [Glu ,Ile ,Phe ,Pro ,Arg ]precursor de la proteína AMBP
humana-(285-340)-péptido, homólogo del segundo dominio Kunitz
de la cadena ligera del inhibidor de la Inter-alfa-tripsina, inhibidor de
la elastasa neutrófila

C282H412N74O75S6

H Glu Ala Cys Asn Leu Pro Ile Val Arg Gly Pro Cys Ile Ala
3 10
Phe Phe Pro Arg Trp Ala Phe Asp Ala Val Lys Gly Lys Cys
20 30
Val Leu Phe Pro Tyr Gly Gly Cys Gln Gly Asn Gly Asn Lys
40
Phe Tyr Ser Glu Lys Glu Cys Arg Glu Tyr Cys Gly Val Pro OH
50

dirlotapidum
dirlotapide N-{(1S)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-
5-[4'-(trifluoromethyl)biphenyl-2-carboxamido]-1H-indol-
2-carboxamide

dirlotapide N-[(1S)-2-(benzylméthylamino)-2-oxo-1-phényléthyl]-1-méthyl-
5-[[[4'-(trifluorométhyl)biphényl-2-yl]carbonyl]amino]-1H-indole-
2-carboxamide

dirlotapida N-[(1S)-2-(bencilmetilamino)-2-oxo-1-feniletil]-1-metil-
5-[[[4'-(trifluorometil)bifenil-2-il]carbonil]amino]-1H-indol-
2-carboxamida

C40H33F3N4O3

H3C O CH3
H
N N
N
F3C H
O
O
NH

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WHO Drug Information, Vol. 19, No. 1, 2005 Recommended INN: List 53

edaglitazonum
edaglitazone (5RS)-5-({4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-
1-benzothiophen-7-yl}methyl)-1,3-thiazolidine-2,4-dione

édaglitazone (5RS)-5-[[4-[2-(5-méthyl-2-phényloxazol-4-yl)éthoxy]-
1-benzothiophén-7-yl]méthyl]thiazolidine-2,4-dione

edaglitazona (5RS)-5-[[4-[2-(2-fenil-5-metiloxazol-4-il)etoxi]-1-benzotiofen-
7-il]metil]tiazolidina-2,4-diona

C24H20N2O4S2

O
N O
S and enantiomer
NH et énantiomère
O y enantiómero
CH3
H O
S

eslicarbazepinum
eslicarbazepine (10S)-10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepin-
5-carboxamide

eslicarbazépine (10S)-10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azépin-
5-carboxamide

eslicarbazepina (10S)-10-hidroxi-10,11-dihidro-5H-dibenzo[b,f]azepin-5-carboxamida

C15H14N2O2

N NH2

HO
H

exbivirumabum
exbivirumab immunoglobulin G, anti-(hepatitis B surface antigen) (human
monoclonal 19.79.5 heavy chain), disulfide with human monoclonal
19.79.5 λ chain, dimer

exbivirumab immunoglobuline G, anti-(antigène de surface du virus de

l'hépatite B) dimère du disulfure entre la chaîne lourde et la chaîne λ
de l'anticorps monoclonal humain 19.79.5

exbivirumab inmunoglobulina G, anti-(antígeno de superficie del virus de la

hepatitis B) dímero del disulfuro entre la cadena pesada y la
cadena λ del anticuerpo monoclonal humano 19.79.5

C6416H9924N1732O1982S44

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Recommended INN: List 53 WHO Drug Information, Vol. 19, No. 1, 2005

fampronilum
fampronil 2-{5-chloro-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3-methyl-
1H-pyrazol-4-yl}-1H-imidazole-4,5-dicarbonitrile

fampronil 2-[5-chloro-1-[2,6-dichloro-4-(trifluorométhyl)phényl]-3-méthyl-
1H-pyrazol-4-yl]-1H-imidazole-4,5-dicarbonitrile

fampronilo 2-[5-cloro-1-[2,6-dicloro-4-(trifluorometil)fenil]-3-metil-1H-pirazol-4-il]-
1H-imidazol-4,5-dicarbonitrilo

C16H6Cl3F3N6

CH3
Cl
N
N N CN

F3C HN
Cl
Cl CN

fidexabanum
fidexaban {[2-(5-carbamimidoyl-2-hydroxyphenoxy)-3,5-difluoro-6-{3-[1-methyl-
4,5-dihydro-1H-imidazol-2-yl]phenoxy}pyridin-4-yl]methylamino}=
acetic acid

fidexaban acide [[2-(5-carbamimidoyl-2-hydroxyphénoxy)-3,5-difluoro-

6-[3-(1-méthyl-4,5-dihydro-1H-imidazol-2-yl)phénoxy]pyridin-
4-yl]méthylamino]acétique

fidexabán ácido [[2-(5-carbamimidoil-2-hidroxifenoxi)-3,5-difluoro-6-[3-(1-metil-

4,5-dihidro-1H-imidazol-2-il)fenoxi]piridin-4-il]metilamino]acético

C25H24F2N6O5

NH F CH3
O N CO2H
H2 N
N
OH F N
O
N
CH3

fingolimodum
fingolimod 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol

fingolimod 2-amino-2-[2-(4-octylphényl)éthyl]propane-1,3-diol

fingolimod 2-amino-2-[2-(4-octilfenil)etil]propano-1,3-diol

C19H33NO2

OH
NH2
OH

H3C

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WHO Drug Information, Vol. 19, No. 1, 2005 Recommended INN: List 53

gadodenteratum
gadodenterate 10,10',10",10''',10'''',10''''',10'''''',10''''''',10'''''''',10''''''''',10'''''''''',10''''''''''',
10'''''''''''',10''''''''''''',10'''''''''''''',10''''''''''''''',10'''''''''''''''',10''''''''''''''''',10'''''''''''''''''',
10''''''''''''''''''',10'''''''''''''''''''',10''''''''''''''''''''',10'''''''''''''''''''''',10'''''''''''''''''''''''-
(benzene-1,3,5-triyltris(carbonylnitrilobis{(ethan-2,1-diylimino)
[(5S)-6-oxohexane-6,1,5-triyl]bis(imino[(5S)-6-oxohexane-
6,1,5-triyl]bis{(2-oxoethane-2,1-diyl)imino[(2S)-1-oxopropane-
1,2-diyl]})]})}tetracosakis[1,4,7,10-tetraazacyclodecane-
1,4,7-triacetato(3–)gadolinium(III)]

gadodentérate 10,10',10'',10''',10'''',10''''',10'''''',10''''''',10'''''''',10''''''''',10'''''''''',10''''''''''',
10'''''''''''',10''''''''''''',10'''''''''''''',10''''''''''''''',10'''''''''''''''',10''''''''''''''''',10'''''''''''''''''',
10''''''''''''''''''',10'''''''''''''''''''',10''''''''''''''''''''',10'''''''''''''''''''''',10'''''''''''''''''''''''-
[benzène-1,3,5-triyltris[carbonylnitrilobis[éthylèneimino=
[(5S)-6-oxohexane-6,1,5-triyl]bis[imino[(5S)-6-oxohexane-
6,1,5-triyl]bis[imino(2-oxoéthylène)imino(1-méthyl-
2-oxoéthylène)]]]]]tétracosakis[[1,4,7,10-tétraazacyclododécane-
1,4,7-triacétato(3-)]gadolinium]

gadodenterato 10,10',10",10''',10'''',10''''',10'''''',10''''''',10'''''''',10''''''''',10'''''''''',10''''''''''',
10'''''''''''',10''''''''''''',10'''''''''''''',10''''''''''''''',10'''''''''''''''',10''''''''''''''''',10'''''''''''''''''',
10''''''''''''''''''',10'''''''''''''''''''',10''''''''''''''''''''',10'''''''''''''''''''''',10'''''''''''''''''''''''-
[benceno-1,3,5-triiltris[carbonilnitrilobis[etilenoimino=
[(5S)-6-oxohexano-6,1,5-triil]bis[imino[(5S)-6-oxohexano-
6,1,5-triil]]bis[imino(2-oxoetileno)imino(1-metil-
2-oxoetileno)]]]]tetracosakis[[1,4,7,10-tetraazaciclododecano-
1,4,7-triacetato(3-)]gadolinio]

C585H927Gd24N165O213

R H
O
R R H
NH O
R H R
H
N NH
R N O
O
O N

R H H R H
N HN
R N O R
O O
R H
-
NH O2C CO 2-
R N N
O Gd3+

N N
CO2-
H3C
-
O
O2C CO2-
N N HN

Gd3+
O
- N N O H NH H
O2C H
N N = R-
N
H 3C H
O O

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Recommended INN: List 53 WHO Drug Information, Vol. 19, No. 1, 2005

gantacurium chloridum
gantacurium chloride (1R,2S)-2-(3-{[(2Z)-2-chloro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-
1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinolinium-
2-yl]propoxy}-4-oxobut-2-enoyl]oxy}propyl)-6,7-dimethoxy-2-methyl-
1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinolinium
dichloride

chlorure de gantacurium dichlorure de (1R,2S)-2-[3-[[(2Z)-2-chloro-4-[3-[(1S,2R)-6,7-

diméthoxy-2-méthyl-1-(3,4,5-triméthoxyphényl)-1,2,3,4-
tétrahydroisoquinoléinio]propoxy]-4-oxobut-2-énoyl]oxy]propyl]-
6,7-diméthoxy-2-méthyl-1-(3,4,5-triméthoxybenzyl)-
1,2,3,4-tétrahydroisoquinoléinium

cloruro de gantacurio dicloruro de (1R,2S)-2-[3-[[(2Z)-2-cloro-4-[3-[(1S,2R)-2-metil-

6,7-dimetoxi-1-(3,4,5-trimetoxifenil)-1,2,3,4-tetrahidroisoquinolinio]=
propoxi]-4-oxobut-2-enoil]oxi]propil]-2-metil-6,7-dimetoxi-
1-(3,4,5-trimetoxibencil)-1,2,3,4-tetrahidroisoquinolinio

C53H69Cl3N2O14

OCH3
Cl-
H3CO OCH3
O
H3C +
O N
H3CO O OCH3
H H
H3CO Cl O
N+
CH3
H3CO H3CO OCH3
Cl-
OCH3

golimumabum
golimumab immunoglobulin G1, anti-(human tumor necrosis factor α) (human
monoclonal CNTO 148 γ1-chain), disulfide with human monoclonal
CNTO 148 κ-chain, dimer

golimumab immunoglobuline G1, anti-(facteur α de nécrose tumorale humain)

dimère du disulfure entre la chaîne γ1 et la chaîne κ de l'anticorps
monoclonal humain CNTO 148

golimumab inmunoglobulina G1, anti-(factor α de necrosis tumoral humano)

dímero del disulfuro entre la cadena γ1 y la cadena κ del anticuerpo
monoclonal humano CNTO 148

C6530H10068N1752O2026S44

idronoxilum
idronoxil 3-(4-hydroxyphenyl)-2H-chromen-7-ol

idronoxil 3-(4-hydroxyphényl)-2H-1-benzopyran-7-ol

idronoxilo 3-(4-hidroxifenil)-2H-1-benzopiran-7-ol

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WHO Drug Information, Vol. 19, No. 1, 2005 Recommended INN: List 53

C15H12O3

OH

HO O

imiglitazarum
imiglitazar (4E)-4-[({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}=
methoxy)imino]-4-phenylbutanoic acid

imiglitazar acide (4E)-4-[[[4-[(5-méthyl-2-phényloxazol-4-yl)méthoxy]benzyl]=

oxy]imino]-4-phénylbutanoïque

imiglitazar ácido (4E)-4-[[[4-[(2-fenil-5-metiloxazol-4-il)metoxi]bencil]oxi]imino]-

4-fenilbutanoico

C28H26N2O5

N
O

N
O
CO2H
O CH3

indacaterolum
indacaterol 5-{(1R)-2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]
-1-hydroxyethyl}-8-hydroxyquinolin-2(1H)-one

indacatérol 5-[(1R)-2-[(5,6-diéthyl-2,3-dihydro-1H-indén-2-yl)amino]-
1-hydroxyéthyl]-8-hydroxyquinoléin-2(1H)-one

indacaterol 5-[(1R)-2-[(5,6-dietil-2,3-dihidro-1H-inden-2-il)amino]-1-hidroxietil]-
8-hidroxiquinolin-2(1H)-ona

C24H28N2O3

H OH H
N
CH3
HO
HN
CH3
O

indibulinum
indibulin 2-[1-(4-chlorophenylmethyl)-1H-indol-3-yl]-2-oxo-N-(pyridin-
4-yl)acetamide

indibuline 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-(pyridin-4-yl)acétamide

indibulina 2-[1-(4-clorobencil)-1H-indol-3-il]-2-oxo-N-(piridin-4-il)acetamida

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Recommended INN: List 53 WHO Drug Information, Vol. 19, No. 1, 2005

C22H16ClN3O2

O
H
N
N
O N

Cl

ismomultinum alfa
ismomultin alfa 47-261-Glycoprotein gp 39 (human clone CDM8-gp39 reduced)

ismomultine alfa [290-isoleucine]glycoprotéine 39 constituant du cartilage humain

(glycoforme alfa)

ismomultina alfa fragmento 47-261 de la glicoproteina 39 constituyente del cartílago

124
humano (variante [Arg ] producida por el clon humano CDM8-
gp39)

C1827H2785N493O530S11

*
YKLVCYYTSW SQYREGDGSC FPDALDRFLC THIIYSFANI
SNDHIDTWEW NDVTLYGMLN TLKNRNPNLK TLLSVGGWNF
GSQRFSKIAS NTQSRRTFIK SVPPFLRTHG FDGLDLAWLY
PGRRDKQHFT TLIKEMKAEF IKEAQPGKKQ LLLSAALSAG
KVTIDSSYDI AKISQHLDFI SIMTYDFHGA WRGTTGHHSP
LFRGQEDASP DRFSNTDYAV GYMLRLGAPA SKLVMGIPTF
GRSFTLASSE TGVGAPISGP GIPGRFTKEA GTLAYYEICD
FLRGATVHRI LGQQVPYATK GNQWVGYDDQ ESVKSKVQYL
KDRQLAGAMV WALDLDDFQG SFCGQDLRFP LTNAIKDALA
AT
* glycosylation site
* sites de glycosylation
* posiciones de glicosilación

lanimostimum
lanimostim 4-221-colony-stimulating factor 1 (human clone p3ACSF-69
reduced)

lanimostim facteur-1 de stimulation de colonie de macrophage humain-(4-221)-

peptide (clone humain p3ACSF-69)

lanimostim factor-1 de la estímulo de colonia de macrófago humano -(4-221)-

péptido (clon humano p3ACSF-69)

C2146H3346N572O686S28

SEYCSHM IGSGHLQSLQ RLIDSQMETS CQITFEFVDQ

EQLKDPVCYL KKAFLLVQDI MEDTMRFRDN TPNAIAIVQL
QELSLRLKSC FTKDYEEHDK ACVRTFYETP LQLLEKVKNV
FNETKNLLDK DWNIFSKNCN NSFAECSSQD VVTKPDCNCL
YPKAIPSSDP ASVSPHQPLA PSMAPVAGLT WEDSEGTEGS
SLLPGEQPLH TVDPGSAKQR P
2

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WHO Drug Information, Vol. 19, No. 1, 2005 Recommended INN: List 53

lemuteporfinum
1
lemuteporfin dimethyl (2RS,2 SR)-8-ethenyl-13,17-bis=
[3-(2-hydroxyethoxycarbonyl)-3-oxopropyl]-2,7,12,18-tetramethyl-
1 1 2
2,2 -dihydrobenzo[b]porphyrin-2 ,2 -dicarboxylate

lémutéporfine trans-8-éthényl-13,17-bis[3-(2-hydroxyéthoxy)-3-oxopropyl]-
1
2,7,12,18-tétraméthyl-2,2 -dihydrobenzo[b]porphyrine-
1 2
2 ,2 -dicarboxylate de diméthyle

lemuteporfina trans-8-etenil-13,17-bis[3-(2-hidroxietoxi)-3-oxopropil]-
1 1 2
2,7,12,18-tetrametil-2,2 -dihidrobenzo[b]porfirine-2 ,2 -dicarboxylate
de dimetilo

C44H48N4O10

O O O
H3C
O O CH3
H3C H3C
O
HO
N HN

NH N
HO
O CH3

H 3C
O CH2

lenalidomidum
lenalidomide (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-
2,6-dione

lénalidomide (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)pipéridine-
2,6-dione

lenalidomide (3RS)-3-(4-amino-1-oxo-1,3-dihidro-2H-isoindol-2-il)piperidina-
2,6-diona

C13H13N3O3

O O
and enantiomer
N NH et énantiomère
H y enantiómero
O
NH2

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lestaurtinibum
lestaurtinib (9S,10S,12R)-10-hydroxy-10-(hydroxymethyl)-9-methyl-2,3,9,10,11,12-
hexahydro-1H-9,12-epoxydiindolo[1,2,3-fg:3',2',1'-kl]pyrrolo=
[3,4-i][1,6]benzodiazocin-1-one

lestaurtinib (9S,10S,12R)-10-hydroxy-10-(hydroxyméthyl)-9-méthyl-2,3,9,10,11,12-
hexahydro-9,12-époxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo=
3,4-i][1,6]benzodiazocin-1-one

lestaurtinib (9S,10S,12R)-10-hidroxi-10-(hidroximetil)-9-metil-2,3,9,10,11,12-
hexahidro-9,12-epoxi-1H-diindolo[1,2,3-fg:3',2',1'-kl]pirrolo=
[3,4-i][1,6]benzodiazocin-1-ona

C26H21N3O4

H
O N

N N
O
H CH3
OH
OH

libivirumabum
libivirumab immunoglobulin G, anti- (hepatitis B surface antigen)(human
monoclonal 17.1.41 heavy chain), disulfide with human monoclonal
17.1.41 κ-chain, dimer

libivirumab immunoglobuline G, anti-(antigène de surface du virus de

l'hépatite B) ; dimère du disulfure entre la chaîne lourde et la
chaîne κ de l'anticorps monoclonal humain 17.1.41

libivirumab inmunoglobulina G, anti-(antígeno de superficie del virus de la

hepatitis B) ; dímero del disulfuro entre la cadena pesada y la
cadena κ del anticuerpo monoclonal humano 17.1.41

C6598H10232N1788O2060S46

maravirocum
maraviroc isopropyl, 4,4-difluoro-N-[(1S)-3-{(1R,3s,5S)-3-[3-methyl-5-(propan-
2-yl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}-
1-phenylpropyl]cyclohexanecarboxamide

maraviroc 4,4-difluoro-N-[(1S)-3-[(1R,3s,5S)-3-[3-méthyl-5-(1-méthyléthyl)-
4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl]-1-phénylpropyl]=
cyclohexanecarboxamide

maraviroc 4,4-difluoro-N-[(1S)-1-fenil-3-[(1R,3s,5S)-3-[3-isopropil-5-metil-
4H-1,2,4-triazol-4-il]-8-azabiciclo[3.2.1]oct-8-il] propil]=
ciclohexanocarboxamida

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WHO Drug Information, Vol. 19, No. 1, 2005 Recommended INN: List 53

C29H41F2N5O

CH3
H3C
F H H
N
F N
H N
N N
H3C
O H H

mecaserminum rinfabas
mecasermin rinfabate insulin-like growth factor I (human), complex with insulin-like growth
factor-binding protein IGFBP-3 (human)

mécasermine rinfabate facteur I de croissance humain analogue à l'insuline (mécasermine)

lié à la [5-alanine]protéine-3 humaine se liant au facteur de
croissance analogue à l'insuline (IGFBP-3 humaine)

mecasermina rinfabato factor I del crecimiento humano semejante a la insulina

(mecasermina) unida a la [5-alanina]proteína-3 humana unida con el
factor de crecimiento similar a la insulina (IGFBP-3 humana)

C1231H1967N371O384S20

GPETLCGAEL VDALQFVCGD RGFYFNKPTG YGSSSRRAPQ

TGIVDECCFR SCDLRRLEMY CAPLKPAKSA
GASSAGLGPV VRCEPCDARA LAQCAPPPAV CAELVREPGC
GCCLTCALSE GQPCGIYTER CGSGLRCQPS PDEARPLQAL
LDGRGLCVNA SAVSRLRAYL LPAPPAPGNA SESEEDRSAG
SVESPSVSST HRVSDPKFHP LHSKIIIIKK GHAKDSQRYK
VDYESQSTDT QNFSSESKRE TEYGPCRREM EDTLNHLKFL
NVLSPRGVHI PNCDKKGFYK KKQCRPSKGR KRGFCWCVDK
YGQPLPGYTT KGKEDVHCYS MQSK

milataxelum
milataxel 1,10β-dihydroxy-9-oxo-5β,20-epoxy-3ζ-tax-11-ene-2α,4,7β,13α-
tetrayl 4-acetate 2-benzoate 13-[(2R,3R)-3-(tert-
butoxycarbonylamino)-3-(furan-2-yl)-2-hydroxypropanoate]
7-propanoate

milataxel 12b-acétate, 12-benzoate, 9-[(2R,3R)-3-[[(1,1-

diméthyléthoxy)carbonyl]amino]-3-(furan-2-yl)-2-hydroxypropanoate]
et 4-propanoate de (2aR,4S,4aS,6R,7E,9S,11S,12S,12bS)-6,11-
dihydroxy-4a,8,13,13-tétraméthyl-5-oxo-3,4,4a,5,6,9,10,11,12,12a-
décahydro-7,11-méthano-1H-cyclodéca[3,4]benzo[1,2-b]oxète-
4,9,12,12b(2aH)-tétrayle

milataxel 12b-acetato, 12-benzoato, 9-[(2R,3R)-3-[[(1,1-

dimetiletoxi)carbonil]amino]-3-(furan-2-il)-2-hidroxipropanoato] y
4-propanoato de (2aR,4S,4aS,6R,7E,9S,11S,12S,12bS)-6,11-
dihidroxi-4a,8,13,13-tetrametil-5-oxo-3,4,4a,5,6,9,10,11,12,12a-
decahidro-7,11-metano-1H-ciclodeca[3,4]benzo[1,2-b]oxeto-
4,9,12,12b(2aH)-tetrail

85
Recommended INN: List 53 WHO Drug Information, Vol. 19, No. 1, 2005

C44H55NO16

O
H O CH3
HO O
H3C CH3 H
O H OH
O CH3
H H
H CH3
H NH O
O O O
HO
O H O
H3C O CH3
H3C
CH3 O

mirococeptum
mirococept protein APT070 (synthetic human clone pET04-01 complement
receptor type 1 short consensus repeat 1-3 fragment), (198→17')-
disulfide with N-(tetradecanoyl)glycyl-L-seryl-L-seryl-L-lysyl-L-seryl-
L-prolyl-L-seryl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-
L-prolylglycyl-L-aspartyl-L-cysteinamide

mirococept (238-17')-disulfure entre le [41-méthionyl]précurseur du récepteur de

type 1 du complément-(41-238)-peptide et
le (N-tétradécanoylglycyl)-L-séryl-L-séryl-L-lysyl-L-séryl-L-prolyl-
L-séryl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-prolylglycyl-
L-aspartyl-L-cystéinamide

mirococept (238-17')-disulfuro entre el [41-metionil]precursor del receptor de tipo

1 del complemento -(41-238)- péptido y el (N-tetradecanoilglicil)-
L-seril-L-seril-L-lisil-L-seril-L-prolil-L-seril-L-lisil-L-lisil-L-lisil-L-lisil-L-lisil-
L-lisil-L-prolilglicil-L-aspartil-L-cisteinamida

C1054H1635N293O312S16

H MQCNAPEWLP FARPTNLTDE FEFPIGTYLN YECRPGYSGR

PFSIICLKNS VWTGAKDRCR RKSCRNPPDP VNGMVHVIKG
IQFGSQIKYS CTKGYRLIGS SSATCIISGD TVIWDNETPI
CDRIPCGLPP TITNGDFIST NRENFHYGSV VTYRCNPGSG
GRKVFELVGE PSIYCTSNDD QVGIWSGPAP QCIIPNKC OH

GSSKSPSKKK KKKPGDC NH2

CH3 O

86
WHO Drug Information, Vol. 19, No. 1, 2005 Recommended INN: List 53

paclitaxelum ceribas
paclitaxel ceribate 7β-[(2RS)-2,3-dihydroxypropoxycarbonyloxy]-1-hydroxy-9-oxo-
5β,20-epoxytax-11-ene-2α,4,10β,13α-tetrayl 4,10-diacetate
2-benzoate 13-[(2R,3S)-3-benzamido-2-hydroxy-
3-phenylpropanoate]

céribate de paclitaxel 6,12b-diacétate, 12-benzoate, 4-[[(2RS)-2,3-dihydroxypropoxy]=

carboxylate] et 9-[(2R,3S)-3-(benzoylamino)-2-hydroxy-
3-phénylpropanoate] de
(2aR,4S,4aS,6R,7E,9S,11S,12S,12aR,12bS)-11-hydroxy-
4a,8,13,13-tétraméthyl-5-oxo-3,4,4a,5,6,9,10,11,12,12a-décahydro-
7,11-méthano-1H-cyclodéca[3,4]benzo[1,2-b]oxète-
4,6,9,12,12b(2aH)-pentayle

ceribato de paclitaxel 6,12b-diacetato, 12-benzoato, 4-[[(2RS)-2,3-dihidroxipropoxi]=

carboxilato] y 9-[(2R,3S)-3-(benzoilamino)-3-fenilpropanoato-
2-hidroxi] de (2aR,4S,4aS,6R,7E,9S,11S,12S,12aR,12bS)-11-
hidroxi-4a,8,13,13-tetrametil-5-oxo-3,4,4a,5,6,9,10,11,12,12a-
decahidro-7,11-metano-1H-ciclodeca[3,4]benzo[1,2-b]oxeto-
4,6,9,12,12b(2aH)-pentailo

C51H57NO18

O CH3 O
H O
O O O * OH
H3C CH3 H
H OH H OH
O CH3
H H and epimer at C*
H CH3
HN H O et l'épimère en C*
O O O y el epímero en el C*
OH H
O O CH3

palosuranum
palosuran 1-[2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl]-3-(2-methylquinolin-
4-yl)urea

palosuran 1-[2-(4-benzyl-4-hydroxypipéridin-1-yl)éthyl]-3-(2-méthylquinoléin-
4-yl)urée

palosurán 1-[2-(4-bencil-4-hidroxipiperidin-1-il)etil]-3-(2-metilquinolin-4-il)urea

C25H30N4O2

CH3
OH
N O
N
N N
H H

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panitumumabum
panitumumab immunoglobulin, anti-(human epidermal growth factor receptor)
(human monoclonal ABX-EGF heavy chain), disulfide with human
monoclonal ABX-EGF light chain, dimer

panitumumab immunoglobuline, anti-(récepteur du facteur de croissance épidermal

humain) dimére du disulfure entre la chaîne lourde et la chaîne
légère de l'anticorps monoclonal humain ABX-EGF

panitumumab inmunoglobulina, anti-(receptor del factor de crecimiento epidérmico

humano) dímero del disulfuro entre la cadena pesada y la cadena
ligera del anticuerpo monoclonal humano ABX-EGF

C6306H9732N1672O1994S46

pegamotecanum
pegamotecan α-{2-[(2S)-1-{[(4S)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-
1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl]oxy}-1-oxopropan-
2-ylamino]-2-oxoethyl}-ω-(2-[(2S)-1-{[(4S)-4-ethyl-3,14-dioxo-
3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-
4-yl]oxy}-1-oxopropan-2-ylamino]-2-oxoethoxy)poly(oxyethane-
1,2-diyl)

pégamotécan dérivé pégylé de la camptothécine obtenu par amidification entre le

(2S)-2-aminopropanoate de (4S)-4-éthyl-3,14-dioxo-3,4,12,14-
tétrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoléin-4-yle
(L-alaninate de camptothécine) et le α-(carboxyméthyl)-
ω-(carboxyméthoxy)poly(oxyéthylène)

pegamotecán derivado pegilado de la camptotecina obtenido por amidificación

entre el (2S)-2-aminopropanoato de (4S)-4-etil-3,14-dioxo-3,4,12,14-
tetrahidro-1H-pirano[3',4':6,7]indolizino[1,2-b]quinolin-4-ilo
(L-alaninato de camptotecina) y el α-(carboximetil)-
ω-(carboximetoxi)poli(oxietileno)

C50H44N6O13 [C2H4O]n

O
O
N O
N O
O
N O O
H N
H3C O O
O CH 3 O CH3
HN O CH3
O N
n
H H
O

pelitinibum
pelitinib (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-
7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide

pélitinib (2E)-N-[4-[(3-chloro-4-fluorophényl)amino]-3-cyano-
7-éthoxyquinoléin-6-yl]-4-(diméthylamino)but-2-énamide

pelitinib (2E)-N-[4-[(3-cloro-4-fluorofenil)amino]-3-ciano-7-etoxiquinolin-6-il]-
4-(dimetilamino)but-2-enamida

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C24H23ClFN5O2

H3 C O N

CH3 HN CN
N HN Cl
H3C O

perflubutanum
perflubutane 1,1,1,2,2,3,3,4,4,4-decafluorobutane

perflubutane décafluorobutane

perflubutano decafluorobutano

C4F10

F F
CF3
F3C
F F

perzinfotelum
perzinfotel [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]=
phosphonic acid

perzinfotel acide [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-én-2-yl)éthyl]=

phosphonique

perzinfotel ácido [2-(8,9-dioxo-2,6-diazabiciclo[5.2.0]non-1(7)-en-2-il)etil]=

fosfónico

C9H13N2O5P

O
HN
OH
N
P OH
O

prasugrelum
prasugrel 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-
4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate

prasugrel acétate de 5-[(1RS)-2-cyclopropyl-1-(2-fluorophényl)-2-oxoéthyl]-

4,5,6,7-tétrahydrothiéno[3,2-c]pyridin-2-yle

prasugrel acetato de 5-[(1RS)-2-ciclopropil-1-(2-fluorofenil)-2-oxoetil]-

4,5,6,7-tetrahidrotieno[3,2-c]piridin-2-ilo

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C20H20FNO3S

F
H and enantiomer
O
et énantiomère
H3C y enantiómero
N
O
O
S

radafaxinum
radafaxine (2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethylmorpholin-2-ol

radafaxine (+)-(2S,3S)-2-(3-chlorophényl)-3,5,5-triméthylmorpholin-2-ol

radafaxina (+)-(2S,3S)-2-(3-clorofenil)-3,5,5-trimetilmorfolin-2-ol

C13H18ClNO2

CH3
O CH3
HO
NH

H CH3

Cl

ranirestatum
ranirestat (3R)-2'-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-
3,4'(1'H)-pyrrolo[1,2-a]pyrazine]-1',2,3',5(2'H)-tetrone

ranirestat (-)-(3R)-2'-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-
3,4'(1'H)-pyrrolo[1,2-a]pyrazine]-1',2,3',5(2'H)-tétrone

ranirestat (-)-(3R)-2'-(4-bromo-2-fluorobencil)espiro[pirrolidina-
3,4'(1'H)-pirrolo[1,2-a]pirazina]-1',2,3',5(2'H)-tetrona

C17H11BrFN3O4

O
NH

O
Br O
N
N

F O

regadenosonum
regadenoson 1-(6-amino-9-β-D-ribofuranosyl-9H-purin-2-yl)-N-methyl-1H-pyrazole-
4-carboxamide

régadénoson 1-(6-amino-9-β-D-ribofuranosyl-9H-purin-2-yl)-N-méthyl-1H-pyrazole-
4-carboxamide

regadenosón 1-(6-amino-9-β-D-ribofuranosil-9H-purin-2-il)-N-metil-1H-pirazol-
4-carboxamida

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C15H18N8O5

NH2

N N
O
N N N
H3C NH N
HO
O

OH OH

reparixinum
reparixin (2R)-2-[4-(2-methylpropyl)phenyl]-N-methylsulfonylpropanamide

réparixine (-)-(2R)-2-[4-(2-méthylpropyl)phényl]-N-(méthylsulfonyl)propanamide

reparixina (-)-(2R)-2-[4-(2-metilpropil)fenil]-N-(metilsulfonil)propanamida

C14H21NO3S

H CH3 H
N CH3
CH3 S
O O O
H3C

retapamulinum
retapamulin (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-5-hydroxy-4,6,9,10-
tetramethyl-1-oxodecahydro-3a,9-propanocyclopenta[8]annulen-
8-yl{[(1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-
yl]sulfanyl}acetate

rétapamuline [[(1R,3s,5S)-8-méthyl-8-azabicyclo[3.2.1]oct-3-yl]sulfanyl]acétate de
(3aS,4R,5S,6S,8R,9R,9aR,10R)-6-éthényl-5-hydroxy-4,6,9,10-
tétraméthyl-1-oxodécahydro-3a,9-propano-3aH-
cyclopenta[8]annulén-8-yle

retapamulina [[(1R,3s,5S)-8-metyl-8-azabiciclo[3.2.1]oct-3-il]sulfanil]acetato de
(3aS,4R,5S,6S,8R,9R,9aR,10R)-6-etenil-5-hidroxi-4,6,9,10-
tetrametil-1-oxodecahidro-3a,9-propano-3aH-ciclopenta[8]anulen-
8-ilo

C30H47NO4S

H
H
CH3
H H H3C
H3C N O O
S
O H
H
H3C
H2C
HO H H CH3

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revaprazanum
revaprazan N-(4-fluorophenyl)-4,5-dimethyl-6-[(1RS)-1-methyl-
3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine

révaprazan N-(4-fluorophényl)-4,5-diméthyl-6-[(1RS)-1-méthyl-
3,4-dihydroisoquinoléin-2(1H)-yl]pyrimidin-2-amine

revaprazán N-(4-fluorofenil)-4,5-dimetil-6-[(1RS)-1-metil-3,4-dihidroisoquinolin-
2(1H)-il]pirimidin-2-amina

C22H23FN4

CH3
H
H and enantiomer
N N N et énantiomère
y enantiómero
N
H3C F
CH3

rilpivirinum
rilpivirine 4-{[4-({4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)pyrimidin-
2-yl]amino}benzonitrile

rilpivirine 4-[[4-[[4-[(1E)-2-cyanoéthényl]-2,6-diméthylphényl]amino]pyrimidin-
2-yl]amino]benzonitrile

rilpivirina 4-[[4-[[4-[(1E)-2-cianoetenil]-2,6-dimetilfenil]amino]pirimidin-
2-il]amino]benzonitrilo

C22H18N6

N
CH3 CN
N

N N N
H H
CH3

ritobegronum
ritobegron [4-(2-{[(1R,2S)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl]amino}=
ethyl)-2,5-dimethylphenoxy]acetic acid

ritobégron acide [4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphényl)-1-méthyléthyl]=

amino]éthyl]-2,5-diméthylphénoxy]acétique

ritobegrón ácido [4-[2-[[(1R,2S)-1-hidroxi-1-(4-hidroxifenil)prop-2-il]amino]etil]-

2,5-dimetilfenoxi]acético

C21H27NO5

H OH H CH3
N

H CH3
HO O CO2H
CH3

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robenacoxibum
robenacoxib {5-ethyl-2-[(2,3,5,6-tetrafluorophenyl)amino]phenyl}acetic acid

robénacoxib acide [5-éthyl-2-[(2,3,5,6-tétrafluorophényl)amino]phényl]acétique

robenacoxib ácido [5-etil-2-(2,3,5,6-tetrafluoroanilino)fenil]acético

C16H13F4NO2

H3C CO2H

NH
F F

F F

rostafuroxinum
rostafuroxin 21,23-epoxy-24-nor-14β,5β-chola-20,21-diene-3β,14,17α-triol

rostafuroxine 17-(furan-3-yl)-5β,14β-androstane-3β,14,17α-triol

rostafuroxina 17-(furan-3-il)-5β,14β-androstano-3β,14,17α-triol

C23H34O4

CH3
OH
CH3 H

H OH
HO
H H

selodenosonum
selodenoson 1-[6-(cyclopentylamino)-9H-purin-9-yl]-1-deoxy-N-ethyl-
β-D-ribofuranuronamide

sélodénoson 1-[6-(cyclopentylamino)-9H-purin-9-yl]-1-désoxy-N-éthyl-
β-D-ribofuranuronamide

selodenosón 1-[6-(ciclopentilamino)-9H-purin-9-il]-1-desoxi-N-etil-
β-D-ribofuranuronamida

C17H24N6O4

HN

N
N

N N
H
H3C N O
O

OH OH

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taltobulinum
taltobulin (2E,4S)-4-{(2S)-N,3,3-trimethyl-2-[(2S)-3-methyl-2-(methylamino)-
3-phenylbutanamido]butanamido}-2,5-dimethylhex-2-enoic acid

taltobuline acide (2E,4S)-4-[[(2S)-3,3-diméthyl-2-[[(2S)-3-méthyl-

2-(méthylamino)-3-phénylbutanoyl]amino]butanoyl]méthylamino]-
2,5-diméthylhex-2-énoïque

taltobulina ácido (2E,4S)-4-{(2S)-N,3,3-trimetil-2-[(2S)-3-metil-2-(metilamino)-

3-fenilbutanamido]butanamido}-2,5-dimetilhex-2-enoico

C27H43N3O4

CH3
H3C
CH3
O CH3
H H
N N CO2H
H3C N
H H H
H3C O CH3
H 3C CH3
H3C

tandutinibum
tandutinib 4-{6-methoxy-7-[3-(piperidin-1-yl)propoxy]quinazolin-4-yl}-
N-[4-(propan-2-yloxy)phenyl]piperazine-1-carboxamide

tandutinib 4-[6-méthoxy-7-[3-(pipéridin-1-yl)propoxy]quinazolin-4-yl]-
N-[4-(1-méthyléthoxy)phényl]pipérazine-1-carboxamide

tandutinib 4-[6-metoxi-7-[3-(piperidin-1-il)propoxi]quinazolin-4-il]-
N-[4-(1-metiletoxi)fenil]piperazina-1-carboxamida

C31H42N6O4

N N

N
H
N N
N O CH3
OCH3 O
O CH3

teglicarum
teglicar (3R)-3-[(tetradecylaminocarbonylamino]-4-(trimethylazaniumyl)=
butanoate

téglicar (3R)-3-[(tétradécylcarbamoyl)amino]-4-(triméthylammonio)butanoate

teglicar (3R)-3-[(tetradecilcarbamoil)amino]-4-(trimetilamonio)butanoato

C22H45N3O3

CO2-
O H CH3
N+ CH3
H3C N N
H H CH3

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telavancinum
telavancin (3S,6R,7R,22R,23S,26S,36R,38aR)-3-(2-amino-2-oxoethyl)-
10,19-dichloro-44-[(3-{[2-(decanylamino)ethyl]amino}-2,3,6-trideoxy-
3-C-methyl-α-L-lyxo-hexopyranosyl-(1→2)-β-D-glucopyranosyl)oxy]-
7,22,28,30,32-pentahydroxy-6-[(2R)-4-methyl-2-(methylamino)=
pentanamido]-2,5,24,38,39-pentaoxo-29-{[(phosphonomethyl)=
amino]methyl}-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-
1H,22H-23,36-(epiminomethano)-8,11:18,21-dietheno-13,16:31,35-
bis(metheno)[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]=
benzoxadiazacyclotetracosine-26-carboxylic acid

télavancine acide (3S,6R,7R,22R,23S,26S,36R,38aR)-3-(2-amino-2-oxoéthyl)-

10,19-dichloro-44-[[2-O-[3-[[2-(décylamino)éthyl]amino]-
2,3,6-tridésoxy-3-C-méthyl-α-L-lyxo-hexopyranosyl]-
β-D-glucopyranosyl]oxy]-7,22,28,30,32-pentahydroxy-
6-[[(2R)-4-méthyl-2-(méthylamino)pentanoyl]amino]-2,5,24,38,39-
pentaoxo-29-[[(phosphonométhyl)amino]méthyl]-
2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tétradécahydro-
23,36-(épiminométhano)-8,11:18,21-diéthéno-22H-13,16:31,35-
diméthéno-1H,13H-[1,6,9]oxadiazacyclohexadécino=
[4,5-m][10,2,16]benzoxadiazacyclotétracosine-26-carboxylique

telavancina ácido (3S,6R,7R,22R,23S,26S,36R,38aR)-3-(2-amino-2-oxoetil)-

10,19-dicloro-44-[[2-O-[3-[[2-(decilamino)etil]amino]-2,3,6-tridesoxi-
3-C-metil-α-L-lixo-hexopiranosil]-β-D-glucopiranosil]oxi]-
7,22,28,30,32-pentahidroxi-6-[[(2R)-4-metil-2-(metilamino)=
pentanoil]amino]-2,5,24,38,39-pentaoxo-29-[[(fosfonometil)amino]=
metil]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahidro-
23,36-(epiminometano)-8,11:18,21-dieteno-22H-13,16:31,35-
dimeteno-1H,13H-[1,6,9]oxadiazaciclohexadecino=
[4,5-m][10,2,16]benzoxadiazaciclotetracosina-26-carboxílico

C80H106Cl2N11O27P

O
H
N P OH
OH
HO OH
OH

H NH2 H 3C
HN O CH3
CO2H O O
H H
H H H H H H H
N N N CH3
O N N N
H H H
O O O
HO H
H OH
O O
OH
Cl O Cl
O
OH
HO
O
O
CH3
CH3
HO

HN
N CH3
H

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tifuvirtidum
tifuvirtide N-acetyl-L-tryptophyl-L-glutaminyl-L-glutamyl-L-tryptophyl-L-glutamyl-
L-glutaminyl-L-lysyl-L-isoleucyl-L-threonyl-L-alanyl-L-leucyl-L-leucyl-
L-glutamyl-L-glutaminyl-L-alanyl-L-glutaminyl-L-isoleucyl-L-glutaminyl-
L-glutaminyl-L-glutamyl-L-lysyl-L-asparagyl-L-glutamyl-L-tyrosyl-
L-glutamyl-L-leucyl-L-glutaminyl-L-lysyl-L-leucyl-L-aspartyl-L-lysyl-
L-tryptophyl-L-alanyl-L-seryl-L-leucyl-L-tryptophyl-L-glutamyl-
L-tryptophyl-L-phenylalaninamide

tifuvirtide acétyl-L-tryptophyl-L-glutaminyl-L-glutamyl-L-tryptophyl-L-glutamyl-
L-glutaminyl-L-lysyl-L-isoleucyl-L-thréonyl-L-alanyl-L-leucyl-L-leucyl-
L-glutamyl-L-glutaminyl-L-alanyl-L-glutaminyl-L-isoleucyl-L-glutaminyl-
L-glutaminyl-L-glutamyl-L-lysyl-L-asparaginyl-L-glutamyl-L-tyrosyl-
L-glutamyl-L-leucyl-L-glutaminyl-L-lysyl-L-leucyl-L-aspartyl-L-lysyl-
L-tryptophyl-L-alanyl-L-séryl-L-leucyl-L-tryptophyl-L-glutamyl-
L-tryptophyl-L-phénylalaninamide

tifuvirtida acetil-L-triptofil-L-glutaminil-L-glutamil-L-triptofil-L-glutamil-
L-glutaminil-L-lisil-L-isoleucil-L-treonil-L-alanil-L-leucil-L-leucil-
L-glutamil-L-glutaminil-L-alanil-L-glutaminil-L-isoleucil-L-glutaminil-
L-glutaminil-L-glutamil-L-lisil-L-asparaginil-L-glutamil-L-tirosil-
L-glutamil-L-leucil-L-glutaminil-L-lisil-L-leucil-L-aspartil-L-lisil-L-triptofil-
L-alanil-L-seril-L-leucil-L-triptofil-L-glutamil-L-triptofil-L-fenilalaninamida

C235H341N57O67

O
Trp Gln Glu Trp Glu Gln Lys Ile Thr Ala Leu Leu Glu
10
H3C
Gln Ala Gln Ile Gln Gln Glu Lys Asn Glu Tyr Glu Leu
20
Gln Lys Leu Asp Lys Trp Ala Ser Leu Trp Glu Trp Phe NH2
30

tilargininum
5
tilarginine N -(methylamidino)-L-ornithine

tilarginine acide (2S)-2-amino-5-(3-méthylguanidino)pentanoïque

5
tilarginina N -(metilamidino)-L-ornitina

C7H16N4O2

H H H NH2
N N
H3C CO2H
NH

topilutamidum
topilutamide (2RS)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-
3-[(trifluoroacetyl)amino]propanamide

topilutamide (2RS)-2-hydroxy-2-méthyl-N-[4-nitro-3-(trifluorométhyl)phényl]-
3-[(trifluoroacétyl)amino]propanamide

topilutamida (2RS)-2-hidroxi-2-metil-N-[4-nitro-3-(trifluorometil)fenil]-
3-[(trifluoroacetil)amino]propanamida

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C13H11F6N3O5

H HO CH3 H
F 3C N N CF3 and enantiomer
et énantiomère
O O y enantiómero
NO2

torapselum
torapsel 42-89-glycoprotein (human clone PMT21:PL85 P-selectin
glycoprotein ligand fusion protein with immunoglobulin (human
constant region)

torapsel dimère de la protéine de fusion de la [48-proline]glycoprotéine

(ligand 1 de la sélectine-P humaine)-(1-48)-peptide avec le peptide
de 224 résidus, partie C-terminale de la chaîne lourde de
l'immunoglobuline G1 humaine

torapsel dímero de la proteína de fusión de la [48-prolina]glicoproteína

(ligando 1 de la selectina-P humana)-(1-48)-péptido con el péptido
de 224 residuos, parte C-terminal de la cadena pesada de la
inmunoglobulina G1 humana

C2726H4186N710O846S20

QATEYEYLDY DFLPETEPPE
MLRNSTDTTP LTGPGTPEST
TVEPAARPHT CPPCPAPEAL
GAPSVFLFPP KPKDTLMISR
TPEVTCVVVD VSHEDPEVKF
NWYVDGVEVH NAKTKPREEQ
YNSTYRVVSV LTVLHQDWLN
GKEYKCKVSN KALPVPIEKT
ISKAKGQPRE PQVYTLPPSR
EEMTKNQVSL TCLVKGFYPS
DIAVEWESNG QPENNYKTTP
PVLDSDGSFF LYSKLTVDKS
RWQQGNVFSC SVMHEALHNH
YTQKSLSLSP GK
2

trodusqueminum
trodusquemine (24R)-3β-{[3-({4-[(3-aminopropyl)amino]butyl}amino)propyl]amino}-
7α-hydroxy-5α-cholestan-24-yl hydrogen sulfate

trodusquémine hydrogénosulfate de (24R)-3β-[[3-[[4-[(3-aminopropyl)amino]butyl]=

amino]propyl]amino]-7α-hydroxy-5α-cholestan-24-yle

trodusquemina hidrogénosulfato de (24R)-3β-[[3-[[4-[(3-aminopropil)amino]butil]=

amino]propil]amino]-7α-hidroxi-5α-colestan-24-ilo

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Recommended INN: List 53 WHO Drug Information, Vol. 19, No. 1, 2005

C37H72N4O5S

H3C H H
OSO3H
CH3
H CH3
H CH3 H
N H3C
HN
H H
H 2N
N OH
H H H H

vandetanibum
vandetanib N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-
4-yl)methoxy]quinazolin-4-amine

vandétanib N-(4-bromo-2-fluorophényl)-6-méthoxy-7-[(1-méthylpipéridin-
4-yl)méthoxy]quinazolin-4-amine

vandetanib N-(4-bromo-2-fluorofenil)-7-[(1-metilpiperidin-4-il)metoxi]-
6-metoxiquinazolin-4-amina

C22H24BrFN4O2

F Br
N N

N
H
O
N OCH3
H3C

vestipitantum
vestipitant (2S)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-
2-methylphenyl)-N-methylpiperazine-1-carboxamide

vestipitant (+)-(2S)-N-[(1R)-1-[3,5-bis(trifluorométhyl)phényl]éthyl]-2-(4-fluoro-
2-méthylphényl)-N-méthylpipérazine-1-carboxamide

vestipitant (+)-(2S)-N-[(1R)-1-[3,5-bis(trifluorometil)fenil]etil]-2-(4-fluoro-
2-metilfenil)-N-metilpiperazina-1-carboxamida

C23H24F7N3O

CF3

HN CH3
N N
CF3
H O H CH3
CH3

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AMENDMENTS TO PREVIOUS LISTS

MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES
MODIFICACIONES A LAS LISTAS ANTERIORES

Recommended International Nonproprietary Names (Rec. INN): List 51

Dénominations communes internationales recommandées (DCI Rec.): Liste 51
Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 51
(WHO Drug Information, Vol. 18, No. 1, 2004)

p. 94 eptoterminum alfa
eptotermin alfa replace the graphic formula by:
eptotermine alfa remplacer la formule développée par:
eptotermina alfa sustitúyase la fórmula desarrollada por la siguiente:

STGSKQRSQN RSKTPKNQEA LRMANVAENS SSDQRQACKK

HELYVSFRDL GWQDWIIAPE GYAAYYCEGE CAFPLNSYMN

ATNHAIVQTL VHFINPETVP KPCCAPTQLN AISVLYFDDS

SNVILKKYRN MVVRACGCH

Recommended International Nonproprietary Names (Rec. INN): List 52

Dénominations communes internationales recommandées (DCI Rec.): Liste 52
Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 52
(WHO Drug Information, Vol. 18, No. 3, 2004)

p. 248 beminafilum
beminafil replace the graphic formula by the following:
béminafil remplacer la formule développée par la suivante:
beminafilo sustitúyase la fórmula desarrollada por la siguiente:

N N
H
H3CO CO2H
Cl

p. 264 zanolimumabum
zanolimumab delete the graphic formula
zanolimumab supprimer la formule développée
zanolimumab suprímase la fórmula desarrollada

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Procedure and Guiding Principles / Procédure et Directives / Procedimientos y principios generales

The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceutical
Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharmaceutical
Substances will be reproduced in proposed INN lists only.
Les textes de la Procédure à suivre en vue du choix de dénominations communes internationales recommandées pour les
substances pharmaceutiques et des Directives générales pour la formation de dénominations communes internationales
applicables aux substances pharmaceutiques seront publiés seulement dans les listes des DCI proposées.
El texto de los Procedimientos de selección de denominaciones comunes internacionales recomendadas para las sustancias
farmacéuticas y de los Principios generales de orientación para formar denominaciones comunes internacionales para
sustancias farmacéuticas aparece solamente en las listas de DCI propuestas.

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