WHO DRUG

INFORMATION
V O L U M E 11 • N U M B E R 2 • 1 9 9 7

P R O P O S E D I N N L I S T 77
INTERNATIONAL NONPROPRIETARY NAMES
FOR P H A R M A C E U T I C A L SUBSTANCES

WORLD HEALTH ORGANIZATION • GENEVA

Volume 11, Number 2, 1997 World Health Organization, Geneva

WHO Drug Information

Contents Cidofovir and renal impairment 72
Granulocyte macrophage colony-stimulating
factor and interstitial pneumonia 72
General Policy Issues Metformin and lactic acidosis 72
Sale of medical products through the Internet 51 Cisapride and asthmatic attacks 72
Future role of ATC and DDDs 51 Withdrawal of fixed paracetamol-methionine
combination 72
Isotretinoin: risks remain 73
Current Topics Withdrawal of fixed-combination barbiturates 73
Oral contraceptives and venous thrombo- Are chlorfluorocarbon propellants essential? 73
embolic disease 53 Conjugated estrogens and generic
pharmaceuticals: update 74
Tramadol associated with anaphylactic
Personal Perspectives reactions 74
Counterfeit medicines: a special case
for concern 57 Essential Drugs:
Future challenges in regulatory control 59
WHO Model Formulary
Anti-infective drugs: anthelminthics
Reports on Individual Drugs Drugs used for cestode (tapeworm) infections 75
Move to triple-drug therapy for HIV 63 Albendazole 75
Amiodarone and post-infarction arrhythmia 65 Mebendazole 76
Niclosamide 76
Praziquantel 76
Regulatory Matters Drugs used for intestinal nematode infections 77
Update on risks of non-sedating antihistamines 67 Albendazole 77
Terfenadine to prescription-only status — Levamisole 77
astemizole under critical review 67 Mebendazole 77
Terfenadine: proposed change to prescription Pyrantel 78
only 67 Drugs used for tissue nematode infections 78
Terfenadine: further reports 68 Antifilarials 79
Anorectic agents: revised recommendations 68 Diethylcarbamazine 79
Baclofen: withdrawal reactions 68 Ivermectin 80
Fluvastatin and muscle disorders: a class Suramin sodium 81
effect 68 Antischistosomals 81
Abuse of gamma hydroxybutyric acid (GHB) 69 Praziquantel 82
Instructions for safe use of systemic Metrifonate 82
corticosteroids 69 Oxamniquine 83
Update on lamotrigine and severe skin Drugs used in fluke infections 83
reactions 70 Praziquantel 83
Drug interactions with grapefruit juice 70
Triazolam and alprazolam and interactions 71
Ticlopidine and white blood cell disorders 71 Proposed International
Selegiline-associated hypertensive reactions 71
Pemoline and liver failure 71
Nonproprietary Names: List 77 85
Ritonavir and interactions 71

i
WHO Drug Information Vol. 11, No. 2, 1997
General Policy Issues
Sale of medical products
through the Internet
The problem of cross-border sales of pharma-
ceutical products through the Internet was first
raised by drug regulators at the International
Conference of Drug Regulatory Authorities which
took place in Bahrain in November 1996. Since
then, WHO has made rapid progress in assessing
the size and importance of the problem and a
resolution was subsequently adopted at the World
Health Assembly in Geneva in May of this year.
The resolution highlights concern at the advertising,
promotion and uncontrolled sale of medical
products through electronic communication and
sets out to initiate procedures to regulate this
practice and to limit the consequent public health
risks.
Most countries prohibit promotion and advertising of
prescription-only medicines to the public in view of
their pharmacological activity and potential to cause
adverse reactions and possible interaction with
other medicines or food. Patient information, which
is often included on the Internet as part of
promotion, cannot replace the medical oversight
and pharmaceutical counselling fundamental to
ensuring safe and appropriate use of drugs.
Additionally, many drugs are promoted on the
Internet for indications that are not approved by the
regulatory authority. Thus, offering prescription-only
medicines for sale to individual consumers without
medical examination, diagnosis, counselling or
pharmacist control poses a very possible risk to
health. Purchase and delivery of these products are
effected beyond the control of any authorities. The
regulatory assurances concerning safety, efficacy,
quality and appropriate product information which
are provided when a product is authorized for
marketing, subsequently distributed and dispensed
through the proper channels, are also lacking.
Problems may also arise if a non-prescription
medicine is on the market in one country but not
approved for over-the-counter use in another
country.
The Health Assembly was also concerned at the
possible circulation of fraudulent imitations of
medical products within this system which pose a
threat to the health of the individual as well as the
community. WHO was requested to convene an ad
hoc working group to consider the main issues of
cross-border advertising, promotion and sale of
medical products on the Internet, and to formulate
recommendations for guidance and action by
governments. The meeting will be organized by the
Division of Drug Management and Policies in
September 1997 at WHO Headquarters in Geneva.
Future role of ATC and DDDs
Little is known about the clinical consequences of
different prescribing patterns between countries or
between regions within a country. There are few
systematic and comprehensive data on the utiliza-
tion of drugs after they have been marketed, but it
is recognized that drugs are frequently not used to
their full potential.
In an effort to strengthen and facilitate the provision
of data and statistics and to provide a tool for use in
drug utilization studies, the Division of Drug
Management and Policies of WHO has agreed to
take over responsibility for the international aspects
of the anatomical therapeutic chemical (ATC)
classification and defined daily dose (DDD) which
continue to be developed by the WHO Collabora-
ting Centre for Drug Statistics Methodology in Oslo,
Norway. Until now, the ATC/DDD methodology has
been implemented mainly within Europe and the
new move is meant to give an international
perspective to the classification and impetus to
global use.
In April of this year, the first meeting of the new
international working group was held at WHO
Headquarters, Geneva. The meeting welcomed
officials from the Norwegian Board of Health, the
WHO Collaborating Centre for International Drug
Monitoring, academia and interested institutions,
including a representative of the International
Federation of Pharmaceutical Manufacturers
Associations (IFPMA). Twelve international experts,
drawn from the different disciplines as reflected in
the WHO Expert Advisory Panels and representing
a diversity of countries, have been invited to serve
as members of the core working group.
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General Policy Issues
The opening day of the meeting was dedicated to
the historical and introductory aspects of the
classification and a general discussion took place
between members of the working group and the
Secretariats. It was agreed that the international
application of the ATC/DDD and its role in new
scenarios would be a priority. It was seen as vital to
encourage studies of drug consumption and
utilization to monitor the rational use of drugs. One
pro-active role would be the establishment of
working groups in each country in collaboration with
national associations and WHO offices to initiate
studies on drug prescribing and use. Also proposed
was the incorporation of the system into the
curricula of postgraduate education, as well as its
inclusion on the agenda of relevant meetings.
Information should be made available on drug
utilization studies collected from each country, and
studies should be carried out on ways to promote
use of the system in both the public and private
sectors.
Discussion during the meeting centred on the
international relevance, further development and
enhancement of the ATC and DDDs. A revision of
the working methods for the group and the criteria
used for the ATC/DDD classification were also
drawn up, as was a timetable for the administration
of applications. These should be forwarded to the
WHO Collaborating Centre in Oslo where they will
be evaluated and classified in consultation with
interested parties.
Once the classification has been established by the
international working group, it will be disseminated
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WHO Drug Information Vol. 11, No. 2, 1997
in WHO Drug Information as a temporary ATC or
DDD and a period of 4 months will be allowed for
any objections to be lodged. After this period, the
ATC or DDD will be published in final form by
WHO. In the event of discord, a consultative
procedure has been set up and the working group
will take a final decision on the matter in
consultation with outside technical experts. A
representative of the Secretariat of the International
Federation of Pharmaceutical Manufacturers
Associations (IFPMA) will be present at the regular
working group meetings as an observer.
A yearly ATC/DDD index will continue to be
published by the WHO Collaborating Centre and
additional information can be obtained from the
guidelines, which will shortly be revised by the
working group together with the new application
form.
At the next meeting of the working group to be held
in October 1997, progress will be reviewed and a
development plan established. It is proposed to
focus on one country at a time to document the
improvements which can be achieved by
application of the ATC/DDD in the rational use of
drugs and to extend this knowledge to other
countries.
Address: WHO Collaborating Centre for Drug Statistics
Methodology, Sven Oftedals Vei 10
N–0518 Oslo, Norway
Telephone: 47 22 16 98 10
Fax: 47 22 16 98 18
WHO Drug Information Vol. 11, No. 2, 1997
Current Topics
Oral contraceptives and
venous thromboembolic
disease
Professor David C.G. Skegg
University of Otago Medical School
Dunedin, New Zealand
Shortly after the introduction of oral contraceptives
in the 1960s, clinical case reports and epidemio-
logical studies suggested that women using these
preparations were at an increased risk of deep vein
thrombosis and pulmonary embolism. There was
vigorous debate as to whether these associations
were due to a causal relationship or bias. As further
evidence became available, a consensus emerged
that oral contraceptives can occasionally cause
venous thromboembolism (VTE), as well as arterial
disease (myocardial infarction and stroke) (1, 2).
However, the excess risk of VTE was found to be
smaller in women using combined oral contra-
ceptives containing a lower dose of estrogen (3, 4).
The potency of the progestogen component
appeared not to be important (5, 6).
Three decades later, renewed controversy has
sprung up concerning oral contraceptives and VTE.
This relates to products containing a new class of
progestogen, known as third-generation com-
pounds to distinguish them from first-generation
progestogens such as norethisterone, and second-
generation progestogens such as levonorgestrel.
Five studies published since December 1995 have
all shown a higher risk of VTE in women using low-
estrogen oral contraceptives containing the third-
generation progestogens, desogestrel or gesto-
dene, rather than levonorgestrel (7–11). The five
studies included two hospital-based case-control
studies (7, 8), a population-based case-control
study (9,) and two cohort studies using the com-
puterized records of general practitioners (10, 11).
The largest of the case-control studies was con-
ducted by the World Health Organization in 21
centres throughout Africa, Asia, Europe and Latin
America (7). In both Europe and the developing
countries, use of oral contraceptives was
associated with a three- or fourfold increase in the
risk of VTE. The study showed a higher risk among
women using third-generation oral contraceptives.
In a detailed analysis, the relative risk estimate was
3.5 (95% confidence interval 2.6–4.7) for contra-
ceptives containing levonorgestrel but 9.1 (95%
confidence interval 4.9–17.0) for contraceptives
containing desogestrel and 9.1 (95% confidence
interval 4.9–16.7) for contraceptives containing
gestodene (12). Using data from the Oxford region
in the United Kingdom, the incidence of idiopathic
VTE (per 100 000 woman-years) was estimated to
be 3.9 for non-users of oral contraceptives, 10.3 for
users of levonorgestrel, and 21.3 for users of
desogestrel or gestodene. Thus the excess risk
associated with oral contraceptives containing
desogestrel or gestodene, instead of levonor-
gestrel, was about 1 in 10 000 women per year.
While there were differences in detail, the
remaining four studies yielded similar results. In the
cohort study using the United Kingdom General
Practice Research Data Base, the incidence of non-
fatal VTE, per 100 000 woman-years, was found to
be 16.1 for users of contraceptives containing
levonorgestrel, 29.3 for desogestrel, and 28.1 for
gestodene (10). After adjusting for potential
confounding factors, the excess risk associated
with oral contraceptives containing desogestrel or
gestodene, rather than levonorgestrel, was
estimated to be 1.6 in 10 000 women per year.
The evidence obtained has been unusually
consistent from this series of observational studies
conducted in different countries and with varying
designs and statistical power. Chance is no longer
a plausible explanation for the original findings, but
it is necessary to consider whether the association
could be due to confounding or bias. The authors of
the five studies took pains to minimize these
possibilities. Farmer et al. (11) suggested that the
increased risks associated with third-generation
oral contraceptives were likely to have been due to
residual confounding by age, but the evidence
adduced does not support this (13). Other non-
causal explanations proposed have included
preferential prescribing of third-generation contra-
ceptives for women at higher risk of VTE,
diagnostic, or referral bias, or a greater tendency
for third-generation contraceptives to be taken by
new or short-term users (14, 15). There is, in fact,
considerable evidence against each of these
suggestions (16, 17) but the debate has continued.
53
Current Topics
A further objection levelled at the causal hypothesis
was the lack of a plausible biological explanation
(14). This objection is no longer valid, since
researchers in the Netherlands (18) have shown
that women who use third-generation, monophasic
oral contraceptives are significantly less sensitive to
activated protein C (APC) than women using
second-generation oral contraceptives. Resistance
to APC is known to be a feature of the most
common type of hereditary thrombophilia due to the
factor V Leiden mutation. The laboratory work from
the Netherlands suggests that the increased risks
of venous thrombosis in women using oral contra-
ceptives and in congenitally APC-resistant
individuals originate from a defect in the same
physiological pathway. A previous Netherlands
case-control study (9) had shown that both carriers
and non-carriers of the factor V Leiden mutation
had a higher relative risk of deep vein thrombosis
when using oral contraceptives containing
desogestrel rather than older progestogens. The
absolute risk of thrombosis appeared to be
especially high in women who both carried the
factor V Leiden mutation and used a third-
generation oral contraceptive. There is a striking
coherence between the predictions from the
laboratory and epidemiological data (17).
The case fatality for VTE is believed to be low (1 to
2%) (7), but non-fatal deep vein thrombosis and
especially pulmonary embolism can be distressing
and disabling for otherwise healthy young women.
Regulatory authorities have already issued advice
about third-generation oral contraceptives in
several countries, including the United Kingdom,
Germany, Norway and New Zealand. Reasons for
delay in other countries have included concern
about possible sources of bias in the
epidemiological studies, the previous lack of a
biological explanation, the fact that the absolute risk
of VTE in women using third-generation oral
contraceptives is low (unless they also have other
risk factors such as hereditary thrombophilia), and
the possibility that the extra risk of VTE may be
outweighed by specific advantages of third-
generation contraceptives.
What are these particular advantages? The contra-
ceptive efficacy of these products appears to be
similar to that of other combined oral contra-
ceptives (19). The new preparations are widely held
to produce fewer minor side effects (especially
androgenic effects) than oral contraceptives
containing levonorgestrel, although there are
surprisingly few well-designed clinical studies (20).
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WHO Drug Information Vol. 11, No. 2, 1997
Studies of the influence of third-generation oral
contraceptives on lipid metabolism (19) encouraged
the hope that these newer preparations might be
associated with a lower risk of other rare but
serious cardiovascular complications of oral
contraception — myocardial infarction and stroke.
There is no evidence of such a difference for stroke
(21) but for myocardial infarction, an international
case-control study produced a lower estimate of
risk for third-generation compared with second-
generation oral contraceptives, although the
difference was not statistically significant (22). The
WHO Collaborative Study of Cardiovascular
Disease and Steroid Hormone Contraception found
a difference in the same direction, based on small
numbers of users of desogestrel or gestodene, but
this difference disappeared when account was
taken of the fact that women receiving the oral
contraceptives containing these progestogens were
more likely to have had their blood pressure
checked (23).
If third-generation oral contraceptives were shown
to confer a lower risk of myocardial infarction or
stroke, this would be mainly relevant to older
women (and especially those who are smokers).
For women under 30 years of age, who constitute
the majority of oral contraceptive users in many
countries, the risk of myocardial infarction or stroke
is extremely small (1, 2).
The outstanding benefit of oral contraception is its
prevention of unplanned pregnancy — with a high
degree of effectiveness, convenience and rever-
sibility. For most women, the non-contraceptive
benefits of oral contraceptives also outweigh the
risks (24). Decisions about the choice of a particular
oral contraceptive formulation should be based on
consideration of all the potential risks and benefits,
having regard to the circumstances of the individual
woman. Women with a personal history of VTE or
with possible hereditary thrombophilia should not
use any combined oral contraceptive. There is now
sufficient evidence to recommend against pre-
scribing oral contraceptives containing desogestrel
or gestodene for women who have other risk
factors for VTE — such as extensive varicose
veins, obesity (defined as a body mass index of 30
kg/m2 or over), the presence of lupus anti-coagulant
or malignancy, or mechanical factors such as
immobility or trauma (25). For the majority of
women without risk factors for VTE, the choice of
an oral contraceptive will depend on a variety of
considerations including the risk of cardiovascular
disease. Contraceptives that may carry additional
WHO Drug Information Vol. 11, No. 2, 1997
risks should be recommended only when there is a
prospect of additional benefits.
Clearly, such decisions would be assisted by reso-
lution of some of the issues discussed here. For
this reason, the World Health Organization will be
convening a Scientific Group in November 1997. It
is expected that their report will provide Member
States, scientists, and family-planning providers
with an authoritative review of all the evidence con-
cerning the cardiovascular effects of oral contra-
ceptives and the implications for family planning.
References
1. Stadel, B.V. Oral contraceptives and cardiovascular
disease. New England Journal of Medicine, 305: 612–618
& 672–677 (1981).
2. Sartwell, P.E., Stolley, P.D. Oral contraceptives and
vascular disease. Epidemiologic Reviews, 4: 95–109
(1982).
3. Inman, W.H.W., Vessey, M.P., Westerholm, B. et al.
Thromboembolic disease and the steroidal content of oral
contraceptives. British Medical Journal, 2: 203–209
(1970).
4. Gerstman, B.B., Piper, J.M., Tomita, D.K. , Ferguson,
W.J. et al. Oral contraceptive estrogen dose and the risk
of deep venous thromboembolic disease. American
Journal of Epidemiology, 133: 32–37 (1991).
5. Prentice, R.L., Thomas, D.B. On the epidemiology of
oral contraceptives and disease. Advances in Cancer
Research, 49: 285–401 (1987).
6. Gerstman, B.B., Piper, J.M., Freiman, J.P. et al. Oral
contraceptive oestrogen and progestin potencies and the
incidence of deep venous thromboembolism. International
Journal of Epidemiology, 19: 931–936 (1990).
7. World Health Organization Collaborative Study of
Cardiovascular Disease and Steroid Hormone Contra-
ception. Venous thromboembolic disease and combined
oral contraceptives: results of international multicentre
case-control study. Lancet, 346: 1575–1582 (1995).
8. Spitzer, W.O., Lewis, M.A., Heinemann, L.A.J. et al.
Third-generation oral contraceptives and risk of venous
thromboembolic disorders: an international case-control
study. British Medical Journal, 312: 83–88 (1996).
9. Bloemenkamp, K.W.M., Rosendaal, F.R., Helmerhorst,
F.M. et al. Enhancement by factor V Leiden mutation of
risk of deep-vein thrombosis associated with oral
contraceptives containing a third-generation progestagen.
Lancet, 346: 1593–1596 (1995).
Current Topics
10. Jick, H., Jick, S.S., Gurewich, V. et al. Risk of
idiopathic cardiovascular death and nonfatal venous
thromboembolism in women using oral contraceptives
with differing progestagen components. Lancet, 346:
1589–1593 (1995).
11. Farmer, R.D.T., Lawrenson, R.A., Thompson, C.R.
et al. Population-based study of risk of venous thrombo-
embolism associated with various oral contraceptives.
Lancet, 349: 83–88 (1997).
12. World Health Organization Collaborative Study of
Cardiovascular Disease and Steroid Hormone Contra-
ception. Effect of different progestagens in low oestrogen
oral contraceptives on venous thromboembolic disease.
Lancet, 346: 1582–1588 (1995).
13. Vandenbroucke, J.P., Helmerhorst, F.M., Bloemen-
kamp, K.W.M. et al. Third-generation oral contraceptives
and venous thrombosis. Lancet, 349: 731 (1997).
14. Lidegaard, O., Milsom, I. Oral contraceptives and
thrombotic diseases: impact of new epidemiological
studies. Contraception, 53: 135–139 (1996).
15. Lewis, M.A., Heinemann, L.A.J., MacRae, K.D. et al.
The increased risk of venous thromboembolism and the
use of third-generation progestogens: role of bias in
observational research. Contraception, 54: 5–13 (1996).
16. Farley, T.M.M., Meirik, O, Poulter, N.R. et al. Oral
contraceptives and thrombotic diseases: impact of new
epidemiological studies. Contraception, 54: 193–195
(1996).
17. Vandenbroucke, J.P., Rosendaal, F.R. End of the line
for "third-generation pill" controversy? Lancet, 349: 1113–
1114 (1997).
18. Rosing, J., Tans, G., Nicolaes, G.A.F. et al. Oral
contraceptives and venous thrombosis: different
sensitivities to activated protein C in women using second
and third generation oral contraceptives. British Journal
of Haematology, 97: 233–238 (1997).
19. Speroff, L., DeCherney, A. and the Advisory Board for
the New Progestins. Evaluation of a new generation of
oral contraceptives. Obstetrics and Gynecology, 81:
1034–1047 (1993).
20. Paul, C. Oral contraceptives and venous thrombo-
embolism. New Zealand Medical Journal, 109: 413–415
(1996).
21. World Health Organization Collaborative Study of
Cardiovascular Disease and Steroid Hormone
Contraception. Ischaemic stroke and combined oral
contraceptives: results of an international, multicentre,
case-control study. Lancet, 348; 498–505 (1996).
55
Current Topics
22. Lewis, M.A., Spitzer, W.O., Heinemann, L.A.J. et al.
Third-generation oral contraceptives and risk of
myocardial infarction: an international case-control study.
British Medical Journal, 312: 88–90 (1996).
23. World Health Organization Collaborative Study of
Cardiovascular Disease and Steroid Hormone Contra-
ception. Acute myocardial infarction and combined oral
contraceptives: results of an international multicentre
case-control study. Lancet, 349: 1202–1209 (1997).
56
WHO Drug Information Vol. 11, No. 2, 1997
24. Vessey, M.P. An overview of the benefits and risks of
combined oral contraceptives. In: Oral contraceptives and
breast cancer. Mann, R.D. ed. Carnforth, Parthenon,
1990, pp. 121–132.
25. Mills, A.M., Wilkinson, C.L., Bromham, D.R. et al.
Guidelines for prescribing combined oral contraceptives.
British Medical Journal, 312: 121–122 (1996).
WHO Drug Information Vol. 11, No. 2, 1997
Personal Perspectives
Counterfeit medicines:
a special case for concern
Margaret Cone
Vice President for Scientific Affairs
International Federation of Pharmaceutical
Manufacturers Associations (IFPMA)
"Counterfeiting of pharmaceuticals is a particularly
serious criminal offence and handling such
counterfeits is an unethical practice because it
endangers human health." This was the principal
message to emerge from the jointly sponsored
WHO/IFPMA workshop held in April 1992, and it
retains its relevance as the main theme in a paper
recently published by the International Federation
of Pharmaceutical Manufacturers Associations
(IFPMA)*.
The term counterfeit, as applied to medicines, can
be used to cover many different circumstances. In
its strictest sense it means a product which is not
made by the legitimate manufacturer but which is
an imitation of an original with the correct active
ingredient in the correct dosage, presented in a
similar form and in an apparently identical pack with
the same, copied, technical literature. There exists,
however, a wide spectrum of counterfeits ranging
from the product containing the correct dose of
active ingredient, to the extreme case of a dosage
form which contains none of the correct active
ingredient, the wrong ingredient or, possibly, a toxic
substance. In all of these cases, however, the
intention is to deceive.
There is a need for far greater awareness of the
hazards to health posed by counterfeit medicines
and a far greater political commitment to interna-
tional cooperation to stop their commercialization.
The harm to patients from counterfeit medicines,
which are rarely effective and, in many cases,
positively dangerous, results in both human
suffering and an increased burden on health
services. Moreover, medicines containing no active
* International Pharmaceutical Issues Handbook. Available from
The International Federation of Pharmaceutical Manufacturers
Associations (IFPMA), 30 rue de St. Jean, P.O. Box 9, 1211
Geneva 18, Switzerland.
ingredient or a subtherapeutic dose are not only a
hazard to the health of the individual and a waste of
money but, in the case of anti-infectives, a risk to
public health in encouraging bacterial and parasitic
resistance when delivered in subtherapeutic doses.
The pharmaceutical industry shares these concerns
and is well aware that health care and patient
confidence are eroded when counterfeits are
reported to be in circulation. Furthermore, losses in
revenue as a result of counterfeiting are enormous,
and the damage inflicted on a company’s reputation
is a serious matter.
Estimates of the level of counterfeiting vary. It is
difficult to obtain a true figure, but this must run into
billions of dollars and possibly involves organized
crime. The prevalence of counterfeits in developing
countries has been acknowledged for some time as
a major threat to public health. However, the
widespread circulation of seriously substandard
products in a situation where there is also an
inadequate product registration system will tend to
“blur” the distinction between a deliberate counter-
feit and a poor quality product which does not
comply with the labelled claim. Reports of high
percentages of counterfeit products in developing
countries may, therefore, be distorted by the
prevalence of very poor quality products. Further-
more, in the more developed countries, there is a
danger that the scale of the problem is masked
because the counterfeits are so similar to the
original product that they are more likely to pass
undetected. It must be emphasized here that all
counterfeit products, no matter how close a copy to
the original, can pose a serious hazard to health
and constitute a “tragedy about to happen” because
they have escaped the regulatory controls which
have been put in place precisely to protect public
health.
Medicines represent one of the most regulated
products available, so why do they attract
counterfeiters? There may be many reasons.
Firstly, medicines are high value items in relation to
their bulk, and ingredient costs can be low if cheap
substitutes are used for active ingredients or if they
are omitted altogether. Manufacture is also cheap
as there are no overheads to pay for quality
57
Personal Perspectives
assurance or meeting GMP standards as would
normally be the case. Gross margins are therefore
very high. In addition, many countries, especially in
the developing world, are without adequate
regulation and enforcement and, even in the
industrialized countries, the risk of prosecution and
penalties for counterfeiting provide a weak
deterrent.
Another reason is the process by which a patient
comes to take a medicine, which is different from
other consumer goods, because the end user is
unable to evaluate the product ingredients. The
doctor prescribes the product but, in most cases,
never sees it. The pharmacist usually buys the
product from one or more of a selection of
wholesalers. Parallel trading opens a door through
which goods of indeterminate origin can enter the
distribution chain. The vulnerability of medicines to
counterfeiting is therefore increased because a
number of possible points of insertion of illicit
material exist even when the system is highly
regulated, as is the case in the industrialized world.
At the joint WHO/IFPMA meeting on counterfeit
medicines in 1992, the view was expressed that
regulation and enforcement are necessary to deal
with counterfeiting of medicines, and that this
regulation was identified as inadequate in both
developed and developing countries. Key factors in
preventing counterfeiting include: stronger and
more specific legislation to take action against
counterfeiters; cooperation and coordination
between all parties concerned — regulatory
agencies, police, customs, private industry,
pharmaceutical professions and WHO. Appropriate
exchange of information and the development of
mutual trust regarding use of such material is
needed, as are tight security measures by
companies to ensure that products, and especially
packaging material, are not diverted from legitimate
distribution channels.
Counterfeit medicines can more easily be
introduced into the distribution chain when this is
too long or where parallel or international trading of
pharmaceuticals as “commodities” by brokers takes
place. Ideally, there should never be more than
three stages in the chain — from licensed
manufacturer to reputable wholesaler to a
supervised dispensary or retail outlet. The TRIPS
agreement (see page 59) imposes obligations on
members of the World Trade Organization to
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“provide for criminal procedures and penalties to be
applied at least in cases of wilful trademark
counterfeiting or copyright piracy on a commercial
scale” (Article 61). The industry believes that these
obligations should be implemented as a matter of
urgency by countries where weak legislation
impedes action against counterfeiters.
The IFPMA has encouraged its constituents to
ensure transparency in the exchange of information
on counterfeits with regulatory authorities and
within the industry. Companies are also expected to
assist official laboratories with the analysis of
suspected counterfeit products. This cooperation
can only be realized, however, if all parties respect
the need to treat all information in a responsible
manner, thereby avoiding damage to legitimate
products and the reputation of the companies
concerned.
Industry has developed anti-counterfeiting
measures such as the use of holograms, but
experience has shown that counterfeiters soon
copy the technology. Efforts to impede counter-
feiting through innovative special packaging need,
therefore, to be pursued by industry. Individual
companies also have a responsibility to ensure that
security measures are in place to detect and
prevent diversion of products and components,
such as packaging, for illegal purposes.
Pharmaceutical companies are making increased
efforts to monitor and investigate the nature and
possible sources of counterfeit and diverted
products which are detected in circulation. By
studying and learning lessons from case histories,
especially those involving diverted ingredients and
other materials, it is hoped to improve guidelines on
good operating practices which can strengthen the
barriers against the illicit and criminal activities of
the counterfeit traders.
In conclusion, there is no such thing as a “good”
counterfeit medicine and it is quite unacceptable to
“tolerate” counterfeiting where the products are
close copies of the original and do not appear to
pose a hazard to health. Any medicinal product
which comes from an unauthorized source is a
potential hazard, as it is not subject to quality
assurance and regulatory control. To ignore this is
to deny the usefulness and responsibility of
regulatory authorities.
WHO Drug Information Vol. 11, No. 2, 1997
Future challenges in
regulatory control
Dr E. Fefer
Pan American Health Organization/
WHO Regional Office for the Americas
Washington, DC, USA
Novel pharmaceutical products and technologies
are being developed at an unprecedented rate in
response to the sophisticated health demands of
populations that are pursuing economic growth. In
such a rapidly changing environment, it is crucial for
drug regulators to be fully informed of the latest
pharmaceutical discoveries, while at the same time
retaining critical oversight of the transformations
that are taking place within the industry. The trends
of broad national and global markets must be
evaluated as they relate to the task of regulation
and their influence defined with regard to public
health objectives.
As a general rule, pharmaceutical markets are
expected to grow in both size and value as a result
of two major factors: the ageing of populations,
which will account for 1000 million people of 60
years or older by the year 2020, and increased
urbanization, where, for example, an estimated
75% of Latin Americans will be living in cities by the
year 2000. In the Americas, almost all countries
now have a democratically elected government and
a similar movement can be seen in other areas in
the world. The opening up of societies has brought
with it a debate on the role of the state and a broad
consensus supports a centralized national policy-
making and regulatory apparatus with relevant
activities delegated to local governments. At the
same time, greater responsibility is being demand-
ed of the private sector and local communities.
In this situation, health remains an important factor.
Much has recently been reported of emerging and
re-emerging infectious diseases, including the re-
appearance of cholera and the spread of dengue in
Latin America. Many problems also occur in other
regions of the world and one particular concern is
the development of resistance to antimicrobials.
The new products and expensive treatments soon
to be launched by the pharmaceutical research
industry in response to this situation will need
careful assessment and regulation in order to
ensure rational and sustainable use. Similarly, new
understanding of biological processes at the cellular
and molecular levels has led to the development of
Personal Perspectives
biotechnology-derived products that will need
specialized knowledge in evaluating their quality,
efficacy and safety prior to marketing.
Paradoxically, in a growing market, and with greater
knowledge of the disease process, the actual
number of companies with innovative research and
development capability and with international
marketing capacity has decreased. Since the late
1980s, there has been a veritable epidemic of
mergers, acquisitions and strategic alliances. This
process of consolidation has been accompanied by
a streamlining of operations which has led to the
closure of many research and operational facilities,
and a reduction in personnel. This trend is fuelled
by open market policies that allow international
companies to supply their markets from the most
cost-effective locations, a situation which has led to
the closure of sites which are financially
unattractive.
The recent World Trade Organization agreement on
trade-related aspects of international property rights
(TRIPS) provides for patent protection worldwide.
The research-based industry is hopeful that this will
further stimulate research, but local industries that
prospered under pre-TRIPS conditions feel that
there will be a resulting restraint on competition
which will lead to higher prices for new drugs.
Implementation of this agreement has been a
particularly contentious subject throughout Latin
America and a source of confrontation. Relevant
legislation has now been approved in many
countries but this new situation will demand
adaptability by locally owned companies obliged to
look for alternative ways to compete in the
marketplace.
Before the end of the present decade, protection of
patents will come to an end for many of the current
best-selling products. This has led to increased
production capacity of generic products — a market
area which ten years ago was of limited interest to
multinational corporations. Today, all the leading
companies have generic product lines, and
governments are finding generic drug policies to be
a valuable instrument in controlling costs.
Free-market policies and the integration of regional
and world economies have together provided
impetus for regulatory harmonization. The
International Conference on Harmonization (ICH),
which has been established by drug regulatory and
pharmaceutical industry representatives of the
European Union, Japan and the United States, is
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Personal Perspectives
the best known process, although harmonization
efforts are also under way in other parts of the
world. The market importance of the ICH member-
ship will mean that the standards for quality, safety
and efficacy which are agreed upon by the ICH may
become de facto standards for the rest of the world.
Pharmaceutical companies in countries outside the
ICH are concerned that they may not be able to
meet such standards which, they argue, are driven
by what is technologically feasible rather than what
is clinically necessary.
The main impact of a market-driven environment is
the pressure to decrease or limit the regulatory role
of the government and, as some extreme groups
say, to "let the market decide". Clearly this cannot
be allowed for pharmaceuticals for obvious reasons
of safety and protection of public health. This pres-
sure is similarly reflected by proposed or actual
legislation and regulations aimed at facilitating and
expediting the approval of pharmaceutical products.
Deregulation has been exaggerated by some
governments that automatically approve products
according to their approval status in selected
reference countries.
Drug regulatory essentials
What must a drug regulatory authority do to
function effectively under political conditions that
give priority to economic considerations and tend to
favour a diminished role for the central govern-
ment? First and foremost, there is a need to focus
on essentials. Governments should not lose sight of
the central mission of the drug regulatory authority
— which is to protect public health. There should be
no compromising on this.
Of course, the regulatory agency also contributes to
promoting public health by approving in a timely
manner applications for new drugs, expediting
access to those products that represent significant
contributions to health, and encouraging the
marketing of well-known essential drugs, as well as
orphan drugs. And, of course, the regulatory
agency should also be responsive to the legitimate
needs of the industry by providing an efficient and
transparent service. Unfortunately, we are far from
these goals in many developing countries.
During a recent working group of the World Bank,
involving WHO, UNICEF and other interested
organizations, this issue was discussed at length.
Many barriers to effective regulation were identified,
such as insufficient human resources, absence of a
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WHO Drug Information Vol. 11, No. 2, 1997
policy, weak legislation and regulation, lack of
political support and will, flawed information flow,
lack of financing, absence of transparent
procedures, corruption, poor attention to cultural
constraints, weak or nonexistent consumer and
professional associations, and an absence of
priorities.
The day-to-day shortcomings of many regulatory
agencies range from a scarcity of qualified staff for
the review of applications for drug approval, to a
lack of enforcement in removing from the market
unsafe or ineffective products. However, the
regulatory situation in any given country will not
improve unless there are fundamental changes in
the structure, staffing and operation of the agencies
and this requires a government willing to invest the
necessary political will and finances to bring about
the required changes. Unfortunately, the import-
ance of strengthening the regulatory role of a
government only seems to come about after a
major tragedy occurs, as we have seen this decade
in Argentina and, more recently, in Haiti.
A visible agency and
qualified regulatory officials
An effective regulatory agency cannot be buried in
the Ministry — it needs to be visible and have an
identity. This can be achieved by upgrading the
status of the responsible department within the
official structure or, better still, by establishing a
semi-autonomous agency with authority and
responsibility for all aspects of drug regulation while
avoiding dispersion of, and competition among, the
available personnel.
This ideal agency would have administrative and
financial flexibility to enable it to carry out its work.
This would include the authority to hire a core of
qualified full-time staff at competitive salaries. Full-
time regulatory personnel require a salary which is
reasonable enough to waylay corrupting influences
and conflicts of interest. This reality needs to be
adequately addressed in many societies.
Where agency staff and expertise are limited,
certain functions can be contracted out. Recent
legislation in Colombia allows inspections, analysis
of samples, and evaluation of drug applications to
be carried out by accredited institutions, although
final approval rests with the agency. Very clear and
transparent arrangements are obviously required
when delegating such responsibilities. Most
importantly, the agency and its staff must be
WHO Drug Information Vol. 11, No. 2, 1997
supported by adequate legislation and regulations
— although in reality this situation can often be the
other way round. Regulations abound but they are
not enforced, in part due to a lack of motivated and
qualified staff.
Financing regulatory activities
Inadequate financing of regulatory agencies has
been a major factor in limiting their performance. It
would not be realistic to expect that the regular
government budget should be used to provide
funding for the kind of agency described above. A
viable alternative is the implementation of user
fees. This concept has been widely accepted in the
developed world, where significant fees are
charged for the registration of products and
inspection of plants. By contrast, in the developing
world the charges are very low. Such low fees are,
in effect, an incentive to submit applications for
products of little or no therapeutic significance. The
Pan American Health Organization has consistently
advised Member States to increase their fees to a
degree that would significantly contribute towards
financing regulatory activities for the duration of the
approval period. Brazil is following this advice with
a recently established fee of $8000. Responsible
pharmaceutical companies do not object to
increased registration fees if these are used to
provide a more effective service.
Transparency of the drug review process
The procedures and criteria for drug review and
approval should be made public, as well as the
results of the process. This is an obvious but, in
practice, frequently violated principle in many
countries, especially where political pressure and
personal favours influence the regulatory process.
A computerized drug registration system developed
by WHO's Division of Drug Management and
Policies and the Pan American Health Organization
has now been installed in a number of Latin
American countries. Computerization will facilitate
monitoring of the review process and the use of a
common software will enable the exchange of
information among countries. Consumers and, of
course, industry must be able to go to the agency
with their concerns and priorities and the agency
must provide feedback on its operations and
decisions. This should be done, to the extent
possible, in an open manner through committees
and other processes accessible to the public
although it is understandable that some data and
documents will need to remain confidential.
Personal Perspectives
Application of international standards
The capability to evaluate pharmaceuticals, both
before and after they are allowed on the market,
varies from country to country. However, at a time
when efficiency is demanded from the public sector,
it makes no sense to duplicate work and harmoni-
zation efforts are welcomed both by industry and
regulators. The International Conference on
Harmonization (ICH) is expected to have a major
impact on standard setting. Even though emphasis
has been on harmonizing registration requirements
of new drugs, many of the criteria which have been
established are applicable to other pharmaceutical
products (see above pp. 59–60).
Harmonization efforts are also under way in Latin
America in response to the formation of free-trade
zones in Central America, the Andean region and
the countries of MERCOSUR — Argentina, Brazil
Paraguay and Uruguay. The harmonization process
requires countries to look beyond traditional ways
of doing business and to examine what is happen-
ing in the rest of the world. As a result, there is a
growing understanding among regulatory officials
and forward-looking national companies that the
acceptance of recognized international standards
for drug quality and for the drug approval process
are prerequisites to participation in the global
market.
WHO has developed useful instruments to assist
agencies in their work, such as the WHO Certifica-
tion Scheme for pharmaceutical products moving in
international commerce, good manufacturing
practices (GMP), good clinical practice for clinical
trials (GCP), and ethical criteria for medicinal drug
promotion. These guidelines are particularly useful
for developing countries engaged in harmonization
efforts. As countries are bound to re-examine their
outdated and at times contradictory regulations,
they will find the WHO recommendations to be an
acceptable and useful guide for the different parties
involved.
Interagency and international cooperation
The World Health Organization regularly provides
information on drug safety, quality and regulation in
order to assist authorities to regulate and monitor
their domestic markets. In addition, the facilities
provided by new communications technology can
offer advantages to the work of regulatory agencies
worldwide. In principle, an electronic network can
now easily be put in place to disseminate informa-
tion regarding approvals, withdrawals, warnings,
etc. Equally, agencies can post enquiries and
61
Personal Perspectives
request assistance for specific problems from
colleagues. This network is within reach of many
agencies and would be cost effective. Why, then,
has such a network not been established at global
level?
The reality is that many regulatory authorities have
no direct access to a fax machine or to the Internet.
I believe that if priority is given to the establishment
and maintenance of an electronic network for
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WHO Drug Information Vol. 11, No. 2, 1997
regulatory agencies, the funds required could be
mobilized from international development agencies
or from the pharmaceutical industry, which has
always expressed interest in strengthening drug
regulation in the developing world.
Numerous issues face regulators, but none is more
important than ensuring that the public health
mission remains unchanged.
WHO Drug Information Vol. 11, No. 2, 1997
Reports on Individual Drugs
Move to triple-drug therapy for HIV
Since 1995, promising new developments in
research have altered the management of HIV
infection and further expansion in the range and
complexity of treatment is expected to continue, as
will greater individualization in patient care. As a
consequence of the promising results obtained with
monotherapy using zidovudine and other first-
generation antiretrovirals such as didanosine,
zalcitabine, stavudine and lamivudine (1), five large
randomized clinical trials were launched to evaluate
different combinations of antiretroviral therapy.
The results of the trials are now available and
indicate that combination therapy is superior to
nucleoside analogue monotherapy (2–7). The
CAESAR trial has demonstrated a highly significant
reduction in progression to AIDS or death for
patients receiving lamivudine added to zidovudine-
containing regimens, as compared to patients
maintained on zidovudine-containing regimens only
(6). The relative reduction in disease progression to
AIDS or death was 57% over one year for the
lamivudine-zidovudine group compared with
placebo, and the study was terminated early.
However, the research team cautioned that the
regimen may not prove sufficient to achieve long-
term suppression of the HIV-1 viral load below
currently detectable limits, which is now considered
by many to be the ultimate goal of treatment (6–8).
In the interim, results have also been received from
the ACTG 175 (3) and DELTA (4) trials which show
the clear superiority of two nucleoside analogues
over zidovudine monotherapy. Results from the
ACTG 320 (6), which compared a triple combina-
tion of zidovudine plus lamivudine plus indinavir
with zidovudine plus lamivudine, confirm that the
addition of a potent protease inhibitor to zidovudine
plus lamivudine delays disease progression and
increases survival (6).
New guidelines
Recent developments are reflected in guidelines
issued by the British HIV Association (8). Those
currently under preparation by the United States
Public Health Service (9) are likely to be similar.
The British guidelines warn that data available are
still incomplete, and well-informed dialogue
between the patient and physician is essential in
achieving a rational individualized treatment
regimen. The following broad principles are
recommended:
• Treatment should be offered before substantial
immunodeficiency occurs.
• Initial treatment should include a combination of at
least two drugs.
• Switches in therapy should involve the substitution
or addition of at least two new agents.
• Measurement of viral load and the CD4 count is
essential.
• Reduction in viral load to below the detection level
of a sensitive assay represents the optimal
treatment response. Failure to achieve or sustain
this control should prompt consideration of
therapy modification. This response is achieved
most reliably by a combination of two nucleoside
analogues plus a third agent — either a protease
inhibitor, a non-nucleoside reverse transcriptase
inhibitor, or a third nucleoside analogue — or two
protease inhibitors.
The rapid advancement of HIV treatment obliges
practitioners caring for HIV-infected persons to
keep abreast of the developments in HIV therapy if
the safe and effective use of new drugs is to be
achieved. The guidelines will be updated and
revised as necessary.
Antiretroviral agents
The following is a list of some of the antiretroviral
drugs which are authorized for marketing in many
countries or are in an advanced stage of clinical
development.
Nucleoside analogues:
zidovudine (ZDV, AZT), zalcitabine (ddC), didano-
sine (ddl), stavudine (d4T), lamivudine (3TC).
Protease inhibitors:
saquinavir (SQV), ritonavir (RTV), indinavir (IDV),
nelfinavir, cidofovir, droxinavir, lasinavir, palinavir,
telinavir.
Non-nucleoside reverse transcriptase inhibitors:
nevirapine (NVP), delavirdine, loviride, atevirdine.
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Reports on Individual Drugs
Can HIV be eliminated from
infection reservoirs?
In untreated HIV-infected individuals, a viral load
below detection limit is associated with either slow
progression of HIV or non-progression (10, 11). A
reduction in the viral load to very low levels such as
those reported in most patients on triple-drug
therapy, is therefore an attractive goal (12).
In May 1997, three research groups published
findings suggesting that HIV could be totally
eradicated from CD4 T cells and lymphoid tissue by
a combination of antiretroviral drugs. One group
studied viral decay in 8 patients given nelfinavir, a
protease inhibitor, and zidovudine and lamivudine,
two nucleoside reverse transcriptase inhibitors (13).
Patients had not received previous retroviral
therapy. After an initial drop of 99% in plasma
concentration of HIV within two weeks of treatment,
a slower second phase of 6–25 days was needed
for elimination and, at 8 weeks, the virus was
undetectable in plasma. By incorporating these
phases into a mathematical model, the researchers
postulated that if antiretroviral drugs completely
inhibit viral replication, then the stores of virus in
blood and tissues could disappear within 3 years.
The authors warned, however, that viral DNA within
mononuclear cells will still be present for many
years — and perhaps for life — leaving the remote
possibility that infectious progeny can be
reactivated or produced.
These findings are broadly in line with another
research group that looked at how long infected
host cells can harbour the virus (14). Some infected
cells linger in a resting state whereby HIV is in-
corporated into the host DNA but does not divide to
produce new viral particles. These infected cells are
neither detectable by the immune system nor
susceptible to antiretroviral therapy. In the study,
levels of HIV DNA were examined in resting CD4
cells in the blood and lymph of 14 asymptomatic
infected patients. Although fewer than 0.05% of the
resting CD4 cells harboured HIV DNA, this was
enough to produce virus when stimulated to divide.
The third group reported that triple therapy with
ritonavir, zidovudine and lamivudine for 6 months
cleared more than 99.9% of HIV from the second-
ary lymphoid tissue (tonsils) of 34 infected patients
(15). The researchers cautioned, however, that a
residue of virus could remain in a certain type of
lymph cell — the follicular dendritic cell. Although
lymphoid tissue is the main reservoir of infection,
there may be secondary sites in the brain and bone
marrow and the presence of one infected cell may
be enough to reactivate replication.
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WHO Drug Information Vol. 11, No. 2, 1997
Triple therapy — obstacles and problems
Although the results of triple antiretroviral therapy
provide the basis for some optimism, many
questions remain unanswered. For example, long-
term critical outcomes are unavailable, and
resistance is known to have occurred with triple
therapy. It is possible that the virus may remain
hidden in the central nervous system or bone
marrow and, when treatment is interrupted, strong
viral rebound may lead to rapid clinical deteriora-
tion. Recently, the United States Food and Drug
Administration has issued a warning that protease
inhibitors are associated with increases in blood
sugar and even diabetes. Among the 83 cases so
far reported of diabetes mellitus or hypoglycaemia
in HIV-infected patients on protease inhibitor
therapy, 27 required hospitalization, of which 6
were in a life-threatening condition (17, 18).
In addition, the regimen is complicated and ardu-
ous. Between fifteen and thirty tablets have to be
taken daily, and failure to comply with a regular
schedule may lead to the emergence of drug
resistance. Side-effects, including nausea,
diarrhoea and blood dyscrasia are common in the
initial months. Finally, clinical and laboratory
monitoring is necessary to detect adverse
reactions, determine safety of treatment, and follow
up the patient's progress. Interactions with other
necessary drugs such as rifampicin and other
antibiotics, or mefloquine, are common and not yet
completely understood.
The greatest obstacle to delivery of effective treat-
ment is accessibility. Treatment is expensive —
somewhere in the region of US$ 1000 to US$ 1500
a month — and requires a wide variety of health-
related support such as laboratory services and
technical expertise, in addition to administration of
a complicated regimen. This puts treatment well
beyond the reach of the vast majority of HIV-
infected people, and especially those living in
countries where resources for health care are
limited. To put the situation into perspective: 90%
of people with HIV infection worldwide live in
developing countries. Over 60% of these live in
sub-Saharan Africa, and many of these countries
have been hit by economic and political upheavals,
and the basic needs of food and shelter remain
unmet.
In conclusion, although the latest research results
are impressive, this does not mean that AIDS will
soon be regarded as a chronic, non-fatal disease.
No data as yet exist to suggest that even vigorous
compliance with the new regimens could ensure
WHO Drug Information Vol. 11, No. 2, 1997
non-infectivity. Commitment to essential, long-term
activities such as prevention programmes and the
search for vaccines and microbicides remains of
vital importance.
References
1. Update on AIDS. WHO Drug Information, 9(4): 196–201
(1995).
2. Saravolacz, L.D., Winslow, D.L., Collins, G. et al.
Zidovudine alone or in combination with didanosine or
zalcitabine in HIV-infected patients with the acquired
immune deficiency syndrome or fewer than 200 CD4 cells
per cubic millimetre. New England Journal of Medicine,
335: 1099–1106 (1996).
3. Hammer, S.M., Katzenstein, D.A., Hughes, M.D. et al.
A trial comparing nucleoside monotherapy with
combination therapy in HIV-infected adults with CD4 cell
counts from 200–500 per cubic millimeter. New England
Journal of Medicine, 335: 1081–1090 (1996).
4. DELTA coordinating committee. DELTA: a randomised
double-blind controlled trial comparing combination of
zidovudine plus didanosine or zalcitabine or zidovudine
alone in HIV infected individuals. Lancet, 348: 283 (1996).
5. Lalezari, J., Haubrich, R., Burger, H.U. et al. Improved
survival and decreased disease progression of HIV in
patients treated with saquinavir plus HIVID. XI
International Conference on AIDS, Vancouver, July 1996.
LB.B. 6033.
6. Katlama, C. on behalf of the CAESAR coordinating
committee. Clinical and survival benefit of 3TC in
combination with zidovudine-containing regimens in HIV-1
infection: interim results of CAESAR study. 3rd
International Congress on drug therapy in HIV infections,
Birmingham, November 1996. Abstract SS2.1.
7. Randomised trial of addition of lamivudine or
lamivudine plus loviride to zidovudine-containing regimens
for patients with HIV-1 infection: the CAESAR trial.
Lancet, 349: 1413–1421 (1997).
8. BHIVA Guidelines Coordinating Committee. British HIV
Association guidelines for antiretroviral treatment of HIV
seropositive individuals. Lancet, 349: 1086–1092 (1997).
9. US Public Health Service. Guidelines for the treatment
of HIV. SCRIP, Number 2234, May 1997.
10. Cao., Y., Qin, L., Zhang, L. et al. Virologic and
immunologic characterization of long-term survivors of
human immunodeficiency virus type 1 infection. New
England Journal of Medicine, 332: 201–208 (1995).
11. Pantaleo, G., Menzo, S., Vaccarezza, M. et al.
Studies in subjects with long-term nonprogressive human
immunodeficiency virus infection. New England Journal of
Medicine, 332: 209-216 (1995).
Reports on Individual Drugs
12. Feinberg, M. Hidden dangers of incompletely
suppressive antiretroviral therapy. Lancet, 349: 1408–
1409 (1997).
13. Perelson, A.S., Essunger, P., Cao, Y. et al. Decay
characteristics of HIV-1-infected compartments during
combination therapy. Nature, 387:188–191 (1997).
14. Chun, T.W., Carruth, L., Finzi, D. et al. Quantification
of latent tissue reservoirs and total body viral load in HIV-1
infection. Nature, 387: 183–187 (1997).
15. Cavert, W., Notermans, D.W., Staskus, K. Kinetics of
response in lymphoid tissues to antiretroviral therapy of
HIV-1 infection. Science, 276: 960–964 (1997).
16. De Cock, K. Great strides in antiviral therapy. AIDS
Targeted Information, Volume 11, Number 1, 1997.
17. FDA Talk Paper, T97–23, June 1997.
18. WHO Drug Alert, Nummber 59, 13 June 1997.
Amiodarone and
post-infarction arrhythmia
Patients surviving the acute phase of myocardial
infarction have a mortality rate of about 10% during
the year following the attack. The main cause of
death during this period is attributed to ventricular
arrhythmia (1, 2) which has provided the rationale
for use of anti-arrhythmic drugs during this period.
However, the results of clinical trials set up to
evaluate various anti-arrhythmic drugs have until
now been disappointing (3–6). Meta-analyses of
various trials have shown calcium-channel blockers
to be harmful and calcium-channel antagonists to
have few beneficial effects (7, 8).
Favourable results were demonstrated, however, in
a pilot study on the use of amiodarone, although
definite conclusions could not be made on all-cause
mortality (9). The beneficial effects of this treatment
have now been confirmed by the results of two
large, long-term mortality trials of amiodarone
among survivors of myocardial infarction at high
risk of cardiac death (10–12).
Both studies — the European Myocardial Infarct
Amiodarone Trial, EMIAT, and the Canadian
Amiodarone Myocardial Infarction Arrhythmia Trial,
CAMIAT— were randomized, placebo-controlled
trials. EMIAT enrolled 743 patients in the amioda-
rone and 747 patients in the placebo group to
assess whether amiodarone reduced all–cause
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Reports on Individual Drugs
mortality, cardiac mortality and arrhythmia death in
survivors of myocardial infarction with a left-
ventricular ejection fraction of 40% or less. Such
patients are known to have a 2-year mortality of
15%, of which the arrhythmic component is about
half. The median follow-up was 21 months.
All-cause mortality and cardiac mortality did not
differ between the two groups, but there was a 35%
risk reduction in arrhythmia death in the amioda-
rone group. The systematic prophylactic use of
amiodarone in all patients with depressed left-
ventricular function after myocardial infarction was
not supported, but the reduction noted in arrhythmia
deaths does support the results of the CAMIAT
study, which assessed the effect of amiodarone
treatment on the risk of resuscitated ventricular
fibrillation or arrhythmia deaths among survivors of
myocardial infarction with frequent or repetitive
ventricular premature depolarizations (VPDs).
Within this study, 606 patients were treated with
amiodarone and 596 patients with placebo.
Amiodarone reduced the incidence of ventricular
fibrillation and arrhythmia deaths, and absolute-risk
reduction was greatest among patients with
congestive heart failure or a history of myocardial
infarction.
These trials have been helpful in clarifying pending
questions on the use of anti-arrhythmic post-
infarction treatment. Amiodarone should not be
used routinely after myocardial infarction as the
data do not demonstrate any improvement in total
mortality. However, the clinician should be
encouraged to consider amiodarone for patients
with symptomatic or sustained and potentially
dangerous arrhythmias after myocardial infarction,
and especially in patients with low ejection fraction
and congestive heart failure. Future results from
several ongoing trials will increase our knowledge
on the risk/benefit of anti-arrhythmia therapy in
these patients.
References
1. Impact Research Group. Report on arrhythmic and
other findings. Journal of American College of Cardio-
logists, 4: 1148–1163 (1984).
2. Furburg, C. D. Effect of antiarrhythmic drugs on
mortality after myocardial infarction. American Journal of
Cardiology, 52: 32C–36C (l983).
66
WHO Drug Information Vol. 11, No. 2, 1997
3. The Cardiac Arrhythmia Suppression Trial (CAST)
investigators. Effect of encainide and flecainide on
mortality in a randomized trial of arrhythmia suppression
after myocardial infarction. New England Journal of
Medicine, 321:406–412 (l989).
4. The Cardiac Arrhythmia Suppression Trial investiga-
tors. Effect of the antiarrhythmic agent moricizine on
survival after myocardial infarction. New England Journal
of Medicine, 327: 227–235 (l992).
5. Waldo, A.L., Camm, A.J., de Ruyter, H. et al. The
SWORD trial. Survival with oral d-sotalol in patients with
left ventricular dysfunction after myocardial infarction:
rationale, design and methods. American Journal of
Cardiology, 75:1023–1027 (l995).
6. Waldo, A.L., Camm, A.J., de Ruyter, H. et al. Effect of
d-sotalol on mortality in patients with left ventricular
dysfunction after recent and remote myocardial infarction.
Lancet, 348: 7–12 (l996).
7. Yusuf, S. et al. Critical review of approaches to the
prevention of sudden death. American Journal of
Cardiology, 72: 51F–58F (l993)
8. Burkart, F., Pfisterer, M., Kiowski, W. et al. Effect of
antiarrhythmic therapy on mortality in survivors of
myocardial infarction with asymptomatic complex
ventricular arrhythmias. Basel Anti-arrhythmic Study of
Infarct Survival (BASIS). Journal of American College of
Cardiologists, 16: 1711–1718 (l990).
9. Ceremuzynski, L., et al. Effect of amiodarone on
mortality after myocardial infarction. A double-blind,
placebo controlled, pilot study. Journal of American
College of Cardiologists, 20: 1051–1062 (l992).
10. Cairns, J.A., et al. Post-myocardial infarction mortality
in patients with ventricular premature depolarizations: the
Canadian amiodarone myocardial infarction arrhythmia
trial. Circulation, 4: 550–557 (l991).
11 Julian, D. G., et al. Randomized trial of effect of
amiodarone on mortality in patients with left-ventricular
dysfunction after recent myocardial infarction: EMIAT.
Lancet, 349: 667–674 (l997).
12. Cairns, J.A., et al. Randomised trial of outcome after
myocardial infarction in patients with frequent or repetitive
ventricular premature depolarisations: CAMIAT. Lancet,
349: 675–682 (l997).
WHO Drug Information Vol. 11, No. 2, 1997
Regulatory Matters
Update on risks of
non-sedating antihistamines
Several countries have recently reconsidered the
regulatory status of the non-sedating antihistamine,
terfenadine, following its association with fatal
cardiac arrhythmias, as reported in the previous
number of this journal (1).
In a recent article in the Lancet, the WHO
Collaborating Centre for International Drug
Monitoring in Uppsala, Sweden has analysed the
reporting rate profile of five non-sedating anti-
histamines: acrivastine, astemizole, cetirizine,
loratadine and terfenadine. Overall, they have many
similarities, but it would appear that terfenadine and
astemizole have a propensity to block cardiac
muscle potassium channels, which is linked with
QT prolongation and cardiac arrhythmia. In
contrast, loratadine has been shown not to have
this action. None the less, reporting of cardiac rate
and rhythm disorders for the five antihistamines
was of a similar order.
The authors conclude that alternatives to terfena-
dine possess similar modes of action, and that
careful consideration of the comparative benefit-risk
profile of all non-sedating antihistamines is
essential. Such an assessment is currently under
way within Europe by the Committee for Proprietary
Medicinal Products (CPMP).
References
1. WHO Drug Information, 11(1): 17 (1997).
2. Lindquist, M., Edwards, I.R. Risks of non-sedating
antihistamines. Lancet, 349: 1322 (1997).
Terfenadine to prescription-only
status — astemizole under critical
review
Australia — The Australian Drug Evaluation
Committee has considered the prescription status
of terfenadine now that fexofenidine, a new and
safer alternative antihistamine has been registered
as a nonprescription drug.
Concerns are still apparent regarding the potentially
life-threatening side-effects and drug interactions of
terfenadine use. The Committee now considers that
the risk/benefit ratio has moved in favour of restric-
tion of the supply of terfenadine on prescription
only. This change will allow better assessment of
individual risks, and communication of such risks to
the patient by the prescribing physician. The
Committee will expedite the urgent safety review of
astemizole.
Reference: Letter from the Therapeutic Goods
Administration on Gazettal notice of 190th Australian Drug
Evaluation Committee, April l997.
Terfenadine: proposed
change to prescription only
United Kingdom — The Committee on Safety of
Medicines has reviewed the safety profile of
terfenadine in relation to cardiac arrhythmias and is
concerned that, despite the measures taken in
1992 and 1994, serious adverse reactions continue
to be reported. Because of the increasing
complexity of the precautions needed for its safe
use, it is unlikely that terfenadine can be used as
safely as alternative non-sedating antihistamines
without medical supervision. For this reason the
Committee has recommended that steps be taken
to revert terfenadine to prescription-only status. By
law, such a change of legal status can only be
made after a period of formal consultation with a
wide range of interested organizations, and this
process will take some months.
Information on the safety of terfenadine, and
precautions needed for its use have meanwhile
been circulated to physicians and pharmacists and
an information sheet has been provided for
patients. If there is any doubt as to whether
terfenadine can be used safely, the precautions
must be consulted and an alternative non-sedating
antihistamine with a more suitable profile should be
considered. These alternative products, such as
cetirizine and loratadine, are available from
pharmacies without prescription. The patient
information sheet also states that the third alterna-
tive, astemizole, is available without prescription.
67
Regulatory Matters
Astemizole also has the potential to produce
serious cardiac arrhythmias in certain circum-
stances as described in the package insert, but
at present there is insufficient evidence to justify
switching prescription status. The situation is
consequently being kept under close review.
Reference: Terfenadine: UK Dear Doctor/Pharmacist
letters, April l997.
Terfenadine: further reports
Germany — The Federal Institute for Drugs and
Medical Devices (BfArM) has received five reports
of "torsades de pointes" associated with the use of
terfenadine and one report with astemizole in
addition to one report of death associated with each
drug. The agency has requested physicians to
monitor and report cardiovascular adverse drug
reactions and, in particular, arrhythmias associated
with use of the non-sedating antihistamines,
terfenadine and astemizole.
Reference: Communication to WHO of 3 June 1997
including text from Arzneimittel-Schnellinformationen of
March 1997.
Anorectic agents:
revised recommendations
United Kingdom — The Medicines Control Agency
has issued recommendations on the use of fen-
fluramine, dexfenfluramine and phentermine based
on a review carried out within the United Kingdom
by the Royal College of Physicians (1), and an
earlier risk-benefit evaluation made by the
European Committee for Proprietary Medicinal
Products (CPMP) during 1995-1996 (2).
As many as 98 randomized controlled clinical trials
of at least six months duration have provided
evidence of the efficacy of anorectic agents in
terms of weight loss. In one such trial, carried out in
800 obese patients, 35% of subjects treated with
dexfenfluramine, but only 17% treated with placebo,
achieved a weight loss in excess of 10% of their
initial weight at four months (3). Significantly more
patients maintained this weight loss for up to 12
months when treated with dexfenfluramine as
compared to placebo, and these results suggest
that dexfenfluramine is effective in sustaining
weight loss in selected patients with a body mass
index of 30 kg/m2 or greater. However, no such
evidence was demonstrated for other anorectic
agents.
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WHO Drug Information Vol. 11, No. 2, 1997
As already reported (2), a link between anorectic
use and primary pulmonary hypertension (PPH)
has been demonstrated in a multinational case-
control study of 95 patients with this condition. This
study indicated that patients taking anorectics were
6 times more likely to suffer from PPH, and 23
times more likely if anorectics were taken for more
than three months.
These revised recommendations for anorectic
therapy, including restricted indications, contra-
indications, duration of treatment and requirements
for supervision and monitoring of therapy, are
consonant with previous recommendations issued
by the CPMP (2).
References
1. Committee on Safety of Medicines. Current Problems in
Pharmacovigilance, No. 23 (1997).
2. WHO Drug Information, 10 (4): 187 (1996).
3. Guy-Grand, B., Apfelbaum, M., Crepaldi, G. et al.
International trial of long-term dexfenfluramine in obesity.
Lancet, 2: 1142–1145 (1989).
Baclofen: withdrawal reactions
United Kingdom — The Medicines Control Agency
has received nine reports of serious psychiatric
reactions caused by abrupt withdrawal of oral
baclofen. Baclofen, a gamma-aminobutyric acid
(GABA) derivative, is used to reduce spasticity in
voluntary muscles. Withdrawal reactions include:
hallucinations, paranoia, delusions, psychosis,
confusion and agitation.
In order to prevent or minimize the risk of these
reactions, baclofen therapy should always be
discontinued by gradual dose reduction over at
least one or two weeks, although a longer period of
withdrawal may be necessary in certain cases.
Reference: Committee on Safety of Medicines. Current
Problems in Pharmacovigilance, No. 23 (1997).
Fluvastatin and muscle
disorders: a class effect
Australia — During 1996, the Adverse Drug
Reactions Advisory Committee received 85 reports
concerning fluvastatin. Of these, 30 describe
muscle disorders such as myalgia, myopathy, myo-
sitis, leg cramps and/or increased creatine kinase.
Fluvastatin was the only drug suspected in all but
WHO Drug Information Vol. 11, No. 2, 1997
two of these cases, and three reports documented
recurrence of symptoms on rechallenge. Similar
problems were documented with previous use of
simvastatin or another “statin” in 13 of the cases.
The Committee reminds prescribers that muscle
involvement is a class effect of all HMG-CoA
reductase inhibitors, and similar reports have been
received in Australia concerning simvastatin (307
reports) and pravastatin (29 reports).
Reference: Australian Adverse Drug Reactions Bulletin,
16: 3 (1997).
Abuse of gamma
hydroxybutyric acid (GHB)
United States of America — The Food and Drug
Administration has re-issued a warning against
"recreational" (intoxicating) and body-building use
of gamma hydroxybutyric acid (GHB). This drug
has not been authorized for marketing within the
United States and its use within the country is
considered as illegal.
Gamma hydroxybutyric acid is a potentially danger-
ous drug, and its use may result in vomiting, dizzi-
ness, tremors and seizures that could cause
injuries requiring hospitalization. Some deaths have
already been linked with consumption of GHB
products.
The Food and Drug Administration and the Depart-
ment of Justice have taken enforcement action
against several firms and individuals involved in
manufacturing, distributing or promoting GHB. The
agency has also instituted an automatic detention
policy to prevent products containing GHB from
being imported. These actions, along with
embargoes, public education campaigns and other
measures taken by state and federal authorities
have reduced distribution and abuse. Recently,
however, there appears to have been an increase
in the availability of GHB produced by clandestine
laboratories, and this has resulted in an increase in
reports of GHB-related injuries and deaths.
Reference: FDA Talk Paper, T97-10, February 1997.
Instructions for safe use of
systemic corticosteroids
United Kingdom — At the request of the Medi-
cines Control Agency, the product information for
Regulatory Matters
systemic corticosteroid products has been
amended to reflect more up-to-date knowledge on
safety. A patient information sheet is now provided
by manufacturers for all systemic corticosteroid
products, and pharmacists and physicians must
ensure that the patient is supplied with a copy.
Special precautions describe certain situations
where diseases may be exacerbated by cortico-
steroids and particular care and monitoring are
required in patients with, or having a history of,
osteoporosis, hypertension, congestive heart
failure, severe affective disorders, diabetes mellitus,
tuberculosis, glaucoma, liver failure, renal in-
sufficiency, epilepsy or peptic ulceration.
The section on use in pregnancy and during
lactation points to the possibility of growth
retardation of the fetus and a small increased risk of
cleft palate. Patients with pre-eclampsia or fluid
retention require close monitoring and infants of
mothers taking systemic corticosteroids during
lactation should be evaluated for signs of adrenal
suppression. Use in children may result in
irreversible dose-related growth retardation in
infancy, childhood and adolescence. Elderly
patients require close supervision.
Corticosteroid action may be reduced during
concomitant use of rifampicin, carbamazepine,
phenobarbital, phenytoin, primidone or amino-
glutethimide. The effects of hypoglycaemic agents,
antihypertensives and diuretics are antagonized by
corticosteroids, while the hypokalaemic effects of
acetazolamide, diuretics and carbenoxolone may
be enhanced.
Adverse reactions to corticosteroids are generally
related to dose and duration. Use of corticosteroids
for less than 7 days (e.g. in acute asthma) is
unlikely to result in serious adverse reactions but
with longer courses many body systems and
functions may be affected. Adverse reactions are
listed in the product information while the serious
reactions are listed on the patient information card.
Patients should always be advised to take the
lowest effective dose for the minimum length of
time. This should be given either as a single
morning dose or on alternate days, with frequent
patient review to titrate dose against disease
activity. Any intercurrent illness, trauma or surgical
procedure may require a temporary increase in
dosage and re-introduction if corticosteroids have
recently been stopped.
69
Regulatory Matters
Withdrawal must be gradual because cortico-
steroids suppress adrenal production of endo-
genous steroids. As a result, the dose should be
tapered off over weeks or months to enable the
adrenal glands to recover activity. Too rapid a
reduction of corticosteroid dosages may result in
acute adrenal insufficiency, which has a high
mortality rate. Patients should carry a Steroid
Treatment Card with them containing any relevant
information for use when consulting a physician.
This comprehensive revision of product information
for systemic corticosteroids, together with the
updated patient information provides a good
example for any drug regulatory authority in similar
situations concerning corticosteroid products.
Reference: Committee on Safety of Medicines. Current
Problems in Pharmacovigilance, No. 23 (1997).
Update on lamotrigine
and severe skin reactions
Australia — Lamotrigine is an anticonvulsant used
for the treatment of epileptic seizures as add-on
therapy in children, and as either monotherapy or
add-on therapy in adults.
The Adverse Drug Reactions Advisory Committee
has received 111 adverse reaction reports involving
lamotrigine. Of these, 36 describe skin reactions —
mostly rashes and often maculopapular, while 8 of
the reports describe severe skin reactions such as
erythema multiforme, Stevens Johnson syndrome,
toxic epidermal necrolysis and bullous eruption.
Of the serious cases, ages range from 3 to 35
years, with five of the eight patients being under 18
years of age. Onset occurred as early as the first
day and as late as 2 years after commencing
therapy. Six of the eight reports also documented
concurrent administration of valproic acid — a drug
that may reduce the hepatic clearance of lamo-
trigine resulting in increased plasma concentrations
of up to twofold.
The Committee reminds prescribers that careful
incremental titration of the dose, and lowering the
dose of valproic acid if administered concomitantly
may help to avoid reactions. Any patient who
develops a rash should be evaluated promptly and
consideration given to immediate withdrawal of the
drug.
Reference: Australian Adverse Drug Reactions Bulletin,
16: 3 (1997).
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WHO Drug Information Vol. 11, No. 2, 1997
United Sates of America and United Kingdom —
Glaxo Wellcome has issued “Dear Doctor” letters in
the above-mentioned countries warning that
children aged 16 years and under treated with
lamotrigine are at a much higher risk of severe,
potentially life-threatening skin reactions than
previously thought.
The incidence of such reactions requiring hospital
admission is estimated to be between 1 in 50 and 1
in 300 children. It was previously thought to be the
same as that in adults, i.e. 1 in every 1000 patients.
The letter points out that concurrent administration
of valproic acid may increase the risk of reactions
because it prolongs the mean half-life of lamotrigine
twofold.
The majority of cases of life-threatening skin
reactions have occurred within 2 to 8 weeks of
initiation of treatment, but isolated cases have been
reported after more prolonged use. All patients,
adults or children, who develop a rash should be
promptly evaluated and lamotrigine withdrawn
immediately unless the rash is clearly not drug-
related.
Lamotrigine is marketed in over 25 countries. The
experiences described above from Australia, the
United States and the United Kingdom may assist
drug regulators in other countries to take approp-
riate action.
Reference: Communication from Glaxo Wellcome dated
30 April 1997 enclosing “Dear Doctor” letters.
Drug interactions
with grapefruit juice
United Kingdom — The Medicines Control Agency
warns that ciclosporin, terfenadine and most cal-
cium channel blockers should not be taken at the
same time as grapefruit juice (1). It has become
apparent that the juice contains a psoralen which
inhibits the metabolism of certain drugs by enzymes
of the CYP 3A subfamily of cytochrome P450 (2).
This effect reduces the metabolism of ciclosporin,
terfenadine, and calcium channel blockers (other
than amlodipine and diltiazem), resulting in
increased plasma concentrations which could be
clinically important (3, 4). In recent studies,
grapefruit juice was administered simultaneously
with these drugs. However, the study did not
demonstrate how long patients should wait after
taking the juice and before taking the drugs and the
WHO Drug Information Vol. 11, No. 2, 1997
duration of metabolic inhibition. There is no
evidence that eating grapefruit also causes inter-
actions.
Patients are therefore advised to avoid drinking
grapefruit juice when taking the drugs indicated
above. Product information to physicians and
patients is to be amended accordingly.
References
1. Committee on Safety of Medicines. Current Problems
in Pharmacovigilance, No. 23 (1997).
2. Edwards, D.J. et al. Drug metabolism and Disposition,
24: 1287–1290 (l996).
3. Fuhr, U. et al. The fate of naringin in humans: a key to
grapefruit juice – drug interactions? Clinical Pharma-
cology and Therapeutics, 58: 365–373 (1995).
4. Honing, P.K., Wortham, D.C., Lazarev, A. et al.
Grapefruit juice alters the systemic bioavailability and
cardiac repolarization of terfenadine in poor metabolizers
of terfenadine. Journal of Clinical Pharmacology, 36:
345–351 (1996).
Triazolam and alprazolam
and interactions
United States of America — The prescribing
information on triazolam and alprazolam has been
revised to indicate that both are metabolized via the
cytochrome P450 3A (CYP 3A) pathway, and
consequently interact with other drugs and foods
that use this same pathway.
Triazolam is contraindicated with ketoconazole,
itraconazole and nefazodone, and alprazolam with
ketoconazole and itraconazole.
Reference: FDA Medical Bulletin, 27: 7 (1997).
Ticlopidine and
white blood cell disorders
United Kingdom — Ticlopidine, an antiplatelet
drug, is used for thrombosis prophylaxis. It causes
neutropenia in about 2.4% of patients and
agranulocytosis may occur within the first three
months of treatment. It is therefore important to
monitor differential white blood cell counts every 2
weeks during this period and patients should be
requested to report any symptoms of fever, sore
throat or mouth ulceration.
Regulatory Matters
Ticlopidine has not been authorized for marketing in
the United Kingdom but is used on a named-patient
(compassionate use) basis and the manufacturer's
product information leaflet is directed both to
physicians and patients.
Reference: Committee on Safety of Medicines. Current
Problems in Pharmacovigilance, No. 23 (1997).
Selegiline-associated
hypertensive reactions
United States of America —The product informa-
tion of the monoamine oxidase inhibitor, selegiline,
which is used for Parkinson‘s disease, has been
modified to note that rare hypertensive reactions
associated with the ingestion of tyramine-containing
foods have occurred. The risk may increase if
selegiline is prescribed in doses exceeding 10 mg
per day. In addition to two reports received by the
Food and Drug Administration, one case of
hypertensive reaction has also been published.
Reference: FDA Medical Bulletin, 27: 5–6 (l997).
Pemoline and liver failure
United States of America — The product labelling
for pemoline products has been modified to include
a boxed warning describing the risk of liver failure
and to indicate that the drug should not ordinarily
be considered as first-line therapy for attention
deficit hyperactivity disorder (ADHD).
Since marketing in 1975, 13 cases of acute hepatic
failure have been reported to the Food and Drug
Administration, 11 of which have resulted in death
or liver transplantation. It is not clear whether
baseline and liver function tests are predictive of
these instances of acute liver failure. The rate of
reports ranges from 4 to 17 times that expected in
the general population, although this estimate may
be conservative due to under-reporting and given
the long latency period before the appearance of an
association.
Reference: FDA Medical Bulletin, 27: 6 ( l997).
Ritonavir and interactions
United States of America — Based on post-
marketing experience, the product information of
ritonavir, a protease inhibitor, now includes new
information on drug interactions. Cardiac and
neurologic events have been reported when co-
71
Regulatory Matters
administered with disopyramide, mexiletine,
nefazodone or fluoxetine. Plasma concentrations of
saquinavir increased more than 20-fold when
administered concomitantly. Contraindications have
been added concerning ergot alkaloid preparations
and pimozide.
In addition, the sections dealing with warnings and
adverse reactions have been revised to include
allergic reactions, hepatic transaminase elevation,
hepatic dysfunction, seizure, hyperglycaemia,
syncope, orthostatic hypotension and renal
insufficiency.
Reference: FDA Medical Bulletin, 27: 6 (l997).
Cidofovir and renal impairment
United States of America — Following several
reports of severe renal impairment, a guideline
has been sent to physicians giving instructions on
appropriate patient selection, and emphasizing the
importance of monitoring treatment to ensure that
cidofovir, an HIV protease inhibitor, is used
correctly.
Prescribers are also alerted to two new contra-
indications: pre-existing renal disease and
concomitant administration with agents having
nephrotoxic potential.
Reference: FDA Medical Bulletin, 27: 6 (l997).
Granulocyte macrophage colony-
stimulating factor and interstitial
pneumonia
Japan — The recombinant granulocyte macro-
phage colony-stimulating factor products filgrastim,
lenograstim and nartograstim have been approved
for the treatment of neutropenia caused by cancer
chemotherapy.
The Pharmaceuticals Affairs Bureau has received
several reports of interstitial pneumonia associated
with use of these drugs. All have a similar action in
increasing neutrophils and macrophages and in
enhancing their function.
The occurrence of excessive increases in neutro-
phils, based on periodic blood testing, or the
appearance of early symptoms of pneumonia
should be dealt with by a decrease in the dose, or
discontinuation of treatment.
72
WHO Drug Information Vol. 11, No. 2, 1997
Reference: Information on Adverse Reactions to Drugs,
No.138, March 1997.
Metformin and lactic acidosis
United States of America — The manufacturer of
metformin has emphasized the importance of
appropriate patient selection in order to minimize
the risk of lactic acidosis in patients with a pre-
disposition to significant drug accumulation and
renal impairment, or in patients with impaired ability
to clear lactate (tissue hypoperfusion, hypoxia, or
liver impairment).
Metformin should consequently be withheld or
discontinued in patients with evidence of renal
disease or dysfunction, unstable haemodynamic or
impaired hepatic function or excessive alcohol
intake, or who are undergoing procedures using
intra-venous iodinated contrast media.
Reference: FDA Medical Bulletin, 27: 7 ( l997).
Cisapride and asthmatic attacks
Japan — Cisapride, a benzimidazole derivative
with prokinetic and antiemetic properties, has a
similar action to metoclopramide and domperidone.
It is used in Japan to treat gastro-oesophageal
reflux disease caused or aggravated by broncho-
dilator therapy in chronic asthma patients.
The Pharmaceutical Affairs Bureau has received
reports in which cisapride may have caused an
asthmatic attack or has aggravated underlying
asthma or bronchospasm. Three cases have also
been published in the scientific literature.
Although the mechanism for this remains unclear,
cisapride may cause asthma through a hyper-
sensitivity reaction or because of its pharmaco-
logical action on the bronchial smooth muscles.
Relevant precautions have been added to the
product information of these drugs in Japan.
Reference: Information on Adverse Reactions to Drugs,
No.138, March 1997.
Withdrawal of fixed paracetamol-
methionine combination
United Kingdom — SmithKline Beecham has
decided to withdraw the fixed paracetamol-
methionine combination product, Pameton®, from
WHO Drug Information Vol. 11, No. 2, 1997 Regulatory Matters

pharmacy sale because excessive intake of negative and this must be stated on the renewal
methionine may result in risks of cardiovascular prescription. When treatment is stopped, the
disease. The product remains available to patients physician must remind the patient that contra-
at high risk of suicidal gestures, mainly those in ception has to be continued for one more month
psychiatric hospitals or prisons. and that unused isotretinoin should be returned to
the pharmacy.
Another similar fixed-combination product with a
Reference: Communication to WHO from the Agence du
lower methionine dose remains on the market. Médicament, April 1997.
Reference: Letter to WHO from the Medicines Control
Agency, 26 March 1997.
Withdrawal of
Isotretinoin: risks remain fixed-combination barbiturates
France — The Pharmacovigilance Committee has
France — Reports continue to be received of
assessed adverse reaction reports associated with
treatment during pregnancy with the retinoid,
the use of a fixed-combination barbiturate product,
isotretinoin (Roaccutane®, Roche), despite detailed
(Atrium®, Riom Laboratories) containing pheno-
information on the dangers to the fetus directed to
barbital, febarbamate and difebarbamate indicated
health professionals and patients since introduction
for the treatment of minor anxiety (100 mg tablet)
of the product onto the market in France in 1986.
and alcohol withdrawal symptoms (300 mg tablet).
Isotretinoin is indicated for severe or recalcitrant
Between 1986 and 1996, 148 reports of liver
acne that has not responded to conventional
damage were received by either the national
treatment, such as antibiotics used topically, of at
monitoring system or the company. In 60% of these
least 3 months duration. Information accompanying
cases, treatment went beyond the limit of 12 weeks
the packaging states that a negative pregnancy test
allowed for anxiolytics. Cases of hepatitis, including
is obligatory before treatment is commenced, and
one necessitating liver transplantation, cirrhosis or
contraceptive measures should be initiated one
fibrosis, hepatocellular failure and jaundice were
month before the start of treatment and continued
reported as well as an increase in transaminase
until one month after it ends.
levels to more that ten times the normal upper limit
in half of the cases. Incidence was estimated at 4.8
Despite these precautions, 318 pregnancies have
cases per 100 000 treatments with 1.05 serious
been reported in France over a period of 10 years
hepatic reactions notified for 100 000 treatments.
— 80 % of which have had to be interrupted. The
majority occurred either during or in the month
Based on a subsequent benefit-risk assessment
following commencement of treatment, and in 16%
of these reports, the marketing authorization of the
of cases isotretinoin was taken by women who
100-mg tablet has been withdrawn and the
were already pregnant. The main reasons identified
indications for the 300-mg tablet have been limited
for this situation were poor compliance with
to the treatment of alcohol withdrawal syndrome
contraceptive measures, no pregnancy test before
with a maximum prescription duration of 4 weeks.
the start of treatment, and use of the medicine by
persons for whom it was not prescribed. Reference: Pharmacovigilance. Agence du Médicament,
April l997.
In view of this situation, the Agency has decided to
further reinforce prescription requirements. Physi-
cians must now check that the pregnancy test Are chlorofluorocarbon
performed at least 3 days previously is negative propellants essential?
and that patients have understood the risks of
treatment and the consequences. Patients are United States of America — The Food and Drug
required to sign a consent form and this is included Administration is seeking public comment on a
as part of the prescription, which must be verified suggested approach for withdrawing “essential use”
by the pharmacist. status for products using chlorofluorocarbon (CFC)
propellants. These products are used mainly for the
At each two-monthly follow-up consultation, the treatment of asthma and chronic obstructive
physician must check that a pregnancy test is pulmonary diseases such as emphysema and other

73
Regulatory Matters
respiratory conditions. Proven alternative aerosol
medications have now become available.
As a result of an international agreement
established through the Montreal Protocol on
Ozone Depleting Substances, CFC production and
importation have been banned for all commercial
purposes in the United States since January 1996.
The only exceptions to this ban are products which
are considered medically essential with no suitable
alternatives.
Reference: FDA Talk Paper, T97-12, March 1997.
Conjugated estrogens and generic
pharmaceuticals: update
United States of America — The Food and Drug
Administration has now completed a document
analysing the scientific data concerning the
composition of conjugated estrogens, as reported
previously in this journal (1). After allowing time for
public comment, the Agency has decided that the
synthetic generic versions of the original product
(Premarin®, Wyeth-Ayerst) cannot be approved
because generic products do not contain the same
active ingredients as the original product and their
74
WHO Drug Information Vol. 11, No. 2, 1997
effect cannot therefore be considered the same.
Conjugated estrogens are used in the treatment of
menopausal symptoms and prevention of
osteoporosis.
References
1. WHO Drug information, 10(3): 137 (1996).
2. HHS News, P97–12, May 1997.
Tramadol associated with
anaphylactic reactions
Sweden — The Medical Products Agency has
received two reports of anaphylactic reactions
related to tramadol, and the WHO International
Drug Monitoring Programme in Uppsala has 54
reported cases of anaphylactic or allergic reactions
associated with tramadol use. Tramadol was
approved for marketing in Sweden in September
1995 for moderate to severe, acute and chronic
pain.
Reference: Information from the Medical Products
Agency, Number 13, 1997
WHO Drug Information Vol. 11, No. 2, 1997

Essential Drugs
WHO Model Formulary

As described in the previous issue of this journal, work is now under way on the WHO Model
Formulary, and draft texts will be published regularly to obtain comments on the material
proposed for publication. Observations concerning the following section related to anthelminthics
should be addressed to: Drug Selection and Information (DSI), Division of Drug Management &
Policies, World Health Organization, 1211 Geneva 27, Switzerland.

Anti-infective drugs: quantel has already been reported. Repeated

anthelminthics
Drugs used for cestode
(tapeworm) infections
Cestode infections include intestinal taeniasis and
cysticercosis, hymenolepiasis, diphyllobothriasis
and echinococcosis.
Praziquantel is generally used for the treatment of
cestode infections due to Taenia solium, T. sagin-
ata, Hymenolepis nana and Diphyllobothrium latum
and D. pacificum. It is well tolerated and extensively
absorbed and kills adult intestinal taenia worms in a
single dose. Cestode infections occurring during
pregnancy should always be treated immediately
because of the risk of cysti-cercosis.
Praziquantel also kills T. solium cysticerci when
taken for 14 days in high doses. It thus offers the
prospect of a cure for neurocysticercosis, which
was previously treatable only by surgery, anti-
inflammatory corticosteroids and use of anti-
convulsants. However, because dying and
disintegrating cysts may induce localized cerebral
oedema, treatment with praziquantel must always
be undertaken in a hospital setting. Albendazole,
which is an alternative to praziquantel, kills
cysticerci, but only when administered at a daily
dosage of 15 mg/kg for 30 days. The longer-
established compound niclosamide acts only
against the adult intestinal worms.
In hymenolepiasis, praziquantel is more effective
than niclosamide, although resistance to prazi-
treatment may be necessary to cure intense
infections or to eliminate the parasite within a family
group or institution.
In diphyllobothriasis, niclosamide or praziquantel in
a single dose is highly effective. Hydroxocobalamin
injections and folic acid supplements may also be
required.
In echinococcosis, although surgery is still the treat-
ment of choice for operable cystic disease due to
Echinococcus granulosus, chemotherapy with
benzimidazoles, such as mebendazole and albend-
azole, may be of value as adjunctive therapy.
Alveolar echinococcosis due to E. multilocularis
requires both surgery and long-term treatment with
either mebendazole or albendazole to inhibit meta-
static spread
ALBENDAZOLE
Anthelminthic agent
Chewable tablet: 200 mg, 400 mg
Uses: Echinococcus multilocularis and E.
granulosus infections prior to or when not amenable
to surgery, and neurocysticercosis.
Dosage:
Cystic echinococcosis
Adults: Up to four 30-day courses of 10–15 mg/kg
daily in two divided doses separated by treatment-
free periods of 15 days. Patients with E. multi-
locularis infections may need further treatment
cycles.

75
Essential Drugs
Neurocysticercosis
Adults: 15 mg/kg daily for 30 days. Recent data
suggest that an 8-day course may be equally
effective.
Contraindications: Known hypersensitivity; first-
trimester pregnancy.
Precautions: Liver function tests and blood counts
should be regularly monitored throughout treatment
when high doses are used.
Adverse effects: Occasionally, transient gastro-
intestinal discomfort and headache occur and,
rarely, rash and fever, alopecia, reversible leuko-
penia and reversible increases in serum levels of
hepatic enzymes.
Drug interactions : These will appear in tabulated
form in the appendix of the published edition of the
WHO Model Formulary.
MEBENDAZOLE
Anthelminthic agent
Chewable tablet: 100 mg, 500 mg
Uses: Echinococcus multilocularis and E. granulo-
sus infections prior to surgery.
Dosage: Each dose should preferably be taken
between meals. Adults: 4.5 g daily in three divided
doses for 6 months.
Contraindications: Known hypersensitivity and
pregnancy.
Adverse effects: Occasionally, transient gastro-
intestinal discomfort and headaches occur and,
rarely, hypersensitivity reactions and liver abnor-
malities.
Drug interactions : These will appear in tabulated
form in the appendix of the published edition of the
WHO Model Formulary.
NICLOSAMIDE
Anthelminthic agent
Chewable tablet: 500 mg
Uses: Infections due to Taenia saginata, T. solium,
Hymenolepis nana and Diphyllobothrium latum.
Dosage : The tablets should be chewed thoroughly
before swallowing and washed down with 250 ml
water.
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WHO Drug Information Vol. 11, No. 2, 1997
Hymenolepis nana infections
Adults: 2 g on day 1, followed by 1 g daily for 6
days.
For all other indications
Adults: 2 g as a single dose.
Children <10 kg: 0.5 g as a single dose.
Children 10–35 kg: 1 g as a single dose.
Precautions: Chronically constipated patients
should receive a purgative before treatment.
Adverse effects: Mild gastrointestinal disturb-
ances.
PRAZIQUANTEL
Anthelminthic agent
Tablet: 150 mg, 600 mg
Uses: Infections due to Taenia saginata, T. solium,
Hymenolepis nana and Diphyllobothrium latum.
Dosage:
Intestinal taeniasis
Adults and children over 4 years: a single dose of
5–10 mg/kg.
Hymenolepiasis
Adults and children over 4 years: a single dose of
15–25 mg/kg.
Diphyllobothriasis
Adults and children over 4 years: a single dose of
10–25 mg/kg.
Cysticercosis
Adults and children over 4 years: a total of 50 mg/
kg daily in three divided doses for 14 days. A
corticosteroid such as prednisolone should be
administered for 2–3 days beforehand and then
throughout the period of treatment.
Because of the risk of pericystic oedema, patients
with neurocysticercosis should always be treated in
a hospital setting.
Dermal cysticercosis
Adults and children over 4 years: a total of 60 mg/
kg in three divided doses for 6 days.
Contraindications: Ocular cysticercosis.
Adverse effects: Occasionally, abdominal dis-
comfort, nausea, headache, dizziness and
drowsiness. Rarely, pyrexia, urticaria and rectal
bleeding.
WHO Drug Information Vol. 11, No. 2, 1997
Drugs used for intestinal
nematode infections
Intestinal nematode infections include ascariasis,
hookworm infection, strongyloidiasis, enterobiasis,
trichuriasis, trichostrongyliasis and capillariasis.
Ideally, all cases of hookworm infection should be
treated. However, when this is impracticable,
priority should be given to women in second- and
third-trimester pregnancy, children and debilitated
patients. In hookworm, broad-spectrum
anthelminthics should be preferred wherever other
nematode infections are endemic. Both
mebendazole and albendazole are effective.
Levamisole is effective in the treatment of mixed
ascaris and hookworm infections and pyrantel has
been highly effective in some community-based
control programmes, although several doses are
often needed to eliminate Necator americanus
infection. Anaemic patients require supplementary
iron salts and should receive ferrous sulfate (200
mg for adults daily) for at least 3 months after the
haemoglobin concentration has regained the
threshold of 12 g/100 ml.
In strongyloidiasis, all infected patients should be
treated. Albendazole, 400 mg administered for 3
consecutive days, is well tolerated by both adults
and children over 2 years of age and reports
suggest it may eradicate up to 80% of infections.
Mebendazole has also been used but to be effec-
tive it must be administered for longer periods as it
has a limited effect on larvae and hence upon the
cycle of autoinfection. Ivermectin is also effective
against strongyloidiasis.
In enterobiasis, all household members should be
treated concurrently with a single dose of mebend-
azole, albendazole or pyrantel. Since reinfection
readily occurs, at least one further dose is required
2–4 weeks later. Piperazine is also effective, but
must be taken regularly for at least 7 consecutive
days.
In trichuriasis, chemotherapy is required whenever
symptoms develop or when faecal samples are
found to be heavily contaminated (over 10 000
eggs per gram). A single dose of albendazole (400
mg) or mebendazole (500 mg) is effective in mild to
moderate infections, but heavy infections require a
3-day course.
Essential Drugs
In symptomatic trichostrongyliasis, a single dose of
pyrantel or albendazole (400 mg) is effective.
In capillariasis, prolonged treatment with mebenda-
zole or albendazole offers the only prospect of cure.
ALBENDAZOLE
Anthelminthic agent
Chewable tablet: 200 mg, 400 mg
Uses: Ascariasis, hookworm infections, strongy-
loidiasis, enterobiasis, trichuriasis, trichostrongy-
liasis and capillariasis.
Dosage: Adults and children over 2 years: a single
dose of 400 mg is sufficient to eliminate most cases
of ascariasis, hookworm infection, enterobiasis,
trichostrongyliasis, and moderate trichuriasis
infections. Strongyloidiasis and heavy trichuriasis
infections require a 3-day course of treatment. The
dose should be continued for at least 10 days in
capillariasis.
Contraindications: Known hypersensitivity; first-
trimester pregnancy.
Adverse effects: Occasionally, transient gastro-
intestinal discomfort and headache.
LEVAMISOLE
Anthelminthic agent
Tablet: 40 mg, 50 mg (as hydrochloride)
Uses: Ascariasis and mixed ascariasis/hookworm
infections.
Dosage: Adults and children: a single dose of 2.5
mg/kg is used widely for both individual treatment
and community-based campaigns. In cases of
severe hookworm infection, a second dose may be
given 7 days after the first.
Adverse effects Occasionally abdominal pain,
nausea, vomiting, dizziness and headache occur.
MEBENDAZOLE
Anthelminthic agent
Chewable tablet: 100 mg, 500 mg
Uses: Hookworm infections, enterobiasis, ascaria-
sis, trichuriasis and capillariasis. Mass treatment
control programmes.
77
Essential Drugs
Dosage: Each dose should preferably be taken
between meals. All doses are suitable for adults
and children over 2 years.
Ascariasis
A single dose of 500 mg.
Hookworm infections and trichuriasis
A dose of 100 mg twice daily for 3 consecutive
days. A second course may be given after 3 to 4
weeks if eggs persist in the faeces. Recently, a
single dose of 500 mg has been effective in mass
treatment control programmes, and this will improve
compliance.
Enterobiasis
A single dose of 100 mg repeated at least once
after an interval of 2 to 4 weeks. All members of the
household should be treated at the same time.
Capillariasis
A dose of 200 mg daily for 20–30 days.
For mass treatment control programmes: A single
dose of 500 mg four times a year.
Contraindications: Known hypersensitivity; first-
trimester pregnancy.
Adverse effects: Occasionally, transient gastro-
intestinal discomfort and headache.
Drug interactions: These will appear in tabulated
form in the appendix of the published edition of the
WHO Model Formulary.
PYRANTEL
Anthelminthic agent
Chewable tablet: 250 mg (as embonate)
Oral suspension: 50 mg (as embonate)/ml
Uses: Hookworm infections, ascariasis, entero-
biasis and trichostrongyliasis.
Dosage: Adults and children: A single dose of 10
mg/kg is sufficient to eliminate many cases of
hookworm infection, ascariasis, enterobiasis and
trichostrongyliasis. Patients with enterobiasis,
however, should receive a second dose after 2–4
weeks. Heavy hookworm infections are relatively
resistant and three further doses should be given
on consecutive days.
Mass treatment control programmes: A single dose
of 2.5 mg/kg 3 or 4 times a year.
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WHO Drug Information Vol. 11, No. 2, 1997
Contraindications: Known hypersensitivity.
Precautions: Lower doses should be administered
to patients with hepatic function impairment.
Adverse effects: Occasionally, mild gastro-
intestinal disturbance, headache, dizziness,
drowsiness, insomnia and rash have been reported.
Drug interactions: Pyrantel, piperazine and older
anthelminthics have antagonistic effects; they
should not be administered together.
Drugs used for tissue
nematode infections
Tissue nematode infections include dracunculiasis,
trichinellosis, cutaneous larva migrans, visceral
larva migrans, anisakiasis and angiostrongyliasis.
In dracunculiasis, metronidazole (25 mg/kg daily for
10 days, with a daily maximum of 750 mg for
children) provides rapid symptomatic relief. It also
weakens the anchorage of the worms in the sub-
cutaneous tissues, and they can then be removed
by traction. However, since it has no effect on pre-
emergent worms, it does not immediately prevent
transmission.
Each case of confirmed or even suspected trichinel-
losis infection should be treated in order to prevent
the continued production of larvae. In both adults
and children, mebendazole (200 mg for 5 days),
albendazole (400 mg for 3 days), and pyrantel (10
mg/kg daily for 5 days) are each effective. Pred-
nisolone, 40–60 mg daily, may be needed to
alleviate allergic and inflammatory responses.
In cutaneous larva migrans, albendazole in a single
dose of 400 mg is effective. Calamine lotion
provides symptomatic relief.
In visceral larva migrans caused by Toxocara canis
and, less frequently, T. cati, treatment should be
reserved for symptomatic infections. A 3-week oral
course of diethylcarbamazine kills the larvae and
arrests the disease, but established lesions are
irreversible. To reduce the intensity of allergic
reactions induced by dying larvae, dosage is
commonly commenced at 1 mg/kg twice daily and
raised progressively to 3 mg/kg twice daily (adults
and children).
In order to suppress allergic inflammatory
responses in patients with ophthalmic lesions,
prednisolone should be administered concurrently,
either topically or systemically.
WHO Drug Information Vol. 11, No. 2, 1997
In anisakiasis, anthelminthic treatment is rarely
necessary. Prevention is dependent upon informing
communities of the hazards of eating raw or
inadequately prepared salt-water fish, and the need
for early evisceration of fish after capture, and
freezing of seafood at – 20 ° C for at least 60 hours
before sale.
In angiostrongyliasis, symptomatic treatment
pending spontaneous recovery is often all that is
required.
Antifilarials
Infections caused by filaria include (1) loiasis, (2)
lymphatic filariasis and (3) onchocerciasis.
1. Loiasis
Diethylcarbamazine (DEC) is effective against both
the adult worms and larvae of all forms of the para-
site and a single weekly dose is normally effective
as prophylaxis. During individual treatment,
particularly of persons with heavy microfilaraemia
(>50 000 microfilariae/ml blood), a condition
simulating meningoencephalitis can occasionally
occur. This probably results from sludging of
moribund microfilariae within the cerebral capilla-
ries. The frequency of meningoencephalitis
associated with DEC therapy of loiasis is reported
as 1.25%, with a mortality rate of about 50% in
affected patients. Permanent cerebral damage is
common among patients who survive and this
possibility should be considered when treatment is
decided upon. Treatment of heavily infected
patients should thus begin at low dosage and
corticosteroid and antihistamine cover should be
provided for the first 2–3 days.
DIETHYLCARBAMAZINE
Antifilarial agent
Tablet: 50 mg (dihydrogen citrate)
Uses: Treatment of loiasis and prophylaxis against
loiasis in temporary residents of endemic areas.
Dosage:
Treatment
Adults: 1 mg/kg as a single dose initially, doubled
on 2 successive days and then adjusted to 2–3 mg/
kg three times daily for a further 18 days.
Prophylaxis
Adults: 300 mg weekly for as long as exposure
continues.
Essential Drugs
The recommended dosage regimen should be
strictly followed to minimize allergic reactions to
dying parasites.
Contraindications: During pregnancy, treatment
should be delayed until after delivery. Dosage
should be reduced in patients with renal
impairment. Patients who are severely ill with other
acute diseases should not receive diethylcarba-
mazine until after recovery.
Adverse effects: Immunological disturbances
(similar to the Mazzotti reaction in onchocerciasis)
are induced by disintegrating microfilariae. Fever,
headache, dizziness, anorexia, malaise, urticaria,
vomiting and asthmatic attacks may occur within a
few hours of the first dose and usually subside by
the fifth day of treatment. When microfilaraemia is
heavy, there is a risk of meningoencephalitis and
the advantages of treatment must be weighed
against the possibility of life-threatening encepha-
litis. Reversible proteinuria may occur.
2. Lymphatic filariasis
Diethylcarbamazine has both microfilaricidal and
macrofilaricidal activity, but some adult worms may
survive even after repeated courses of therapy.
Total cumulative dosages of 72 mg/kg are generally
recommended for Wuchereria bancrofti infections,
with half this dose for Brugia malayi and B. timori
infections. In all cases where microfilaraemia is
heavy, treatment is best initiated with smaller
doses for 2–3 days in order to avoid the danger of
immunological reactions.
It has recently been shown that ivermectin, admin-
istered in a single dose of 400 µg/kg is as effective
as a single dose of 6 mg/kg diethylcarbamazine.
Mass treatment control programmes: A single
yearly dose of 6 mg/kg diethylcarbamazine can be
used. The addition of DEC to table salt at a
concentration of 0.1–0.3% is also effective.
DIETHYLCARBAMAZINE
Antifilarial agent
Tablet: 50 mg (dihydrogen citrate)
Uses: Individual and community treatment of
systemic lymphatic filariasis and occult filariasis
(tropical pulmonary eosinophilia).
79
Essential Drugs
Dosage: The following dosage schedules are
intended only as a guide since many countries have
developed their own specific treatment regimens.
The doses given are suitable for both adults and
children aged over 10 years. Children under 10
years of age should be given half the total adult
dose.
W. bancrofti infections
6 mg/kg daily for 12 days administered orally,
preferably in divided doses after meals.
Mass treatment control programmes: 6 mg/kg
weekly, monthly or as a single annual dose.
B. malayi and B. timori infections
3–6 mg/kg daily for 6–12 days administered orally,
preferably in divided doses after meals.
Mass treatment control programmes: 3–6 mg/kg,
6 times either weekly or monthly.
In China and India several trials have shown that
when used consistently over a period of at least 6
months, table salt fortified with diethyl-carbamazine
at a concentration of 0.1% can eliminate W.
bancrofti lymphatic filariasis. A
concentration of 0.3% for 3–4 months may be
necessary where B. malayi is endemic.
Occult filariasis
A dose of 8 mg/kg daily for 14 days repeated, as
necessary, if symptoms return.
Contraindications: During pregnancy, treatment
should be delayed until after delivery. Dosage
should be reduced in patients with renal impair-
ment. Patients who are severely ill with other acute
diseases should not receive diethylcarbamazine
until after recovery.
Adverse effects: Immunological disturbances
(similar to the Mazzotti reaction in onchocerciasis)
are induced by disintegrating microfilariae. Fever,
headache, dizziness, anorexia, malaise, urticaria,
vomiting and asthmatic attacks may occur within a
few hours of the first dose and usually subside by
the fifth day of treatment. When microfilaraemia is
heavy, there is a risk of meningoencephalitis and
the advantages of treatment must be weighed
against the possibility of life-threatening encepha-
litis. Reversible proteinuria may occur. Recently-
killed adult worms often form nodules which are
palpable subcutaneously and along the spermatic
cord; their death may result in transient lymphan-
gitis and an exacerbation of lymphoedema.
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WHO Drug Information Vol. 11, No. 2, 1997
3. Onchocerciasis
Ivermectin has transformed the treatment of oncho-
cerciasis and it is now used extensively in control
programmes in many countries. Its microfilaricidal
action is more persistent and less liable to provoke
adverse reactions than that of diethylcarbamazine.
A single oral dose reduces the microfilarial count to
low levels for up to a year. It appears to kill both
microfilariae and to inhibit their expulsion from the
uterus of female worms. Available data suggest that
a single annual dose will suppress microfilaraemia
to a degree that prevents development of clinical
disease. Although the drug is generally well
tolerated, it is advisable to have medical support
available during treatment programmes. Patients
with a heavy microfilarial load occasionally react
adversely and, rarely, transient severe postural
hypotension has occurred within 12–24 hours of
treatment.
Treatment of pregnant women with ivermectin
should be limited to those situations where the risk
of complications from untreated onchocerciasis
exceeds the potential risk to the fetus from
treatment. Diethylcarbamazine is now largely
superseded as a microfilaricide in onchocerciasis
because of the frequency with which it induces
severe host (Mazzotti) reactions characterized by
itching, skin rash, oedema, pain and swelling of the
lymph nodes, fever and severe eye lesions.
Suramin is the only macrofilaricide that is currently
available for use against Onchocerca volvulus .
Administered intravenously over a period of several
weeks, suramin also kills microfilariae. It is,
however, one of the most toxic substances used in
clinical medicine and should always be given under
medical supervision in a hospital. A careful assess-
ment must always be made of the patient's capacity
to withstand the effects of suramin treatment both
before and during administration.
IVERMECTIN
Antifilarial agent
Scored tablet: 6 mg
Uses: As a microfilaricide in the suppressive treat-
ment of onchocerciasis. Although it may not be
effective against immature larval stages of O.
volvulus, it seems to impair the fecundity of the
adult worm.
Dosage: Effective suppression of microfilariae is
obtained by annual administration of a single oral
WHO Drug Information Vol. 11, No. 2, 1997
dose of 150 µg/kg (adults and children over 5 years
of age).
Contraindications: Known hypersensitivity.
Precautions: Breast-feeding mothers should not
be treated until the infant is at least 1 week old, by
which time the blood-brain barrier should be fully
developed.
Adverse effects: Mild ocular irritation may occur.
Somnolence has been reported as well as Mazzotti
reactions. Transient symptoms that may occur
within 3 days of treatment include headache,
pruritus, rash, arthralgia, myalgia, lymphadeno-
pathy, lymphadenitis, oedema, fever, weakness,
tachycardia, nausea, conjunctivitis, diarrhoea and
vomiting, including reactions resulting from a heavy
microfilarial load.
Drug interactions : These will appear in tabulated
form in the appendix of the published edition of the
WHO Model Formulary.
SURAMIN SODIUM
Antifilarial agent
Powder for injection: 1 g in vial
Uses: As a macrofilaricide in the curative treatment
of onchocerciasis.
Dosage: Suramin is administered by slow intra-
venous injection of a 10% solution in water for
injection.
Adults: a total of 66.0 mg/kg should be
administered in six incremental weekly doses
apportioned as follows.
Week 1 2 3 4 5 6
Dose(mg/kg) 3.3 6.7 10.0 13.3 16.7 16.0
Because loss of consciousness has occasionally
occurred, the first injection (0.2 g in 2 ml of water
for injection for a 60 kg adult) should be
administered with particular caution. Wait at least
one minute after injecting the first few microlitres,
inject the next 0.5 ml over 30 seconds and wait one
more minute. Inject the remainder over several
minutes.
Contraindications: Previous anaphylactic
reactions or sensitivity to suramin; pregnancy;
children less than 10 years old; elderly or infirm
Essential Drugs
patients with impaired liver or renal function; total
blindness — unless required for relief from intense-
ly itchy lesions.
Precautions: Suramin is extremely toxic and
should always be given under medical supervision
in a hospital. A satisfactory food and fluid intake
should be maintained throughout treatment. Urine
samples should be taken before and during treat-
ment to detect the presence of albumin. Moderate
albuminuria indicates that the dose should be
reduced but heavy albuminuria with the passage of
casts indicates the need for immediate discontinu-
ation of treatment.
Adverse effects: Direct toxic effects require
immediate withdrawal. Rarely, potentially fatal loss
of consciousness may occur during the first
injection. Heavy albuminuria, stomal ulceration,
exfoliative dermatitis, severe diarrhoea, prolonged
high fever and prostration may occur. Lesser, but
common, symptoms include tiredness, anorexia,
malaise, polyuria, increased thirst and tenderness
of the palms of the hands and soles of the feet.
Indirect reactions due to the death of the parasites
including urticaria, swelling, tenderness and
abscess formation around adult worms, painful
immobilization of the hip, intensely itchy urtico-
papular rash, inflammatory and subsequent
degenerative changes in the optic nerve and retina,
and swollen, painful joints particularly of the hands
and feet.
Drug interactions : These will appear in tabulated
form in the appendix of the published edition of the
WHO Model Formulary.
Antischistosomals
Schistosomiasis, a waterborne parasitic infection,
is caused by several species of trematode worms
(blood flukes). Its socioeconomic impact as a
parasitic disease is outstripped only by that of
malaria. Intestinal schistosomiasis is caused
principally by Schistosoma mansoni, as well as
S. japonicum, S. mekongi, and S. intercalatum.
Urinary schistosomiasis is caused by S. haema-
tobium. The latter is an important predisposing
cause of squamous-cell cancer of the bladder.
Praziquantel has transformed the treatment of
schistosomiasis and is often effective in a single
dose against all species of the parasite. It can be of
particular value in patients with mixed infections
and those who do not respond adequately to other
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Essential Drugs WHO Drug Information Vol. 11, No. 2, 1997

drugs. It is also extremely well tolerated and well
suited for mass treatment control programmes.
Extensive use over several years has provided no
evidence of serious adverse effects or long-term
toxicity, nor has mutagenic or carcinogenic activity
been shown in animals. Despite lack of terato-
genicity and embryotoxicity, however, it is
preferable to delay treatment during pregnancy until
after delivery, unless absolutely essential.
Other drugs still widely used for schistosomiasis
include metrifonate, which is active against S.
haematobium, and oxamniquine, which is effective
against S. mansoni.
Strains resistant to oxamniquine, which have been
reported in South America, have been treated
effectively with praziquantel. Although neither metri-
fonate nor oxamniquine has been shown to be
teratogenic or embryotoxic, it is preferable to delay
treatment during pregnancy until after delivery
unless immediate intervention is essential. There is
no information on whether metrifonate or oxamni-
quine is excreted in breast milk, and it is therefore
preferable not to administer these drugs to nursing
mothers.
PRAZIQUANTEL
Anthelminthic agent
Tablet: 600 mg
Uses: Intestinal schistosomiasis due to S.
japonicum, S. intercalatum or S. mekongi which is
not responsive to oxamniquine. S. mansoni
infections unresponsive to oxamniquine, co-
infections of S. haematobium and S. mansoni
otherwise requiring treatment with both metrifonate
and oxamniquine.
Dosage: The dosage for both adults and children is
given in the table below.
Adverse effects: In patients with heavy worm
loads, these include abdominal discomfort, nausea,
headache, dizziness, drowsiness and rarely,
pyrexia, urticaria and rectal bleeding.
Drug interactions : These will appear in tabulated
form in the appendix of the published edition of the
WHO Model Formulary.
METRIFONATE
Anthelminthic agent
Tablet: 100 mg
Uses: Urinary schistosomiasis.
Dosage: Adults and children: A dose of 7.5–10
mg/kg on three occasions at intervals of 2 weeks
will cure 40–80% of cases.
Precautions: Mass chemotherapy should not be
undertaken in communities recently exposed to
insecticides or other agricultural chemicals with
anticholinesterase action. Treated patients should
not receive depolarizing neuromuscular blocking
agents such as suxamethonium until at least 48
hours after administration of metrifonate.

Dosage of praziquantel in schistosomiasis

Parasite species Single dose Initial Reduction in

(mg/kg) cure rate (%)a egg count after
adults & children 1 year (%)b

S. haematobium 40 80–95 90–95

S. mansoni 40c 60–90 95
Mixed S. haematobium/ S. mansoni 40c 60–75 S. haematobium>
S. mansoni
S. intercalatum 40 60–80 95
S. japonicum 40c 60–80 95
S. mekongi 40c 60–80 95
a
A “cure” is considered to be a complete absence of eggs from the urine or faeces 6 months after completion of
treatment.
b
In patients who have not been cured.
c
In some areas dosage may be increased to 60 mg/kg.

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WHO Drug Information Vol. 11, No. 2, 1997
Adverse effects: Abdominal pain, nausea,
vomiting, diarrhoea, headache and vertigo are
common. Cholinergic symptoms very rarely occur
with currently recommended dosages.
Drug interactions : These will appear in tabulated
form in the appendix of the published edition of the
WHO Model Formulary.
OXAMNIQUINE
Anthelminthic agent
Capsule: 250 mg
Syrup: 250 mg/5 ml
Uses: Intestinal schistosomiasis (S. mansoni) both
in the acute stage and in patients with hepato-
splenic involvement.
Dosage: The effective dose varies. The following
regimens provide general guidance but definitive
recommendations should be based on local
experience.
West Africa, South America and the Caribbean
Adults: A single dose of 15 mg/kg.
Children (less than 30 kg): 20 mg/kg in two divided
doses.
East and central Africa and the Arabian peninsula
Adults and children: 30 mg/kg in two divided doses
Egypt and southern Africa
Adults and children: 60 mg/kg administered over
2–3 days. The maximum single dose should not
exceed 20 mg/kg.
Precautions: Epileptic patients should remain
under observation for several hours following
treatment since seizures may be precipitated.
Patients should be advised not to drive or operate
machinery for at least 24 hours, since drowsiness
may occur.
Adverse effects: Mild and transient dizziness and
drowsiness occur in about one-third of patients.
Headache, vomiting and diarrhoea may also be
troublesome and intense orange-red discoloration
of the urine may occur. Rarely, hallucinations,
excitation and epileptiform convulsions are report-
ed; transient but inconsequential increases in levels
of serum transaminases are sometimes detected.
In Egypt and some other countries of the Eastern
Mediterranean region many patients develop
Essential Drugs
transient fever, peripheral blood eosinophilia and
scattered pulmonary infiltrates (Loeffler’s
syndrome) following a 3-day course of treatment.
Drug interactions : These will appear in tabulated
form in the appendix of the published edition of the
WHO Model Formulary.
Drugs used in fluke infections
The intestinal flukes include Fasciolopsis buski,
Metagonimus yokogawai, Heterophytes hetero-
phytes, Echinostoma spp and Gastrodiscoides
hominis. The liver flukes include Clonorchis
sinensis, Opisthorchis viverrini, O. felineus and
Fasciola hepatica. In some areas Clonorchis
sinensis and Opisthorchis spp. infections are
strongly associated with cholangiocarcinoma
(cancer of the bile duct). Lung flukes belong to the
genus Paragonimus.
Praziquantel has transformed the therapy of most
fluke infections. Parasitological cure has been
obtained in virtually all cases (with the exception
of fasciola infections) without significant adverse
effects, but the drug should be taken for several
days for treatment of paragonimus infections.
Evidence suggests that a single dose of tricla-
bendazole is effective and well tolerated in a high
proportion of cases of both fasciola and
paragonimus infections.
PRAZIQUANTEL
Anthelminthic agent
Tablet: 150mg, 600 mg
Uses: Intestinal, liver and lung fluke infections
including those due to Fasciolopsis buski, Meta-
gonimus yokogawai, Heterophytes heterophytes,
Echinostoma spp., Clonorchis sinensis, Opisthor-
chis viverrini, O. felineus and various species of
paragonimus.
Dosage:
Intestinal fluke infections
Adults and children over 4 years: a single dose of
25 mg/kg is recommended.
Liver and lung fluke infections
Adults and children over 4 years: a dose of 25 mg/
kg three times a day for 2 consecutive days
produces virtually 100% cure rates in the majority of
liver and lung fluke infections. A single dose of
40 mg/kg has also been shown to be effective.
83
Essential Drugs
Precautions: Patients with paragonimus infections
should always be treated in a hospital since flukes
can invade the central nervous system.
Adverse effects: Occasionally, abdominal
discomfort, nausea, headache, dizziness and
84
WHO Drug Information Vol. 11, No. 2, 1997
drowsiness. Rarely, pyrexia, urticaria and rectal
bleeding.
Drug interactions: These will appear in tabulated
form in the appendix of the published edition of the
WHO Model Formulary.
WHO Drug Information, Vol. 11, No 2. 1997 Proposed INN: List 77

International Nonproprietary Names for

Pharmaceutical Substances (INN)
Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended
International Nonproprietary Names for Pharmaceutical Substances, the names given in the list on the following
pages are under consideration by the World Health Organization as Proposed International Nonproprietary Names.
The inclusion of a name in the lists of Proposed International Nonproprietary Names does not imply any
recommendation of the use of the substance in medicine or pharmacy.

Lists of Proposed (1-73) and Recommended (1-35) International Nonproprietary Names can be found in Cumulative
List No. 9, 1996. The statements indicating action and use are based largely on information supplied by the
manufacturer. This information is merely meant to provide an indication of the potential use of new substances at the
time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these
statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors
will neither be revised nor included in the Cumulative Lists of INNs.

Dénominations communes internationales

des Substances pharmaceutiques (DCI)
Il est notifié que, conformément aux dispositions de l'article 3 de la Procédure à suivre en vue du choix de
Dénominations communes internationales recommandées pour les Substances pharmaceutiques les dénominations
ci-dessous sont mises à l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes
internationales proposées. L'inclusion d'une dénomination dans les listes de DCI proposées 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 (1-73) et recommandées ( 1 -

35) dans la Liste récapitulative No. 9, 1996. Les mentions indiquant les propriétés et les indications des substances
sont fondées sur les renseignements communiqués par le fabricant. Elles ne visent qu'à donner une idée de
l'utilisation potentielle des nouvelles substances au moment où elles sont l'objet de propositions de DCI. L'OMS n'est
pas en mesure de confirmer ces déclarations ni dé faire de commentaires sur l'efficacité du mode d'action ainsi décrit.
En raison de leur caractère provisoire, ces informations ne figureront pas dans les listes récapitulatives de DCI.

Denominaciones Comunes Internacionales

para las Sustancias Farmacéuticas (DCI)
De conformidad con lo que dispone el párrafo 3 del "Procedimiento de Selección de Denominaciones Comunes
Internacionales Recomendadas para las Sustancias Farmacéuticas", se comunica por el presente anuncio que las
denominaciones detalladas en las páginas siguientes están sometidas a estudio por la Organización Mundial de La
Salud como Denominaciones Comunes Internacionales Propuestas. La inclusión de una denominación en las listas
de las DCI Propuestas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina
o en farmacia.

Las listas de Denominaciones Comunes Internacionales Propuestas (1-73) y Recomendadas (1-35) se encuentran
reunidas en Cumulative List No. 9, 1996. Las indicaciones sobre acción y uso que aparecen se basan principalmente
en la información facilitada por los fabricantes. Esta información tiene por objeto dar una idea únicamente de las
posibilidades de aplicación de las nuevas sustancias a las que se asigna una DCI Propuesta. La OMS no está
facultada para respaldar esas indicaciones ni para formular comentarios sobre la eficacia de la acción que se atribuye
a! producto, Debido a su carácter provisional, esos datos descriptivos no deben incluirse en las listas recapitulavas
de DCI.

85
Proposed INN: List 77 WHO Drug Information, Vol. 11, No. 2, 1997

Proposed International Nonproprietary Names: List 77

Comments on, or formal objections to, the proposed names may be forwarded by any person to the INN Programme
of the World Health Organization within four months of the date of their publication in WHO Drug Information, i.e.,
for List 77 Proposed INN not later than 30 November 1997.

Dénominations communes internationales proposées: Liste 77

Des observations ou des objections formelles à l'égard des dénominations proposées peuvent être adressées par
toute personne au Programme des Dénominations communes internationales de l'Organisation mondiale de la
Santé dans un délai de quatre mois à compter de la date de leur publication dans WHO Drug Information, c'est-à-
dire pour la Liste 77 de DCI Proposées le 30 novembre 1997 au plus tard.

Denominaciones Comunes Internacionales Propuestas: Lista 77

Cualquier persona puede dirigir observaciones u objeciones respecto de las denominaciones propuestas, al
Programa de Denominaciones Comunes Internacionales de la Organización Mundial de la Salud, en un plazo de
cuatro meses, contados desde la fecha de su publicación en WHO Drug Information, es decir, para la Lista 77 de
DCI Propuestas el 30 de noviembre de 1997 a más tardar.

Proposed INN Chemical name or description: Action and use: Molecular formula
(Latin, English, French, Spanish) Chemical Abstracts Service (CAS) registry number: Graphic formula

DCI Proposée Nom chimique ou description: Propriétés et indications: Formule brute

Numéro dans le registre du CAS: Formule développée

DCI Propuesta Nombre químico o descripción: Acción y uso: Fórmula empírica

Número de registro del CAS: Fórmula desarrollada

acidum iocanlidicum (123I)

iocanlidic acid (123I)
acide iocanlidique (123l)
ácido iocanlídico (123l)
15-(p-[123l]iodophenyl)pentadecanoic acid
radiodiagnostic agent
acide 15-(4-[123l]iodophényl)pentadécanoïque
produit à usage radiodiagnostique
ácido 15-(p-[123l]iodofenil)pentadecanoico
agente de radiodiagnóstico
C21H33123lO2 74855-17-7

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W H O Drug Information, Vol. 1 1 , No. 2, 1997 Proposed INN: List 77

acreozastum
N,N-(2-chloro-5-cyano-m-phenylene)bis[glycolamide]diacetate (ester)
acreozast antiallergic, antiasthmatic

diacétate de 2,2'-[2-chloro-5-cyano-1,3-phénylènebis(imino)]bis(2-oxoéthyle)
acréozast antiallergique, antiasthmatique

éster diácetico de N,N-(2-cloro-5-ciano-m-fenilen)bis[glicolamida]

acreozast antialérgico, antiasmático

C 1 5 H 1 4 CIN 3 O 6 123548-56-1

aseripidum
aseripide (2R,4R)-3-[N-[[3-[(S)-1-carboxyethy]]phenyl]carbamoyl]glycyl]-
2-(o-fluorophenyl)-4-thiazolidinecarboxyIic acid, 4-tert-butylester
cholecystokinin receptor antagonist

aséripide acide (2S)-2-[3-[3-[2-[(2R,4R)-4-[(1,1-diméthyléthoxy)carbonyl]-

2-(2-fluorophényl)thiazolidin-3-yl]-2-oxoéthyl]uréido]phényl]propanoique
antagoniste du récepteur de la cholécystokinine

aseripida (2R,4R)-3-[N-[[3-[(S)-1-carboxietil]fenil]carbamoil]glicil]-
2-(o-fluorofenil)-4-tiazolidinacarboxilato de terc-butilo
antagonista del receptor de la colecistoquinina

C 2 6 H 3 0 FN 3 O 6 S 153242-02-5

avoterminum
avotermin transforming growth factor β3 (human), dimer
transforming growth factor

avotermine facteur de croissance transformant β3 (humain)

facteur de croissance "transformant"

avotermina factor β3 de crecimiento transformador(humano), dímero

factor de crecimiento transformador

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Proposed INN: List 77 W H O Drug Information, Vol. 1 1 , No. 2, 1997

C1128H1702N269O336S20 182212-66-4

cedelizumabum
cedelizumab immunoglobulin G 4 (human-mouse monoclonal OKTcdr4a complementary
determining region-grafted γ-chain anti-human CD 4 antigen), disulfide with
human-mouse monoclonal OKTcdr4a complementary determining region-
grafted κ-chain, dimer
immunomodulator

cédélizumab immunoglobuline G 4 (chaîne γ de l'anticorps monoclonal de souris

humanisé OKTcdr4a dirigé contre l'antigène CD 4 humain), dimère du
disulfure avec la chaîne K de l'anticorps monoclonal d e souris humanisé
OKTcdr4a
immunomodulateur

cedelizumab inmunoglobulina G 4 (cadena γ del anticuerpo monoclonal humanizado de

ratón OKTcdr4a, dirigido contra el antigeno CD4 humano), dimero del
disulfuro con la cadena K del anticuerpo monoclonal humanizado de ratón
OKTcdr4a
inmunomodulador

156586-90-2

ceftizoximum alapivoxilum
ceftizoxime alapivoxil (+)-(pivaloyloxy)methyl (6R,7R)-7-[2-[2-(L-alanylamino)thiazol-
4-yl]glyoxylamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
7 2 -(Z)-(O)-methyloxime)
antibacterial

ceftizoxime alapivoxil (+)-(6R,7R)-7-[[2-[2-[[(2S)-2-aminopropanoyl]amino]thiazol-4-yl]-2-[(Z)-

méthoxyimino]acétyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ène-2-
carboxylate de [(2,2-diméthylpropanoyl)oxy]méthyle
antibactérien

ceftizoxima alapivoxilo (6R,7R)-7-[2-[2-(L-alanilamino)tiazolin-4-il]glioxilamido]-8-oxo-5-tia-1-

azabiciclo[4 2.0]oct-2-en-2-carboxilato de (+)-pivaloxi)metil, 72-(Z)-(O)-
methiloxime)
antibacteriano

C22H28N6O8S2 135821 -54-4

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WHO Drug Information, Vol. 11. No. 2, 1997 Proposed INN: List 77

celgosivirum
(1S,6S,7S,8R,8aH)-octahydro-1,7,8-trihydroxy-6-indolizinyl butyrate
celgosivir antiviral
butanoate de (1S,6S,7S,8R,8aR)-1,7,8-trihydroxyoctahydroindolizin-6-yle
celgosivir antiviral
butirato de (1S,6S,7S,8R,8aR)-1,7,8-trihidroxioctahidro 6-indolizinilo
celgosivir antiviral
C12H21NO5 121104-96-9

clenoliximabum
clenoliximab immunoglobulin G 4 (human-Macaca monoclonal CE9γ4PE γ4-chain anti¬
human antigen CD 4), disulfide with human-Macaca monoclonal CE9γ4PE
κ-chain, dimer
immunomodulator
clenoliximab immunoglobuline G 4 (chaîne γ4 de l'anticorps monoclonal chimérique
homme-Macaque CE9γ4PE dirigé contre l'antigène CD 4 humain), dimère du
disulfure avec la chaîne Κ de l'anticorps monoclonal chimérique homme-
Macaque CE9γ4PE
immunomodulateur

clenoliximab inmunoglobulina G 4 (cadena γ4 del anticuerpo monoclonal quimérico

hombre-Macaca CE9γ4PE dirigido contra el antigeno antigen CD 4 humano),
dimero del disulfuro con la cadena Κ del anticuerpo monoclonal quimérico
hombre-Macaca CE9y4PE
mmunomodulador

colesevelamum
colesevelam allylamine polymer with 1-chloro-2,3-epoxypropane [6-(alIylamino)=
hexyl]trimethylammonium chloride and N-allyldecylamine
antihyperlipidaemic

colésévelam copolymère de prop-2-én-1-amine, de dodécan-1-amine et de

N,N,N-triméthyl-6-(prop-2-énylamino)hexan-1-aminium réticulé à l'aide de
2-(chlorométhyl)oxirane (épichlorhydrine)
antihyperlipidémiant

colesevelam copolimero de prop-2-en-1-amino, de dodecan-1-amino y de

N,N,N-trimetil-6-(prop-2-enilamino)hexan-1-aminio reticulado con
2-(clorometil)oxirano (epiclorhidrina)
antihiperlipémico
182815-43-6

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Proposed INN. List 77 WHO Drug Information, Vol. 11, No. 2, 1997

eniIuracilum
eniluracil 5-ethynyluracil
uracil reductase inhibitor
eniIuracil 5-éthynylpyrimidine-2,4(1H,3H)-dione
inhibiteur de l'uracile réductase

eniluracilo 5-etiniluracilo
inhibidor de la reductasa de uracilo
C6H4N2O2 59989-18-3

enlimomabum pegolum
enlimomab pegol immunoglobulin G 2a (mouse monoclonal BI-RR-1 anti-human antigen
CD 54), disulfide with mouse monoclonal BI-RR-1 light chain, dimer, reaction
product with α-(2-carboxyethyl)-ω- methoxypoly(oxy-1,2-ethanediyl)
immunomodulator
enlimomab pégol N, N',N",N'", N"-pentakis[α-méthylpoly(oxyéthylène)-ω-
(oxypropanoyl)immunoglobuline G2a (anticorps monoclonal de souris
BI-RR-1 dirigé contre l'antigène CD 54 humain), dimère du disulfure avec la
chaîne légère de l'anticorps monoclonal de souris BI-RR-1
immunomodulateur

enlimomab pegol inmunoglobulina G 2a (anticuerpo monoclonal de ratón BI-RR-1 dirigido

contra el antigeno CD 54 humano), dimero del disulfuro con la cadena ligera
del anticuerpo de ratón BI-RR-1, producto de reacción con α-(2-carboxietil)-
ω-metoxipali(oxi-1,2-etanodiil)

inmunomodulador
169802-84-0

eplerenonum
eplerenone 9,11α-epoxy-17-hydroxy-3-oxo-17α-pregn-4-ene-7α,21-dicarboxylic acid,
γ-lactone, methyl ester
aldosterone receptor antagonist
éplérénone (2'R)-9,11α-époxy-3,5'-dioxo-4',5'-dihydrospiro[androst-4-éne-17,
2'(3H)-furane]-7α-carboxylate de méthyle
antagoniste
eplerenona éster metílico de la γ-lactona del ácido 9,11α-epoxi-17-hidroxi-3-oxo-
17α-pregn-4-en-7α,21-dicarboxílico
antagonista de los receptores

90
WHO Drug Information, Vol. 11, No. 2, 1997 Proposed INN: List 77

C24H30O6 107724-20-9

felvizumabum
felvizumab immunoglobulin G 1 (human-mouse monoclonal, γ-chain anti-respiratory
syncytial virus), disulfide with human-mouse monoclonal κ-chain, dimer
immunomodulator
felvizumab immunoglobuline G 1 (chaîne γ de l'anticorps monoclonal de souris
humanisé dirigé contre le virus syncytial respiratoire), dimère du disulfure
avec la chaîne κ de l'anticorps monoclonal de souris humanisé
immunomodulateur
felvizumab inmunoglobulina G 1 (cadena γ del anticuerpo monoclonal humanizado de
ratón, dirigido contra el virus sincitial respiratorio), dimero del disulfuro con la
cadena κ del anticuerpo humanizado de ratón
inmunomodulador
167747-20-8

fudosteinum
(-)-3-[(3-hydroxypropyl)lhio]-L-alanine
fudosteine expectorant
(-)-acide (2R)-2-amino-3-[(3-hydroxypropyl)sulfanyl]propanoïque
fudostéine expectorant
(-)-3-[(3-hidroxipropil)tio]-L-alanina
fudosteína expectorante
C6H13NO3S 13189-98-5

gavestinelum
gavestinel 4,6-dichloro-3-[(E)-2-(phenylcarbamoyl)vinyl]indole-2-carboxylicacid
NMDA receptor antagonist
gavestinel acide 4,6-dichloro-3-[(E)-2-(phényIcarbamoyl)éthényl]-1H-indole-2-
carboxylique
antagoniste des récepteurs du NMDA

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gavestinel ácido 4,6-dicloro-3-[(E)-2-(fenilcarbamoil)vinil]indol-2-carboxílico

antagonista de los receptores de NMDA
C18H12Cl2N2O3 153436-22-7

glufosfamidum
β-D-glucopyranose 1-[N,N'-bis(2-chloroethyl)phosphorodiamidate]
glufosfamide antineoplastic
N,N'-bis(2-chloroéthyl)phosphorodiamidate de β-D-glucopyranosyle
glufosfamide antinéoplasique
1-[N,N'-bis(2-cloroetil)fosforodiamidato] de β-D-glucopiranosa
glufosfamida antineoplásico
C10H21CI2N2O7P 132682-98-5

infliximabum
infliximab immunoglobulin G (human-mouse monoclonal cA2 heavy chain anti-human
tumor necrosis factor), disulfide with human-mouse monoclonal cA2 light
chain, dimer
immunomodulator

infliximab immunoglobuline G (chaîne lourde de l'anticorps monoclonal chimérique

homme-souris cA2 dirigé contre le facteur de nécrose tumorale humain),
dimère du disulfure avec la chaîne légère de l'anticorps monoclonal
chimérique homme-souris cA2
immunomodulateur
infliximab inmunoglobulina G (cadena pesada del anticuerpo monoclonal quimérico
hombre-ratón cA2 dirigido contra el factor de necrosis tumoral humano),
dimero del disulfuro con la cadena ligera del anticuerpo monoclonal
quimérico hombre-ratón cA2
inmunomodulador
170277-31-3

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WHO Drug Information, Vol. 11, No. 2, 1997 Proposed INN: List 77

interferonum alfacon-1
interferon alfacon-1
interféron alfacon-1
interferón alfacón-1
N-L-methionyl-22-L-arginine-76-L-alanine-78-L-aspartic acid-79-L-glutamic
acid-86-L-tyrosine-90-L-tyrasine-156-L-threonine-157-L-asparagine-
158-L-leucineinterferon α1 (human lymphoblast reduced)
antiviral
N-L-méthionyl-[22-L-arginine-76-L-alanine-78-L-acide aspartique-79-L-acide
glutamique-86-L-tyrosine-90-L-tyrosine-156-L-thréonine-157-L-asparagine-
158-L-leucine]interféron α1 (lymphoblastique humain réduit)
antiviral
N-L-metionil-22-L-arginina-76-L-alanina-78-ácido L-aspártico-79-ácido
L-glutámico-86-L-tirosina-90-L-tirasina-156-L-treonina-157-L-asparagina-
158-L-leucinainterferón α1(linfoblástico humano reducido)
antiviral
C670H1366N236O259S9 118390-30-0

MCDLPQTHSLG NRRALILLAQ MRRISPFSCL KDRHDFGFPQ

EEFDGNQFQK AQAISVLHEM IQQTFNLFST KDSSAAWDES
LLEKFYTELY QQLNDLEACV IQEVGVEETP LMNVDSILAV
KKYFQRITLY LTEKKYSPCA WEVVRAEIMR SFSLSTNLQE
RLRRKE

lanepitantum
lanepitant N-[(R)-2-indol-3-yl-1-[[N-(o-methoxybenzyl)acetamido] methyl]ethyl] [1,4'-
bipiperidine]-1'-acetamide
tachykinin receptor antagonist
lanépitant N-[(1R)-1-[[acétyl(2-méthoxybenzyl)amino]méthy[]-2-(1H-indol-3-yl)éthyl]-
2-(1,4'-bipipéridin-1'-yl)acétamide
antagoniste de récepteurs de la tachykinine

lanepitant N-[(R)-2-indol-3-il-1-[[N-(o-metoxibencil)acetamido]metiI]etil][1,4'-
bipiperidina]-1'-acetamída
antagonista del receptor de taquiquinina
C33H45N5O3 170566-84-4

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licostinelum
6,7-dichloro-1,4-dihydro-5-nitro-2,3-quinoxalinedione
licostinel NMDA receptor antagonist
6,7-dichloro-5-nitro-1,4-dihydroquinoxaline-2,3-dione
licostinel antagoniste des récepteurs du NMDA
6,7-dicloro-1,4-dihidro-5-nitro-2,3-quinoxalinadiona
licostinel antagonista de los receptores de NMDA
C8H3CI2N3O4 153504-81 -5

lumefantrinum
lumefantrine (±)-2,7-dichloro-9-[(Z)-p-chlorobenzylidene]-α[(dibutylamino)methyl]fluorene-
4-methanol
antimalarial
luméfantrine (1RS)-2-(dibutylamino)-1-[(Z)-2,7-dichloro-9-(4-chlorobenzylidène)-
9H-fluorén-4-yl]éthanol
antipaludéen
lumefantrina (±)-2,7-dicloro-9-[(Z)-p-clorobencilideno]-α[(dibutilamino)metil]fluoreno-
4-metanol
antipalúdico
C30H32CI3NO 82186-77-4

and enantiomer
et énantiomère
y enantiómero

milacainidum
(-)-(R)-2-amino-N-[3-(3-pyridyl)propyl]-2',6'-propionoxylidide
milacainide antiarrhythmic
(-)-(R)-2-amino-N-(2,6-diméthylphényl)-N-[3-(pyridin-3-yl)propyl]propanamide
milacaïnide antiarythmique
(-)-(R)-2-amino-N-[3-(3-piridil)propil]-2',6'-propionoxilidida
milacainida antiarrítmico

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C19H25N3O 141725-10-2

mivobulinum
mivobulin ethyl (S)-5-amino-1,2-dihydro-2-methyl-3-phenyIpyrido[3,4-b]pyrazine-
7-carbamate
antineoplastic
mivobuline [(2S)-5-amino-2-méthyl-3-phényl-1,2-dihydropyrido[3,4-5]pyrazin-
7-yl]carbamate d'éthyle
antinéoplasique
mivobulina (S)-5-amino-1,2-dihidro-2-metil-3-fenilpirido [3,4-b]pirazina-7-carbamato de
etilo
antineoplásico
C17H19N5O2 122332-18-7

nateglinidum
nateglinide (-)-N-[(trans-4-isopropylcyclohexyl)carbonyl]-D-phenyIalanine
antidiabetic
natéglinide (-)-acide (2R)-2-[[[trans-4-(1-méthyléthyl)cyclohexyl]carbonyl]amino]
3-phényIpropanoique
antidiabétique
nateglinida (-)-N-[(trans-4-isopropilciclohexil)carbonil]-D-tenilalanina
antidiabético
C19H27NO3 105816-04-4

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nonacogum alfa
blood-coagulation factor IX (human), glycoform α
nonacog alfa blood-coagulation factor
facteur IX de coagulation sanguine humain, glycoforme α
nonacog alfa facteur de coagulation sanguine
factor IX (humano) de la coagulación sanguínea, forma glucosilada α
nonacog alfa factor de coagulación sanguínea
113478-33-4

oberadilolum
oberadilol (±)-4-chloro-2-[3-[[1,1-dimethyl-2-[p-(1,4,5,6-tetrahydro-4-methyl-6-oxo-
3-pyridazinyl)anilino]ethyl]amino]-2-hydroxypropoxy]benzonitrile
β-adrenoceptor antagonist
obéradilol 4-chloro-2-[3-[[1,1-diméthyl-2-[[4-(4-méthyl-6-oxo-1,4,5,6-tétrahydro=
pyridazin-3-yl)phényl]amino]éthyl]amino]-2-hydroxypropoxy]benzonitrile
antagoniste β-adrénergique
oberadilol (±)-4-cloro-2-[3-[[1,1-dimetil-2-[p-(1,4,5,6-tetrahidro-4-metil-6-oxo-
3-piridazinil)anilino]etil]amino]-2-hidroxipropoxi]benzonitrilo
antagonista de los receptores β-adrenérgicos
C 2 5 H 3 0 CIN 5 O 3 114856-44-9

opanixilum
opanixil 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)-N-ethyl-α,α,α-trifluoro-
5-pyrimidinecarboxy-m-toluidide
antihyperlipidaemic
opanixil 4-amino-2-(4,4-diméthyl-2-oxoimidazolidin-1-yl)-N-éthyl-
N-[3-(trifluorométhyl)phényl]pyrimidin-5-carboxamide
hyperlipidémiant
opanixilo 4-amino-2-(4,4-dimetil-2-oxo-1-imidazolidinil)-N-etil-α,α,α-trifluoro-
5-pirimidinacarboxi-m-toluidida
antihiperlipémico
C19H21F3N6O2 152939-42-9

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oraziponum
3-[p-(methylsulfonyl)benzylidene]-2,4-pentanedione
orazipone immunosuppressant
3-[4-(méthylsulfonyl)benzylidène]pentane-2,4-dione
orazipone immunosuppresseur
3-[p-(metilsulfonil)benciliden]-2,4-pentanodiona
orazipona inmunosupresor
C13H14O4S 137109-78-5

pegmusirudinum
pegmusirudin L-vaiyl-L-valyl-L-tyrosyl-L-threonyl- L-α-aspartyl-L-cysteinyl-threonyl-L-α-
glutamyl-L-serylglycyl-L-glutaminyl-L-asparaginyl-L-leucyl-L-cysteinyl-L-leucyl-
L-cysteinyl-L-α-glutamylglycyl-L-seryl-L-asparaginyl-L-valyl-L-cysteinylglycyl-
L-glutamylglycyl- L-asparaginyl-N6-carboxy-L-lysyl-L-cysteinyl-L-isoleucyl-
L-leucylglycyl-L-seryl-N6-carboxy-L-lysylglycyl-L-α-glutamyl-L-arginyl-L-
asparaginyl-L-glutaminyl-L-cysteinyl-L-valyl-L-threonylglycyl-L-α-
glutamylglycyl-L-threonyl-L-prolyl-L-arginyl-L-prolyl-L-glutaminyl-
L-seryl-L-histidyl-L-asparaginyl-L-α-aspartylglycyl-L-α-aspartyl-L-phenylalanyl-
L-α-glutamyl-L-α-glutamyl-L-isoleucyl-L-prolyl-L-α-glutamyl-L-α-glutamyl-L-
tyrosyl-L-leucyl-L-glutamine cyclic (6→14), (16→28), (22→39)-
tris(disulfide) 27,33-diester with polyethylene glycol monoethyl ether
platelet aggregation inhibitor
pegmusirudine N6,27,N6 33-bis[α-méthylpoly(oxyèthylène)-ω-(oxycarbonyl)]-[33-L-lysine-
36-L-arginine-47-L-arginine]-O63-désulfohirudine (hirudo medicinalis)
antiagrégant plaquettaire
pegmusirudina L-valil-L-valil-L-tirosil-L-treonil- L-α-aspartil-L-cisteinil-L-treonil-L-α-glutamil-
L-serilglicil-L-glutaminil-L-asparaginil-L-leucil-L-cisteinil-L-leucil-L-cisteinil-
L-α-glutamilglicil-L-seril-L-asparaginil-L-valil-L-cisteinilglicil-L-glutamilglicil-
L-asparaginil-N6-carboxi-L-lisil-L-cisteinil-L-isoleucil-L-leucilglicil-L-seril-N6-
carboxi-L-lisilglicil-L-α-glutamil-L-arginil-L-asparaginil-L-glutaminil-L-cisteinil-
L-valil-L-treonilglicil-L-α-glutamilglicil-L-treonil-L-prolil-L-arginil-L-prolil-
L-glutaminil-L-seril-L-histidil-L-asparaginil-L-α-aspartilglicil-L-α-aspartil-
L-fenilalanil-L-α-glulamil-L-α-glutamil-L-isoIeucil-L-prolil-L-α-glutamil-
L-α-glutamil-L-tirosil-L-leucil-L-glutamine tris(disulfuro) cíclico (6→14),(16
→28), (22→39), 27,33-diester con polietilen glicol monoetil eter
inhibidor de la agregación plaquetaria

(C2H4O)n(C2H4O)n C302H451N85O112S6 186638-10-8

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pifonakinum
36-L-aspartic acid-141-L-serineinterleukin 1α (human clone p10A)
pifonakin immunomodulator, interleukin derivative
[36-acide L-aspartique-141-L-sérine]interleukine 1α (clone humain p10A)
pifonakine immunomodulateur, dérivé d'interleukine
36-L-ácido aspártico-141-L-serinainterleuquina 1α (clon humano p10A)
pifonakina inmunomodulador, derivado de las interleuquinas
112721-39-8

SAPFSFLSNV KYNFMRIIKY EFILNDALNQ SIIRADDQYL

TAAALHNLDE AVKFDMGAYK SSKDDAKITV ILRISKTQLY
VTAQDEDQPV LLKEMPEIPK TITGSETNLL FFWETHGTKN
YFTSVAHPNL FIATKQDYWV SLAGGPPSIT DFQILENQA

pleconarilum
pleconaril 3-[4-[3-(3-methyl-5-isoxazolyl)propoxy]-3,5-xylyl]-5-(trifluoromethyl)-
1,2,4-oxadizole
antiviral
pléconaril 3-[3,5-diméthyl-4-[3-(3-méthylisoxazol-5-yl)propoxy]phényl]-
5-(trifluorométhyl)-1,2,4-oxadiazole
antiviral
pleconarilo 3-[4-[3-(3-metil-5-isoxazolil)propoxi]-3,5-xilil]-5-(trifluorometil)-
1,2,4-oxadizol
antiviral
C18H18F3N3O3 153168-05-9

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pralmorelinum
pralmorelin D-alanyl-3-(2-naphthyl)-D-alanyl-L-alanyl-L-tryptophyl-D-phenylalanyl-
L-lysinamide
growth hormone release stimulating peptide
pralmoréline D-alanyl-[3-(naphtalén-2-yl)-D-alanyl]-L-alanyl-L-tryptophyl-D-phénylalanyl-
L-lysinamide
peptide stimulant la libération de l'hormone de croissance
pralmorelina D-alanil-3-(2-naftil)-D-alanil-L-aIanil-L-triptofil-D-fenilalanil-L-lisinamida
peptido estimulante de la liberación de la hormona del crecimiento
C45H55N3O6 158861-67-7

rituximabum
rituximab immunoglobulin G 1 (human-mouse monoclonal IDEC-C2B8 γ1-chain anti¬
human antigen CD 20), disulfide with human-mouse monoclonal IDEC-C2B8
κ-chain, dimer
immunomodulator
rituximab immunoglobuline G1 (chaîne γ1 de l'anticorps monoclonal chimérique
homme-souris IDEC-C2B8 dirigé contre l'antigène CD20 humain), dimère du
disulfure avec la chaîne K de l'anticorps monoclonal chimérique homme-
souris IDEC-C2B8
immunomodulateur
rituximab inmunoglobulina G 1 (cadena γ1 del anticuerpo monoclonal quimerico
hombre-ratón IDEC-C2B8 dirigido contra el antigeno CD 20 humano), dimero
del disulfuro con la cadena K del anticuerpo monoclonal quimérico hombre-
ratón IDEC-C2B8
inmunomodulador
174722-31-7

rivastigminum
(-)-m-[(S)-1 -(dimethylamino)ethyl]phenyl ethylmethylcarbamate
rivastigmine nootropic agent
(-)-éthylméthylcarbamate de 3-[(1S)-1-(diméthylamino)éthyl]phényle
rivastigmine nootrope
etilmetilcarbamato de (-)-m-[(S)-1-(dimetilamino)etil]fenilo
rivastigmina nootropo

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C14H22N2O2 123441-03-2

roflumilastum
roflumilast 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)=
benzamide
antiasthmatic
roflumilast 3-(cyclopropylméthoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluorométhoxy)=
benzamide
antiasthmatique
roflumilast 3-(ciclopropilmetoxi)-N-(3,5-dicloro-4-piridil)-4-(difluorometoxi)benzamida
antiasmático
C17H14Cl2F2N2O3 162401-32-3

roxifibanum
roxifiban (2S)-3-[2-[(5R)-3-(p-amidinophenyl)-2-isoxazolin-5-yl] acetamido]-
2-(carboxyamino)propionic acid, 2-butyl methyl ester
antithrombotic, fibrinogen receptor antagonist
roxifiban (2S)-3-[[2-[(5R)-3-(4-carbamimidoylphényl)-4,5-dihydroisoxazol-
5-yl]acétyl]amino]-2-[(butoxycarbonyl)amino]propanoate de méthyle
antithrombotique, antagoniste du récepteur du fibrinogène
roxifibán 2-butil metil éster del ácido (2S)-3-[2-[(5R)-3-(p-amidinofenil)-2-isoxazolin-
5-il]acetamido]-2-(carboxiamino)propiónico
antitrombótico, antagonista del receptor del fibrinógeno
C21H29N5O6 170902-47-3

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sevelamerum
sevelamer allylamine polymer with 1-chloro-2,3-epoxypropane
phosphate binder

sevelamer copolymère de prop-2-én-1-amine et de 1,3-bis(prop-2-énylamino)propan-

2-ol
fixateur de phosphate

sevelámero copolimero de prop-2-en-1-amino y de 1,3-bis(prop-2-enilamino)propan-

2-ol
captador del fosfato

52757-95-6

sibrafibanum
sibrafiban ethyl (Z)-[[1 -[N-[(p-hydroxyamidino)benzoyl]-L-alany[]-4-piperidyl]oxy] acetate
fibrinogen receptor antagonist

sibrafiban [[1-[(2S)-2-[[4-[(Z)-
amino(hydroxyimino)rnéthyl]benzoyl]amino]propanoyl]pipéridin-
4-yl]oxy]acétate d'éthyle
antagoniste du récepteur du fibrinogene

sibrafibán (Z)-[[1-[N-[(p-hidroxiamidino)benzoil]-L-alani[]-4-pipendil]oxi] acetato de etilo

antagonista del receptor del fibrinógeno

C20H28N4O6 172927-65-0

tazomelinum
3-[4-(hexylthio)-1,2,5-thiadiazol-3-yl]1,2,5,6-tetrahydro-1-methyIpyridine
tazomeline cholinergic

3-[4-(hexylsulfanyl)-1 2,5-thiadiazol-3-yl]-1-méthyi-1,2,5,6-tétrahydropyridine
tazoméline cholinergique

3-[4-(hexiltio)-1,2,5-tiadiazol-3-il]1,2,5,6-tetrahidro-1-metilpiridina
tazomelina colinérgico

C14H23N3S2 131987-54-7

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trecovirsenum
trecovirsen P-thiothymidylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-P-thiothymidylyl-
(5'→3')-P-thiothymidylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-2'-deoxy-P-
thiocytidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-
P-thiothymidylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-thiothymidylyl-
(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-deoxy-P-
thioadenylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-
(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-2'-deoxy-P-thioadenylyl-(5'→3')-2'-
deoxy-P-thiocytidylyl-(5'→3')-2'-deoxy-P-thioguanylyl-(5'→3')-2'-deoxy-P-
thiocytidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-
P-thiothymidylyl-(5'→3')-2'-deoxycytosine
antiviral

trécovirsen P-thiothymidylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-P-thiathymidylyl-
(5'→3')-P-thiothymidylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-2'-désoxy-
P-thiocytidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-
(5'→3')-P-thiothymidylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-P-
thiothymidylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-2'-thiothymidylyl-
(5'→3')-2'-désoxy-P-thioadénylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-2'-
désoxy-P-thiocytidylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-2'-désoxy-P-
thioadénylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-2'-désoxy-P-
thioguanylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-P-thiothymidylyl-
(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'-
désoxycytosine
antiviral

trecovirseno P-tiotimidilil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-P-tiotimidilil-(5'→3')-P-
tiotimidilil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-
P-tiotimidilil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-P-tiotimidilil-(5'→3')-2'-
desoxi-P-tiocitidilil-(5'→3')-P-tiotimidilil-(5'→3')-2'-desoxi-P-tiacitidilil-(5'→3')-
P-tiotimidilil-(5'→3')-2'-desoxi-P-tioadenilil-(5'→3')-2'-desoxi-P-tiocitidilil-
(5'→3')-desoxi-P-tiocitidilil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-2'-desoxi-
P-tioadenilil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-2'-desoxi-P-tioguanilil-
(5'→3')-2'-desoxi-P-tiocitidilíl-(5'→3')-P-tiotimidilil-(5'→3')-2'-desoxi-P-
tiocitidilil-(5'→3')-P-tiotimidilil-(5'→3')-2'-desoxicitosina
antiviral

C 2 3 7 H 3 1 0 N 7 2 O 1 3 1 P 2 4 S 2 4 148998-94-1

upenazimum
3,3'-(tetramethylenediimino)bis[3-methyl-2-butanone] dioxime
diagnostic agent
upenazime
3,3'-(butane-1,4-diyldiimino)bis(3-méthylbutan-2-one) (E,E)-dioxime
produit à usage diagnostique
upénazime
3,3'-(tetrarnetilendiimino)bis[3-metil-2-butanona] dioxima
agente de diagnóstico
upenazima
C14H30N4O2 95268-62-5

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urokinasum alfa
urokinase alfa urokinase (enzyme-activating) (human clone pA3/pD2/pF1 high-molecular-
weight isoenzyme protein moiety)
thrombolytic

urokinase alfa activateur du plasminogène (partie protéique de l'isoenzyme de masse

moléculaire élevée fournie par le clone humain pA3/pD2/pF1)
thrombolytique

urokinasa alfa uroquinasa, activador del plasminógeno (fracción proteica de la isoenzima

de masa molecular elevada producida por el clon humano pA3/pD2/pF1)
trombolítico

99821-47-3

vatanidipinum
vatanidipine (±)-p-[4-(diphenylmethyl)-1-piperazinyl]phenethyl methyl 1,4-dihydro-2,6-
dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate
calcium channel blocker

vatanidipine (4RS)-2,6-diméthyl-4-(3-nitrophény])-1,4-dihydropyridine-3,5-dicarboxylate
de 2-[4-[4-(diphénylrnéthyl)pipérazin-1-y]]phényl]éthyle et de méthyle
antagoniste des canaux calciques

vatanidipino 1,4-dihidro-2,6-dimetil-4-(m-nitrofenil)-3,5-piridinadicarboxilato de (±)-p-[4-

(difenilmetil)-1-piperazinil]fenetilo y metilo
antagonista del calcio

C41H42N4O6 116308-55-5

and enantiomer
et l'énantiomère
y enantiámero

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AMENDMENTS TO PREVIOUS LISTS

Proposed International Nonproprietary Names (Prop. INN): List 64

(WHO Drug Information, Vol. 4, No. 4, 1990)

p. 8 dalteparinum natricum replace the definition by the following:

daltepann sodium
Sodium salt of a low molecular mass heparin that is obtained by nitrous acid
depolymerization of heparin from porcine intestinal mucosa; the majority of
the components have a 2-Osulfo-α-L-idopyranosuronic acid structure at the
non-reducing end and a 6-O-sulfo-2,5-anhydro-D-mannitol structure at the
reducing end of their chain, the mass-average molecular mass ranges
between 5600 and 6400 with a characteristic value of about 6000; the
degree of sulfatation is 2.0 to 2.5 per disaccharidic unit.

Proposed International Nonproprietary Names (Prop. INN): List 65

(WHO Drug Information, Vol. 5, No. 2, 1992)

p. 27 enoxaparinum natricum replace the definition by the following:

enoxaparin sodium
Sodium salt of a low molecular mass heparin that is obtained by alkaline
depolymerization of the benzyl ester derivative of heparin from porcine
intestinal mucosa; the majority of the components have a 2-O-sulfo-4-
desoxy-4-α-L-threo-hex-4-enopyranosuronic acid structure at the non-
reducing end of their chain; the mass-average molecular mass ranges
between 3500 and 5500 with a characteristic value of about 4500, the
degree of sulfatation is about 2 per disaccharidic unit.

p 18 nadroparinum calcium replace the definition by the following:

nadroparin calcium
Calcium salt of a low molecular mass heparin obtained by nitrous acid
depolymerization of heparin from pork intestinal mucosa, followed by
fractionation to eliminate selectively most of the chains with a molecular
mass lower than 2000; the majority of the components have a 2-O-sulfo-
α-L-idopyranosuronic acid structure at the non-reducing end and a 6-O-sulfo-
2,5-anhydro-D-mannitol structure at the reducing end of their chain; the
mass-average molecular mass ranges between 3600 and 5000 with a
characteristic value of about 4300; the degree of sulfatation is about 2 per
disaccharidic unit.

p 18 pamaparinum natricum replace the definition by the following:

parnaparim sodium
Sodium salt of a low molecular mass heparin that is obtained by radical-
catalyzed depolymerization, with hydrogen peroxide and with a cupric salt, of
heparin from bovine or pork intestinal mucosa; the majority of the compo­
nents have a 2-O-sulfo-α-L-idopyranosuronic acid structure at the non-
reducing end and a 2-N,6-O-disulfo-D-glucosamine structure at the reducing

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end of their chain; the mass-average molecular mass ranges between 4000
and 6000 with a characteristic value of about 5000; the degree of sulfatation
is 2.0 to 2.6 per disaccharidic unit

p. 18 tinzaparinum natricum replace the definition by the following:

tinzaparin sodium Sodium salt of a low molecular mass heparin that is obtained by controlled
enzymatic depolymerization of heparin from porcine intestinal mucosa using
heparinase from Flavobacterium heparinum; the majority of the components
have a 2-O-sulfo-4-desoxy-4-α-L-threo-hex-4-enopyranosuronic acid
structure at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine
structure at the reducing end of their chain, the mass-average molecular
mass ranges between 5500 and 7500 with a characteristic value of about
6500; the degree of sulfatation is 1.8 to 2.5 per disaccharidic unit

Proposed International Nonproprietary Names (Prop. INN): List 71

Dénominations communes internationales proposées (DCI Prop.): Liste 71

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 71

(WHO Drug information, Vol. 8, No. 2, 1994)

p. 15 itamelinum
itameline replace the chemical name by the following.
(E)-p-chlorophenyl 3-formyl-5,6-dihydro-1(2H)-pyridinecarbaxylate,
O-methyloxirne
itamelina sustituyase el nombre químico por lo siguiente:
3-formil-5,6-dihidro-1 (2H)-piridinacarboxilato de (E)- p-clorofenilo,
O-metiloxima

Proposed International Nonproprietary Names (Prop. INN): List 72

Dénominations communes internationales proposées (DCI Prop.): Liste 72

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 72

(WHO Drug information, Vol. 8, No. 4, 1994)

p. 11 eptacogum alfa (activatum)

eptacog alfa (activated) replace the molecular formula and CAS registry number by the following.
eptacog alfa (activé) remplacer la formule brute et le numéro dans le registre de CAS p a r .
eptacog alfa (activado) sustituyase la fórmula empírica y el número de registro del CAS por.

C1982H3054N560O618S28 102786-61-8

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Proposed INN List 77 WHO Drug Information, Vol. 11, No. 2, 1997

Proposed International Nonproprietary Names (Prop. INN): List 73

Dénominations communes internationales proposées (DCI Prop.): Liste 73
Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 73
(WHO Drug Information, Vol. 9, No. 2, 1995)

p.20 thymalfasinum
thymalfasin replace the molecular formula by the following.
thymalfasine remplacer la formule brute par la suivante:
timalfasina sustituyase la fórmula empírica por:

C129H215N33O55

Proposed International Nonproprietary Names (Prop. INN): List 74

Dénominations communes internationales proposées (DCI Prop.): Liste 74
Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 74
(WHO Drug Information, Vol. 9, No. 4, 1995)

p. 3 acidum ranelicum
ranelic acid replace the CAS registry number by the following:
acide ranélique remplacer le numéro dans le registre du CAS par le suivant:
ácido ranélico sustituyase el número del registro del CAS por el siguiente:
135459-90-4

p. 14 fexofenadinum
fexofenadine replace the CAS registry number by the following:
fexofénadine remplacer le numéro dans le registre du CAS par le suivant:
fexofenadina sustituyase el número del registro del CAS por el siguiente:
83799-24-0

p 16 igovomabum
igovomab replace the description by the following:
immunoglobulin G 1 (mouse monoclonal OC125 F(ab')2 F(ab')2fragment
anti-human ovarian cancer antigen CA 125), disulfide with mouse mono­
clonal OC125 F(ab')2 light chain
igovomab remplacer la description par la suivante:
fragment F(ab')2 de l'anticorps monoclonal OC 125 F(ab')2 dirigé contre
l'antigène CA 125 associé à certaines tumeurs ovariennes
igovomab sustituyase la descripción por la siguiente:
fragmento F(ab')2 del anticuerpo monoclonal OC 125 F(ab')2 anti-antígeno
CA 125 asociado a ciertos tumores ováricos

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W H O Drug Information, Vol. 1 1 , No. 2, 1997 Proposed INN: List 77

p.23 palonosetronum
palonosetron replace the chemical name, the molecular formula and the graphic formula
by the following:
(3aS)-2,3,3a,4,5,6-hexahydro-2-[(3S)-3-quinuclidinyl]-1H-
benz[de]isoquinolin-1-one
palonosétron remplacer le nom chimique, la formule brute et la formule développée par :
(3aS)-2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-
1H-benzo[de]isoquinaléin-1-one
palonosetrón sustituyanse el nombre quimico, la fórmula empírica y la fórmula empírica
por.
(3aS)-2,3,3a,4,5,6-tetrahidro-2-[(3S)-3-quinucliclinil]-1H-benz[de]isoquinolin-
1-ona

C19H24N2O

Proposed International Nonproprietary Names (Prop. INN): List 75

Dénominations communes internationales proposées (DCI Prop.): Liste 75
Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 75
(WHO Drug Information, Vol. 10, No. 2, 1996)

p. 112 atliprofenum
atliprofen replace the CAS registry number by the following
atliprofène remplacer le numéro dans le registre de CAS par le suivant
atliprofeno sustituyase el número de registro del CAS por.
108912-17-0

Proposed International Nonproprietary Names (Prop. INN): List 76

Dénominations communes internationales proposées (DCI Prop.): Liste 76
Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 76
(WHO Drug Information, Vol. 10, No. 4, 1996)

p. 208 lasinavirum
lasinavir replace the graphic formula by the following:

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Proposed INN: List 77 WHO Drug Information, Vol 11, No. 2, 1997

lasinavir remplacer le nom chimique et la formule développée par:

[(1S,2S,4R)-1-benzyl-2-hydroxy-5-[[(1S)-1-[(2-méthoxyéthyl)carbamoyl]-
2-méthylpropyl]amino]-5-oxo-4-(2,3,4-triméthoxybenzyl)pentyl]carbamate de
1,1-diméthyléthyle

lasinavir sustituyase la fórmula desarrollada por:

p 218 delete/supprimer/suprimase insert/insérer/insértese

teserstigminum terestigminum
teserstigmine terestigmine
téserstigmine térestigmine
teserstigmina terestigmina

MODIFICATIONS APPORTEES AUX LISTES ANTERIEURES

Dénominations communes internationales proposées (DCI Prop.): Liste 64

(Informations pharmaceutiques OMS, Vol. 4, No. 4, 1990)

p 9 dalteparinum natricum remplacer la description par:

daltéparine sodique Sel sodique d'une héparine de basse masse moléculaire obtenue par
dépolymerisation, au moyen d'acide nitreux, d'héparine de muqueuse
intestinale de porc; la majorité des composants de la daltéparine sodique
possèdent une structure acide 2-O-sulfo-α-L-idopyranosuronique à
l'extrémité non réductrice de leur chaîne et une structure 6-O-sulfo-2,5-
anhydro-D-mannitol à l'extrémité réductrice de leur chaîne, la masse
moléculaire relative moyenne est de 5600 à 6400, avec une valeur
caractéristique de 6000 environ; le degré de sulfatation est de 2.0 à 2.5 par
unité disaccharidique.

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W H O Drug Information. Vol. 1 1 , No. 2, 1997
p. 18 nadroparinum calcicum
nadroparine calcique
p. 29 enoxaparinum natricum
énoxaparine sodique
Dénominations communes internationales proposées (DCI Prop.): Liste 65
(Informations pharmaceutiques OMS, Vol. 5, No, 2, 1991)
p. 13 tinzaparinum natricum
tinzaparine sodique
parnaparinum natricum
parnaparine sodique
Proposed INN: List 77
remplacer la description par:
Sel calcique d'une héparine de basse masse moléculaire obtenue par
dépolymerisation, au moyen d'acide nitreux, d'héparine de muqueuse
intestinale de porc puis fractionnement visant à éliminer sélectivement la
majeure partie des chaînes de masse moleculaire inférieure à 2000; la
majorité des composants de la nadroparine calcique possèdent une
structure acide 2-O-sulfo-α-L-idopyranosuronique à l'extrémité non
réductrice de leur chaîne et une structure 6-O-sulfo-2,5-anhydro-D-mannitol
à l'extrémité réductrice de leur chaîne; la masse moléculaire relative
moyenne est de 3600 à 5000, avec une valeur caractéristique de 4300
environ; le degré de sulfatation est de 2 par unité disaccharidique.
remplacer la description par
Sel sodique d'une héparine de basse masse moléculaire obtenue par
dépolymerisation alcaline de l'ester benzylique d'héparine de muqueuse
intestinale de porc; la majorité des composants de l'énoxaparine sodique
possèdent une structure acide 2-O-sulfo-4-désoxy-4-α-L-threo-hex-4-
énopyranosuronique à l'extrémité non réductrice de leur chaîne; la masse
moléculaire relative moyenne est de 3500 à 5500, avec une valeur
caractéristique de 4500 environ; le degré de sulfatation est de 2 par unité
disaccharidique.
remplacer la description par:
Sel sodique d'une héparine de basse masse moléculaire obtenue par
dépolymerisation enzymatique controlée, au moyen de l'héparinase de
Flavobacterium heparinum, d'héparine de muqueuse intestinale de porc, la
majorité des composants de la tinzaparine sodique possèdent une structure
acide 2-O-sulfo-4-desoxy-4-α-L-thréo-hex-4-énopyranosuranique à
l'extrémité non réductrice de leur chaîne et une structure 6-N.6-O-disulfo-D-
glucosamine à l'extrémité réductrice de leur chaîne; la masse moléculaire
relative moyenne est de 5500 a 7500. avec une valeur caractéristique de
6500 environ, le degré de sulfatation est de 1.8 à 2.5 par unité
disaccharidique.
remplacer la description par
Sel sodique d'une héparine de basse masse moléculaire obtenue par
dépolymerisation à catalyse radicalaire au moyen de peroxyde
d'hydrogène et d'un sel de cuivre d'héparine de muqueuse intestinale de
boeuf ou de porc; la majorité des composants de la parnaparine sodique
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Proposed INN: List 77 WHO Drug Information, Vol. 11, No 2, 1997

possèdent une structure acide 2-O-sulfo-α-L-idopyranosuronique à

l'extrémité non réductrice de leur chaîne et une structure 2N,6-N,6-O-
disulfo-D-glucosamine à l'extrémité réductrice de leur chaîne; la masse
moléculaire relative moyenne est de 4000 à 6000, avec une valeur
caractéristique de 5000 environ; le degré de sulfatation est de 2.0 à 2.6 par
unité disaccharidique.

Pour toutes modifications apportées aux Dénominations communes internationales proposées (DCI Prop.): Listes
71 -76 voir page 104, section AMENDMENTS TO PREVIOUS LISTS.

MODIFICACIONES A LAS LISTAS ANTERIORES

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 64
(Información Farmacéutica, OMS, Vol. 4, No. 4, 1990)

p. 8 dalteparinum natricum sustituyase la descripción por la siguiente:

dalteparina sódica
Sal sódica de una heparina de baja masa molecular obtenida por
despolimenzación con ácido nitroso de la heparina de la mucosa intestinal
de cerdo; la mayoria de los componentes tienen una estructura de ácido 2-
O-sulfo-α-L-idopiranosurónico en el extremo no reductor y una estructura de
6-O-sulfo-2,5-anhidro-D-mannitol en el extremo reductor de la cadena; la
masa molecular relativa media es de 5600 a 6400, con un valor
caracteristico de 6000 aproximadamente; el grado de sulfatación es de 2.0 a
2.5 por unidad de disacárido.

p. 17 nadroparinum calcicum sustituyase la descripción por la siguiente:

nadroparina cálcica Sal cálcica de una heparina de baja masa molecular obtenida por
despolimerización con ácido nitroso de la heparina de la mucosa intestinal
de cerdo seguida del fraccionamiento a fin de eliminar selectivamente la
mayor parte de las cadenas de masa molecular inferior a 2000; la mayoría
de los componentes tienen una estructura de ácido 2-O-sulfo-α-L-
idopiranosurónico en el extremo no reductor y una estructura de 6-O-sulfo-
2,5-anhidro-D-manitol en el extremo reductor de la cadena; la masa
molecular relativa media es de 3600 a 5000, con un valor caracteristico de
4300 aproximadamente; el grado de sulfatación es de 2 por unidad de
disacárido.

p. 27 enoxaparinnum natricum sustituyase la descripción por la siguiente:

enoxaparina sódica Sal sódica de una heparina de baja masa molecular obtenida por
despolimerización alcalina del éster bencilico de la heparina de la mucosa
intestinal de cerdo; la mayona de los componentes tienen una estructura de
ácido 2-O-5ulfo-4-desoxi-4-α-L-threo-hex-4-enopiranosuronico en el extremo
no reductor en el extremo reductor de la cadena; la masa molecular relativa

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WHO Drug Information, Vol. 11. No. 2, 1997 Proposed INN: List 77

media es de 3500 a 5500, con un valor caracteristico de 4500

aproximadamente; el grado de sulfatación es de 2 por unidad de disacárido.

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 65

(Información Farmacéutica, OMS, Vol. 5, No. 2, 1991)

p. 8 tinzaparinum natricum sustituyase la descripción por la siguiente:

tinzaparina sódica
Sal sodica de una heparina de baja masa molecular obtenida por
despolimenzación enzimatica controlada con heparinasa de Flavobacterium
heparinum de la heparina de la mucosa intestinal de cerdo, la mayoria de los
componentes tienen una estructura de ácido 2-O-sulfo-4-desoxy-4-α-L-threo-
hex-4-enopiranosurónico en el extremo no reductor y una estructura de 6-
O-6-N-disulfo-D-glucosamina en el extremo reductor de la cadena; la masa
molecular relativa media es de 5500 a 7500, con un valor caracteristico de
6500 aproximadamente, el grado de sulfatación es de 1.8 a 2.5 por unidad
de disacárido.

p. 16 parnaparinum natricum sustituyase la descripción por la siguiente:

parnaparina sódica
Sal sódica de una heparina de baja masa molecular obtenida por
despolimenzación con peróxido de hidrógeno y un sal de cobre de la
heparina de la mucosa intestinal de buey o de cerdo; la mayoria de los
componentes tienen una estructura de ácido 2-O-sulfo-α-L-idopiranosurónico
en el extremo no reductor y una estructura de 6-O-6-N-disulfo-D-
glucosamina en el extremo reductor de la cadena; la masa molecular relativa
media es de 4000 a 6000, con un valor característico de 5000
aproximadamente; el grado de sulfatación es de 2 0 a 2.6 por unidad de
disacárido.

Para cualquier modificación de las Denominaciones Comunes Internacionales Propuestas (DCI Prop.):
Listas 71-76 vease pagina 104, sección AMENDMENTS TO PREVIOUS LISTS.

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Annex 1
PROCEDURE FOR THE SELECTION OF RECOMMENDED INTERNATIONAL
NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES*
The following procedure shall be followed by the World Health Organization in the selection of recommended interna­
tional nonproprietary names for pharmaceutical substances, in accordance with the World Health Assembly resolution
WHA3.11:

1. Proposals for recommended international nonproprietary names shall be submitted to the World Health Organization
on the form provided therefor.

2. Such proposals shall be submitted by the Director-General of the World Health Organization to the members of the
Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations designated for this
purpose, for consideration in accordance with the "General principles for guidance in devising International Nonpropri­
etary Names", appended to this procedure. The name used by the person discovering or first developing and marketing
a pharmaceutical substance shall be accepted, unless there are compelling reasons to the contrary.

3. Subsequent to the examination provided for in article 2, the Director-General of the World Health Organization shall
give notice that a proposed international nonproprietary name is being considered.

A. Such notice shall be given by publication in the Chronicle of the World Health Organization1 and by letter to
Member States and to national pharmacopoeia commissions or other bodies designated by Member States.

(i) Notice may also be sent to specific persons known to be concerned with a name under consideration.

B. Such notice shall:

(i) set forth the name under consideration;

(ii) identify the person who submitted a proposal for naming the substance, if so requested by such person;

(iii) identify the substance for which a name is being considered;

(iv) set forth the time within which comments and objections will be received and the person and place to whom
they should be directed;

(v) state the authority under which the World Health Organization is acting and refer to these rules of proce­
dure.

C. In forwarding the notice, the Director-General of the World Health Organization shall request that Member States
take such steps as are necessary to prevent the acquisition of proprietary rights in the proposed name during the
period it is under consideration by the World Health Organization.

4. Comments on the proposed name may be forwarded by any person to the World Health Organization within four
months of the date of publication, under article 3, of the name in the Chronicle of the World Health Organization '

5. A formal objection to a proposed name may be filed by any interested person within four months of the date of
publication, under article 3, of the name in the Chronicle of the World Health Organization.1

A. Such objection shall:

(i) identify the person objecting;

* Text adopted by the Executive Board of WHO in resolution EB15.R7(Off Rec Wld Health Org, 1955, 60, 3) and amended by the Board
in resolution EB43.R9 (Off Rec. Wld Hlth Org., 1969, 173,10)
1
The title of this publication was changed to WHO Chronicle in January 1959 From 1987 onwards lists of INNs are published in WHO
Drug Information

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WHO Drug Information, Vol. 11, No. 2, 1997 Proposed INN List 77

(ii) state his interest in the name;

(iii) set forth the reasons for his objection to the name proposed.

6. Where there is a formal objection under article 5, the World Health Organization may either reconsider the proposed
name or use its good offices to attempt to obtain withdrawal of the objection Without prejudice to the consideration by
the World Health Organization of a substitute name or names, a name shall not be selected by the World Health
Organization as a recommended international nonproprietary name while there exists a formal objection thereto filed
under article 5 which has not been withdrawn.

7. Where no objection has been filed under article 5, or all objections previously filed have been withdrawn, the
Director-General of the World Health Organization shall give notice in accordance with subsection A of article 3 that the
name has been selected by the World Health Organization as a recommended international nonproprietary name.

8. In forwarding a recommended international nonproprietary name to Member States under article 7, the Director-
General of the World Health Organization shall:

A. request that it be recognized as the nonproprietary name for the substance; and

B. request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the
name, including prohibiting registration of the name as a trade-mark or trade-name.

Annex 2
GENERAL PRINCIPLES FOR GUIDANCE IN DEVISING INTERNATIONAL
NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES*
1. International Nonproprietary Names (INN) should be distinctive in sound and spelling. They should not be inconve­
niently long and should not be liable to confusion with names in common use.

2. The INN for a substance belonging to a group of pharmacologically related substances should, where appropriate,
show this relationship. Names that are likely to convey to a patient an anatomical, physiological, pathological or
therapeutic suggestion should be avoided.

These primary principles are to be implemented by using the following secondary principles:

3. In devising the INN of the first substance in a new pharmacological group, consideration should be given to the
possibility of devising suitable INN for related substances, belonging to the new group.

4. In devising INN for acids, one-word names are preferred; their salts should be named without modifying the acid
name, e.g. "oxacillin" and "oxacillin sodium", "ibufenac" and "ibufenac sodium"'.

5. INN for substances which are used as salts should in general apply to the active base or the active acid. Names for
different salts or esters of the same active substance should differ only in respect of the name of the inactive acid or
the inactive base.

For quaternary ammonium substances, the cation and anion should be named appropriately as separate components
of a quaternary substance and not in the amine-salt style.

6. The use of an isolated letter or number should be avoided; hyphenated construction is also undesirable.

* In its twentieth report (WHO Technical Report Series, No. 581, 1975), the WHO Expert Committee on Nonproprietary Names for
Pharmaceutical Substances reviewed the general principles for devising, and the procedures for selecting, international nonproprietary
names (INN) in the light of developments in pharmaceutical compounds in recent years. The most significant change has been the
extension to the naming of synthetic chemical substances of the practice previously used for substances originating in or derived from
natural products. This practice involves employing a characteristic "stem" indicative of a common property of the members of a group
The reasons for, and the implications of, the change are fully discussed.

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Proposed INN: List 77 WHO Drug Information, Vol. 11, No. 2, 1997

7 To facilitate the translation and pronunciation of INN, "f" should be used instead of "ph", "t" instead of "th", "e" instead
of "ae" or "oe", and "i" instead of "y"; the use of the letters "h" and "K" should be avoided.

8. Provided that the names suggested are in accordance with these principles, names proposed by the person
discovering or first developing and marketing a pharmaceutical preparation, or names already officially in use in any
country, should receive preferential consideration.

9. Group relationship in INN (see Guiding Principle 2) should if possible be shown by using a common stem. The
following list contains examples of stems for groups of substances, particularly for new groups. There are many other
stems in active use.1 Where a stem is shown without any hyphens it may be used anywhere in the name.

Latin English

-acum -ac anti-inflammatory agents of the ibufenac group

-actidum -actide synthetic polypeptides with a corticotropin-like action
-adolum -adol )
analgesics
-adol- -adol- )
-astum -ast antiasthmatic, antiallergic substances not acting primarily as antihistaminics
-astinum -astine antihistamics
-azepamum -azepam diazepam derivatives
-bactamum -bactam β-lactamase inhibitors
bol bol steroids, anabolic
-buzonum -buzone anti-inflammatory analgesics, phenylbutazone derivatives
-cain- -cain- antifibrillant substances with local anaesthetic activity
-cainum -caine local anaesthetics
cef- cef- antibiotics, cefalosporanic acid derivatives
-cillinum -cillin antibiotics, derivatives of 6-aminopenicillanic acid
-conazolum -conazole systemic antifungal agents, miconazole derivatives
cort cort corticosteroids, except prednisolone derivatives
-dipinum -dipine calcium channel blockers, nifedipine derivatives
-fibratum -fibrate clofibrate derivatives
gest gest steroids, progestogens
gli- gli- sulfonamide hypoglycaemics
io- io- iodine-containing contrast media
-ium -ium quaternary ammonium compounds
-metacinum -metacin anti-inflammatory substances, indometacin derivatives
-mycinum -mycin antibiotics, produced by Streptomyces strains
-nidazolum -nidazole antiprotozoal substances, metronidazole derivatives
-ololum -olol β-adrenoreceptor antagonists
-oxacinum -oxacin antibacterial agents, nalidixic acid derivatives
-pridum -pride sulpiride derivatives
-pril(at)um pril(at) angiotensin-converting enzyme inhibitors
-profenum -profen anti-inflammatory substances, ibuprofen derivatives
prost prost prostaglandins
-relinum -relin hypophyseal hormone release-stimulating peptides
-terolum -terol bronchodilators, phenethylamine derivatives
-tidinum -tidine histamine H2-receptor antagonists
-trexatum -trexate folic acid antagonists
-verinum -verine spasmolytics with a papaverine-like action
vin- vin- ) vinca alkaloids
-vin- -vin- )

1
A more extensive listing of stems is contained in the working document Pharm. S/Nom. 15 which is regularly updated and can be
requested from Pharmaceuticals, WHO, Geneva

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W H O Drug Information, Vol 1 1 , No. 2, 1997 Proposed INN: List 77

Annexe 1

PROCEDURE A SUIVRE EN VUE DU CHOIX DE

DENOMINATIONS COMMUNES INTERNATIONALES
RECOMMANDEES POUR LES SUBSTANCES PHARMACEUTIQUES*
L'Organisation mondiale de la Santé observe la procédure exposée ci-dessous pour l'attribution de dénominations
communes internationales recommandées pour les substances pharmaceutiques, conformément à la résolution
WHA3 11 de l'Assemblée mondiale de la Santé:

1. Les propositions de dénominations communes internationales recommandées sont soumises à l'Organisation

mondiale de la Santé sur la formule prévue à cet effet.

2. Ces propositions sont soumises par le Directeur général de l'Organisation mondiale de la Santé aux experts
désignés à cette fin parmi les personnalités inscrites au Tableau d'experts de la Pharmacopée internationale et des
Préparations pharmaceutiques; elles sont examinées par les experts conformément aux "Directives générales pour
la formation des dénominations communes internationales", reproduites ci-après. La dénomination acceptée est la
dénomination employée par la personne qui découvre ou qui, la première, fabrique et lance sur le marché une
substance pharmaceutique, à moins que des raisons majeures n'obligent à s'écarter de cette règle

3. Après l'examen prévu à l'article 2, le Directeur général de l'Organisation mondiale de la Santé notifie qu'un projet
de dénomination commune internationale est à l'étude.

A. Cette notification est faite par une insertion dans la Chronique de l'Organisation mondiale de la Santé1 et par
l'envoi d'une lettre aux Etats Membres et aux commissions nationales de pharmacopée ou autres organismes
désignés par les Etats Membres

(i) Notification peut également être faite à toute personne portant à la dénomination mise à l'étude un
intérêt notaire.

B Cette notification contient les indications suivantes

(i) dénomination mise à l'étude;

(ii) nom de l'auteur de la proposition tendant à attribuer une dénomination à la substance, si cette personne
le demande;

(m) définition de la substance dont la dénomination est mise à l'étude,

(iv) délai pendant lequel seront reçues les observations et les objections à l'égard de cette dénomination;
nom et adresse de la personne habilitée à recevoir ces observations et objections;

(v) mention des pouvoirs en vertu desquels agit l'Organisation mondiale de la Santé et référence au présent
règlement.

C. En envoyant cette notification, le Directeur général de l'Organisation mondiale de la Santé demande aux
Etats Membres de prendre les mesures nécessaires pour prévenir l'acquisition de droits de propriété sur la
dénomination proposée pendant la période au cours de laquelle cette dénomination est mise à l'étude par
l'Organisation mondiale de la Santé.

4. Des observations sur la dénomination proposée peuvent être adressées à l'Organisation mondiale de la Santé
par toute personne, dans les quatre mois qui suivent la date de publication de la dénomination dans la Chronique de
l'Organisation mondiale de la Santé1 (voir l'article 3).

* Le texte reproduit ici a été adopté par le Conseil exécutif dans la résolution EB15.R7 (Actes off. Org. mond. Santé, 1955, 60, 3) qui
l'a ultérieurement amendé par la resolution EB43.R9 (Actes off. Org. mond. Santé, 1969,173, 10).
1
Depuis janvier 1959, cette publication porte le titre de Chronique OMS A partir de 1987, les listes des DCIs sont publiées dans les
Informations pharmaceutiques OMS

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5 Toute personne intéressée peut formuler une objection formelle contre la dénomination proposée dans les quatre
mois qui suivent la date de publication de la dénomination dans la Chronique de l'Organisation mondiale de la
Santé1 (voir l'article 3).

A. Cette objection doit s'accompagner des indications suivantes

i) nom de l'auteur de l'objection;

ii) intérêt qu'il porte à la dénomination en cause;

iii) raisons motivant l'objection contre la dénomination proposée.

6. Lorsqu'une objection formelle est formulée en vertu de l'article 5, l'Organisation mondiale de la Santé peut soit
soumettre la dénomination proposée à un nouvel examen, soit intervenir pour tenter d'obtenir le retrait de l'objection.
Sans préjudice de l'examen par elle d'une ou de plusieurs appellations de remplacement, l'Organisation mondiale de
la Santé n'adopte pas d'appellation comme dénomination commune internationale recommandée tant qu'une
objection formelle présentée conformément à l'article 5 n'est pas levée.

7. Lorsqu'il n'est formulé aucune objection en vertu de l'article 5 ou que toutes les objections présentées ont été
levées, le Directeur général de l'Organisation mondiale de la Santé fait une notification conformément aux disposi­
tions de la sous-section A de l'article 3, en indiquant que la dénomination a été choisie par l'Organisation mondiale
de la Santé en tant que dénomination commune internationale recommandée.

8. En communiquant aux Etats Membres, conformément à l'article 7, une dénomination commune internationale
recommandée, le Directeur général de l'Organisation mondiale de la Santé:

A. demande que cette dénomination soit reconnue comme dénomination commune de la substance considérée,
et

B. demande aux États Membres de prendre les mesures nécessaires pour prévenir l'acquisition de droits de
propriété sur cette dénomination, notamment en interdisant le dépôt de cette dénomination comme marque
ou appellation commerciale.

Annexe 2
DIRECTIVES GENERALES POUR LA FORMATION DE DENOMINATIONS
COMMUNES INTERNATIONALES APPLICABLES AUX
SUBSTANCES PHARMACEUTIQUES*

1. Les dénominations communes internationales (DCI) devront se distinguer les unes des autres par leur conso­
nance et leur orthographe. Elles ne devront pas être d'une longueur excessive, ni prêter à confusion avec des
appellations déjà couramment employées.

2. La DCI de chaque substance devra, si possible, indiquer sa parenté pharmacologique. Les dénominations sus­
ceptibles d'évoquer pour les malades des considérations anatomiques, physiologiques, pathologiques ou théra­
peutiques devront être évitées dans la mesure du possible.

Outre ces deux principes fondamentaux, on respectera les principes secondaires suivants:

* Dans son vingtième rapport (Série de Rapports techniques de l'OMS, No 581, 1975), le Comité OMS d'experts des Denominations
communes pour les Substances pharmaceutiques a examiné les directives générales pour la formation des dénominations communes
internationales et la procedure à suivre en vue de leur choix, compte tenu de l'évolution du secteur pharmaceutique au cours des
dernières années. La modification la plus importante a été l'extension aux substances de synthese de la pratique normalement suivie pour
désigner les substances tirées ou dérivées de produits naturels. Cette pratique consiste a employer des syllabes communes ou groupes
de syllabes communes (segments clés) qui sont caracteristiques et indiquent une propriété commune aux membres du groupe des
substances pour lequel ces segments clés ont été retenus Les raisons et les conséquences de cette modification ont fait l'objet de
discussions approfondies

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3. Lorsqu'on formera la DCI de la première substance d'un nouveau groupe pharmacologique, on tiendra compte de
la possibilité de former ultérieurement d'autres DCI appropriées pour les substances apparentées du même groupe.

4. Pour former des DCI des acides, on utilisera de préférence un seul mot. Leurs sels devront être désignés par un
terme qui ne modifie pas le nom de l'acide d'origine: par exemple "oxacilline" et "oxacilline sodique", "ibufénac" et
"ibufénac sodique".

5. Les DCI pour les substances utilisées sous forme de sels devront en général s'appliquer à la base active (ou à
l'acide actif). Les dénominations pour différents sels ou esters d'une même substance active ne différeront que par
le nom de l'acide inactif (ou de la base inactive).

En ce qui concerne les substances à base d'ammonium quaternaire, la dénomination s'appliquera de façon
appropriée au cation et à l'anion en tant qu'éléments distincts d'une substance quaternaire. On évitera de choisir
une désignation évoquant un sel aminé.

6. On évitera d'ajouter une lettre ou un chiffre isolé; en outre, on renoncera de préférence au trait d'union.

7 Pour simplifier la traduction et la prononciation des DCI, la lettre "f" sera utilisée à la place de "ph", "t" à la place
de "th", "e" à la place de "ae" ou "oe" et "i" à la place de "y"; l'usage des lettres "h" et "k" sera aussi évité.

8 On retiendra de préférence, pour autant qu'elles respectent les principes énoncés ici, les dénominations
proposées par les personnes qui ont découvert ou qui, les premières, ont fabriqué et lancé sur le marché les
préparations pharmaceutiques considérées, ou les dénominations déjà officiellement adoptées par un pays.

9. La parenté entre substances d'un même groupe (voir Directive générale 2) sera si possible indiquée dans les DCI
par l'emploi de segments clés communs. La liste ci-après contient des exemples de segments clés pour des
groupes de substances, surtout pour des groupes récents. Il y a beaucoup d'autres segments clés en utilisation
active.1 Les segments clés indiqués sans trait d'union pourront être insérés n'importe où dans une dénomination.

Latin Français

-acum -ac substances anti-inflammatoires du groupe de l'ibufénac

-actidum -actide polypeptides synthétiques agissant comme la corticotropine
-adolum -adol ) analgésiques
-adol- -adol- )
-astum -ast antiasthmatiques, antiallergiques n'agissant pas principalement en tant
qu'antihistaminiques
-astinum -astine antihistaminiques
-azepamum -azépam substances du groupe du diazepam
-bactamum -bactame inhibiteurs de fi - lactamases
bol bol stéroïdes anabolisants
-buzonum -buzone analgésiques anti-inflammatoires du groupe de la phenylbutazone
-cain- -cain- substances antifibriIIantes à action anesthésique locale
-cainum -caine anesthésiques locaux
cef- céf- antibiotiques, dérivés de l'acide céphalosporanique
-cillinum -cilline antibiotiques, dérivés de l'acide 6-aminopénicillanique
-conazolum -conazole agents antifongiques systémiques du groupe du miconazole
cort cort corticostéroides, autres que les dérivés de la prednisolone
-dipinum -dipine inhibiteurs du calcium du groupe de la nifedipine
-fibratum -fibrate substances du groupe du clofibrate
gest gest stéroïdes progestogènes
gli- gli- sulfamides hypoglycémiants
io- io- produits de contraste iodés
-ium -ium ammoniums quaternaires
-rnetacinum -métacine substances anti-inflammatoires du groupe de l'indométacine
-mycinum -mycine antibiotiques produits par des souches de Streptomyces
-nidazolurr -nidazole substances antiprotozoaires du groupe du métronidazole

1
Une liste plus complète de segments clés est contenue dans le document de travail Pharm S/Nom.15 qui est régulièrement mis à jour et
qui peut être demandé auprès de l'Unité pharmaceutique. OMS, Genève.

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Latin Français

ololum -olol antagonistes des récepteurs β-adrénergiques

-oxacinum -oxacine substances antibactériennes du groupe de l'acide nalidixique
-pridum -pride substances du groupe du sulpiride
-profenum -profène substances anti-inflammatoires du groupe de l'ibuprofène
-pril(at)um -pril(ate) inhibiteurs de l'enzyme de conversion de l'angiotensine
prost prost prostaglandines
-relinum -réline peptides stimulant la libération d'hormones hypophysaires
-terolum -térol bronchodilatateurs, dérivés de la phénéthylamine
-tidinum -tidine antagonistes des récepteurs H2 de l'histamine
-trexatum -trexate antagonistes de l'acide folique
-verinum -vérine spasmolytiques agissant comme la papavérine
vin- vin- ) alcaloides du type vinca
-vin- -vin- )

Anexo 1

PROCEDIMIENTO DE SELECCION DE DENOMINACIONES COMUNES

INTERNACIONALES RECOMENDADAS PARA LAS SUSTANCIAS FARMACEUTICAS*

La Organización Mundial de la Salud seguirá el procedimiento que se expone a continuación para la selección de
denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas, de conformidad con lo
dispuesto en la resolución WHA3.11 de la Asamblea Mundial de la Salud:

1. Las propuestas de denominaciones comunes internacionales recomendadas se presentarán a la Organización

Mundial de la Salud en los formularios que se proporcionen a estos efectos.

2 Estas propuestas serán sometidas por el Director General de la Organización Mundial de la Salud a los Miembros
del Cuadro de Expertos de la Farmacopea Internacional y las Preparaciones Farmacéuticas encargados de su
estudio, para que fas examinen de conformidad con los "Principios Generales de Orientación para formar
Denominaciones Comunes Internacionales para Sustancias Farmacéuticas", anexos a este Procedimiento. A
menos que haya poderosas razones en contra, la denominación aceptada será la empleada por la persona que
haya descubierto, fabricado o puesto a la venta por primera vez una sustancia farmacéutica.

3. Una vez terminado el estudio a que se refiere el artículo 2, el Director General de la Organización Mundial de la
Salud notificará que está en estudio un proyecto de denominación internacional.

A. Esta notificación se hará mediante una publicación en la Crónica de la Organización Mundial de la Salud1 y el
envío de una carta a los Estados Miembros y a las comisiones nacionales de las farmacopeas u otros
organismos designados por los Estados Miembros.

(i) La notificación puede enviarse también a las personas que tengan un interés especial en una
denominación objeto de estudio.

* El texto corregido que aquí se reproduce fue adoptado por el Consejo Ejecutivo en la resolución EB15.R7 (Act. of Org mund Salud,
1955, 60, 3) y enmendado por el Consejo en la resolución EB43.R9 (Act of Org. mund. Salud, 1969, 173, 10)
1
Denominada Crónica de la OMS desde enero de 1959. A partir de 1987, las listas de DCI se publican en Información Farmacéutica
OMS.

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B. En estas notificaciones se incluyen los siguientes datos:

(i) denominación sometida a estudio;

(ii) nombre de la persona que ha presentado la propuesta de denominación de la sustancia si lo pide

esta persona;

(iii) definición de la sustancia cuya denominación está en estudio;

(iv) plazo fijado para recibir observaciones y objeciones, así como nombre y dirección de la
persona a quien deban dirigirse, y

(v) mención de los poderes conferidos para el caso a la Organización Mundial de la Salud y
referencia al presente procedimiento.

C Al enviar esta notificación, el Director General de la Organización Mundial de la Salud solicitará de los Estados
Miembros la adopción de todas las medidas necesarias para impedir la adquisición de derechos de propiedad
sobre la denominación propuesta, durante el periodo en que la Organización Mundial de la Salud tenga en
estudio esta denominación.

4. Toda persona puede formular a la Organización Mundial de la Salud observaciones sobre la denominación
propuesta, dentro de los cuatro meses siguientes a su publicación en la Crónica de la Organización Mundial de la
Salud, conforme a lo dispuesto en el artículo 3.

5. Toda persona interesada puede presentar una objeción formal contra la denominación propuesta, dentro de los
cuatro meses siguientes a su publicación en la Crónica dé la Organización Mundial de la Salud, conforme a lo
dispuesto en el artículo 3.

A. Esta objeción deberá acompañarse de los siguientes datos:

i) nombre de la persona que formula la objeción;

ii) causas que motivan su interés por la denominación, y

iii) causas que motivan su objeción a la denominación propuesta

6. Cuando se haya presentado una objeción formal en la forma prevista en el artículo 5, la Organización Mundial de
la Salud puede someter a nuevo estudio la denominación propuesta, o bien utilizar sus buenos oficios para lograr
que se retire la objeción. Sin perjuicio de que la Organización Mundial de la Salud estudie una o varias
denominaciones en sustitución de la primitiva, ninguna denominación podrá ser seleccionada por la Organización
Mundial de la Salud como denominación común internacional recomendada en tanto que exista una objeción formal,
presentada como previene el artículo 5, que no haya sido retirada.

7. Cuando no se haya formulado ninguna objeción en la forma prevista en el artículo 5, o cuando todas las
objeciones presentadas hayan sido retiradas, el Director de la Organización Mundial de la Salud notificará,
conforme a lo dispuesto en el párrafo A del artículo 3, que la denominación ha sido seleccionada por la
Organización Mundial de la Salud como denominación común internacional recomendada

8. Al comunicar a los Estados Miembros una denominación común internacional conforme a lo previsto en el
artículo 7, el Director General de la Organización Mundial de la Salud:

A. solicitará que esta denominación sea reconocida como denominación común para la sustancia de que se
trate, y
B. solicitará de los Estados Miembros la adopción de todas las medidas necesarias para impedir la adquisición
de derechos de propiedad sobre la denominación, incluso la prohibición de registrarla como marca de fábrica o
como nombre comercial.

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Anexo 2

PRINCIPIOS GENERALES DE ORIENTACION PARA FORMAR DENOMINACIONES

COMUNES INTERNACIONALES PARA SUSTANCIAS FARMACEUTICAS*

1. Las Denominaciones Comunes Internacionales (DCI) deberán diferenciarse tanto fonética como ortográficamente.
No deberán ser incómodamente largas, ni dar lugar a confusión con denominaciones de uso común.

2. La DCI de una sustancia que pertenezca a un grupo de sustancias farmacológicamente emparentadas deberá
mostrar apropiadamente este parentesco. Deberán evitarse los nombres que puedan inducir fácilmente en el paciente
sugestiones anatómicas, fisiológicas, patológicas o terapéuticas.

Estos principios primarios deberán ser tenidos en cuenta al aplicar los siguientes principios secundarios:

3. Al idear la DCI de la primera sustancia de un nuevo grupo farmacológico, deberá tenerse en cuenta la posibilidad
de formar DCI convenientes para las sustancias emparentadas que vengan a incrementar el nuevo grupo.

4. Al idear DCI para ácidos, se preferirán las de una sola palabra; sus sales deberán denominarse sin modificar el
nombre de ácido; p. ej., "oxacilina" y "oxacilina sódica", "ibufenaco" e "ibufenaco sódico".

5. Las DCI para las sustancias que se usan en forma de sal, deberán en general aplicarse a la base activa o,
respectivamente, al ácido activo. Las denominaciones para diferentes sales o ésteres de la misma sustancia activa
solamente deberán diferir en el nombre de ácido o de la base inactivos.

En los compuestos de amonio cuaternario, el catión y el anión deberán denominarse adecuadamente por separado,
como componentes independientes de una sustancia cuaternaria y no como sales de una amina.

6. Deberá evitarse el empleo de una letra o un número aislados; también es indeseable el empleo de guiones.

7. Para facilitar la traducción y la pronunciación se emplearán de preferencia las letras "f" en lugar de "ph", "t" en
lugar de "th", "e" en lugar de "ae" u "oe" e "i" en lugar de "y"; se deberá evitar el empleo de las letras "h" y "k".

8. Siempre que las denominaciones que se sugieran estén de acuerdo con estos principios, recibirán una
consideración preferente las denominaciones propuestas por la persona que haya descubierto la sustancia, o la que
primeramente fabrique o ponga a la venta la sustancia farmacéutica, así como las denominaciones oficialmente
adoptadas en cualquier país.

9 En las DCI, la relación de grupo o parentesco (véanse los Principios Generales de Orientación, apartado 2) se
indicará en lo posible utilizando una partícula común. En la lista siguiente se dan algunos ejemplos de estas
partículas en relación con diversos grupos de sustancias, en particular los de nuevo cuño. Hay otras muchas
partículas comunes en uso.1 Cuando la partícula no lleva ningún guión, cabe utilizarla en cualquier parte de la
denominación.

* En su 20° informe (OMS, Serie de Informes Técnicos, No. 581, 1975) el Comité de Expertos de la OMS en Denominaciones Comunes
para Sustancias Farmacéuticas examina los principios generales de orientación para formar denominaciones comunes internacionales
(DCI) y el procedimiento de selección de las mismas, teniendo en cuenta las novedades registradas en los últimos años en materia de
preparaciones Farmacéuticas. Entre las modificaciones, la más importante ha sido la extensión a las sustancias químicas sintéticas de la
práctica reservada anteriormente para designar sustancias originarias o derivadas de productos naturales. Esta práctica consiste en
emplear una partícula característica que indique una propiedad común a los miembros de un determinado grupo de sustancias En el
informe se examinan a fondo las razones de esta modificación y sus consecuencias.
1
El documento de trabajo Pharm S/Norm 15, que se pone al día regularmente, contiene una lista más extensa de partículas comunes.
Las personas que deseen recibirlo deberán solicitar su envío al Servicio de Preparaciones Farmacéuticas, OMS, Ginebra (Suiza).

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Latin Español

-acum -aco antiinflamatorios del grupo del ibufenaco

-actidum -actida polipéptidos sintéticos de acción semejante a la corticotropina
-adolum -adol }
analgésicos
-adol- -adol- }
-astum -ast antiasmáticos y antialérgicos que no actúan principalmente como antihistaminicos
-astinum -astina antihistaminicos
-azepamum -azepam sustancias del grupo del diazepam
-bactamum -bactam inhibidores de β - lactamasas
bol bol esteroides anabólizantes
-buzonum -buzona analgésicos antiinflamatorios del grupo de la fenilbutazona
-cain- -cain- antifíbrilantes con actividad anestésica local
-cainum -caina anestésicos locales
cef- cef- antibióticos derivados del ácido cefalosporánico
-cillinum -cilina antibióticos derivados del ácido 6-aminopenicilánico
-conazolum -conazol antifúngicos sistémicos del grupo del miconazol
cort cort cortícosteroides, excepto los del grupo de la prednisolona
-dipinum -dipino antagonistas del calcio del grupo del nifedipino
-fibratum -fibrato sustancias del grupo del clofibrato
gest gest esteroides progestágenos
gli- gli-
sulfonamidas hipoglucemiantes
io- io-
medios de contraste que contienen yodo
-ium -io
compuestos de amonio cuaternario
-metacinum -metacina
antiinflamatorios del grupo de la indometacina
-mycinum -micina
antibióticos, producidos por cepas de Streptomyces
-nidazolum -nidazol
antiprotozoarios del grupo del metronidazol
-ololum -olol
bloqueadores β-adrenérgicos
-oxacinum -oxacino
antibacterianos del grupo del ácido nalidíxico
-pridurn -prida
-pril(at)um -pril(at) sustancias del grupo de la sulpirida
-profenum -profeno inhibidores de la enzima transformadora de la angiotensina
prost prost antiinflamatorios del grupo del ibuprofeno
-relinum -relina prostaglandinas
-terolum -terol péptidos estimulantes de la liberación de hormonas hípofisarias
-tidinum -tidina broncodílatadores derivados de la fenetilamina
-trexatum -trexato antagonistas del receptor H, de la histamina
-verinum -verina antagonistas del ácido fólico
vin- vin- espasmolíticos de acción semejante a la de la papaverina
-vin- -vin- } alcaloides de la vinca
}

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