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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

WHO Drug Information Vol. 11, No. 2, 1997

General Policy Issues

Sale of medical products medical products within this system which pose a
threat to the health of the individual as well as the
through the Internet community. WHO was requested to convene an ad
hoc working group to consider the main issues of
The problem of cross-border sales of pharma- cross-border advertising, promotion and sale of
ceutical products through the Internet was first medical products on the Internet, and to formulate
raised by drug regulators at the International recommendations for guidance and action by
Conference of Drug Regulatory Authorities which governments. The meeting will be organized by the
took place in Bahrain in November 1996. Since Division of Drug Management and Policies in
then, WHO has made rapid progress in assessing September 1997 at WHO Headquarters in Geneva.
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. Future role of ATC and DDDs
The resolution highlights concern at the advertising,
promotion and uncontrolled sale of medical Little is known about the clinical consequences of
products through electronic communication and different prescribing patterns between countries or
sets out to initiate procedures to regulate this between regions within a country. There are few
practice and to limit the consequent public health systematic and comprehensive data on the utiliza-
risks. tion of drugs after they have been marketed, but it
is recognized that drugs are frequently not used to
Most countries prohibit promotion and advertising of their full potential.
prescription-only medicines to the public in view of
their pharmacological activity and potential to cause In an effort to strengthen and facilitate the provision
adverse reactions and possible interaction with of data and statistics and to provide a tool for use in
other medicines or food. Patient information, which drug utilization studies, the Division of Drug
is often included on the Internet as part of Management and Policies of WHO has agreed to
promotion, cannot replace the medical oversight take over responsibility for the international aspects
and pharmaceutical counselling fundamental to of the anatomical therapeutic chemical (ATC)
ensuring safe and appropriate use of drugs. classification and defined daily dose (DDD) which
continue to be developed by the WHO Collabora-
Additionally, many drugs are promoted on the ting Centre for Drug Statistics Methodology in Oslo,
Internet for indications that are not approved by the Norway. Until now, the ATC/DDD methodology has
regulatory authority. Thus, offering prescription-only been implemented mainly within Europe and the
medicines for sale to individual consumers without new move is meant to give an international
medical examination, diagnosis, counselling or perspective to the classification and impetus to
pharmacist control poses a very possible risk to global use.
health. Purchase and delivery of these products are
effected beyond the control of any authorities. The In April of this year, the first meeting of the new
regulatory assurances concerning safety, efficacy, international working group was held at WHO
quality and appropriate product information which Headquarters, Geneva. The meeting welcomed
are provided when a product is authorized for officials from the Norwegian Board of Health, the
marketing, subsequently distributed and dispensed WHO Collaborating Centre for International Drug
through the proper channels, are also lacking. Monitoring, academia and interested institutions,
Problems may also arise if a non-prescription including a representative of the International
medicine is on the market in one country but not Federation of Pharmaceutical Manufacturers
approved for over-the-counter use in another Associations (IFPMA). Twelve international experts,
country. drawn from the different disciplines as reflected in
the WHO Expert Advisory Panels and representing
The Health Assembly was also concerned at the a diversity of countries, have been invited to serve
possible circulation of fraudulent imitations of as members of the core working group.

General Policy Issues WHO Drug Information Vol. 11, No. 2, 1997

The opening day of the meeting was dedicated to in WHO Drug Information as a temporary ATC or
the historical and introductory aspects of the DDD and a period of 4 months will be allowed for
classification and a general discussion took place any objections to be lodged. After this period, the
between members of the working group and the ATC or DDD will be published in final form by
Secretariats. It was agreed that the international WHO. In the event of discord, a consultative
application of the ATC/DDD and its role in new procedure has been set up and the working group
scenarios would be a priority. It was seen as vital to will take a final decision on the matter in
encourage studies of drug consumption and consultation with outside technical experts. A
utilization to monitor the rational use of drugs. One representative of the Secretariat of the International
pro-active role would be the establishment of Federation of Pharmaceutical Manufacturers
working groups in each country in collaboration with Associations (IFPMA) will be present at the regular
national associations and WHO offices to initiate working group meetings as an observer.
studies on drug prescribing and use. Also proposed
was the incorporation of the system into the A yearly ATC/DDD index will continue to be
curricula of postgraduate education, as well as its published by the WHO Collaborating Centre and
inclusion on the agenda of relevant meetings. additional information can be obtained from the
Information should be made available on drug guidelines, which will shortly be revised by the
utilization studies collected from each country, and working group together with the new application
studies should be carried out on ways to promote form.
use of the system in both the public and private
sectors. At the next meeting of the working group to be held
in October 1997, progress will be reviewed and a
Discussion during the meeting centred on the development plan established. It is proposed to
international relevance, further development and focus on one country at a time to document the
enhancement of the ATC and DDDs. A revision of improvements which can be achieved by
the working methods for the group and the criteria application of the ATC/DDD in the rational use of
used for the ATC/DDD classification were also drugs and to extend this knowledge to other
drawn up, as was a timetable for the administration countries.
of applications. These should be forwarded to the
WHO Collaborating Centre in Oslo where they will
be evaluated and classified in consultation with Address: WHO Collaborating Centre for Drug Statistics
interested parties. Methodology, Sven Oftedals Vei 10
N–0518 Oslo, Norway
Once the classification has been established by the Telephone: 47 22 16 98 10
Fax: 47 22 16 98 18
international working group, it will be disseminated

WHO Drug Information Vol. 11, No. 2, 1997

Current Topics
Oral contraceptives and In a detailed analysis, the relative risk estimate was
3.5 (95% confidence interval 2.6–4.7) for contra-
venous thromboembolic ceptives containing levonorgestrel but 9.1 (95%
disease confidence interval 4.9–17.0) for contraceptives
containing desogestrel and 9.1 (95% confidence
Professor David C.G. Skegg interval 4.9–16.7) for contraceptives containing
University of Otago Medical School gestodene (12). Using data from the Oxford region
Dunedin, New Zealand in the United Kingdom, the incidence of idiopathic
VTE (per 100 000 woman-years) was estimated to
Shortly after the introduction of oral contraceptives be 3.9 for non-users of oral contraceptives, 10.3 for
in the 1960s, clinical case reports and epidemio- users of levonorgestrel, and 21.3 for users of
logical studies suggested that women using these desogestrel or gestodene. Thus the excess risk
preparations were at an increased risk of deep vein associated with oral contraceptives containing
thrombosis and pulmonary embolism. There was desogestrel or gestodene, instead of levonor-
vigorous debate as to whether these associations gestrel, was about 1 in 10 000 women per year.
were due to a causal relationship or bias. As further
evidence became available, a consensus emerged While there were differences in detail, the
that oral contraceptives can occasionally cause remaining four studies yielded similar results. In the
venous thromboembolism (VTE), as well as arterial cohort study using the United Kingdom General
disease (myocardial infarction and stroke) (1, 2). Practice Research Data Base, the incidence of non-
However, the excess risk of VTE was found to be fatal VTE, per 100 000 woman-years, was found to
smaller in women using combined oral contra- be 16.1 for users of contraceptives containing
ceptives containing a lower dose of estrogen (3, 4). levonorgestrel, 29.3 for desogestrel, and 28.1 for
The potency of the progestogen component gestodene (10). After adjusting for potential
appeared not to be important (5, 6). confounding factors, the excess risk associated
with oral contraceptives containing desogestrel or
Three decades later, renewed controversy has gestodene, rather than levonorgestrel, was
sprung up concerning oral contraceptives and VTE. estimated to be 1.6 in 10 000 women per year.
This relates to products containing a new class of
progestogen, known as third-generation com- The evidence obtained has been unusually
pounds to distinguish them from first-generation consistent from this series of observational studies
progestogens such as norethisterone, and second- conducted in different countries and with varying
generation progestogens such as levonorgestrel. designs and statistical power. Chance is no longer
Five studies published since December 1995 have a plausible explanation for the original findings, but
all shown a higher risk of VTE in women using low- it is necessary to consider whether the association
estrogen oral contraceptives containing the third- could be due to confounding or bias. The authors of
generation progestogens, desogestrel or gesto- the five studies took pains to minimize these
dene, rather than levonorgestrel (7–11). The five possibilities. Farmer et al. (11) suggested that the
studies included two hospital-based case-control increased risks associated with third-generation
studies (7, 8), a population-based case-control oral contraceptives were likely to have been due to
study (9,) and two cohort studies using the com- residual confounding by age, but the evidence
puterized records of general practitioners (10, 11). adduced does not support this (13). Other non-
The largest of the case-control studies was con- causal explanations proposed have included
ducted by the World Health Organization in 21 preferential prescribing of third-generation contra-
centres throughout Africa, Asia, Europe and Latin ceptives for women at higher risk of VTE,
America (7). In both Europe and the developing diagnostic, or referral bias, or a greater tendency
countries, use of oral contraceptives was for third-generation contraceptives to be taken by
associated with a three- or fourfold increase in the new or short-term users (14, 15). There is, in fact,
risk of VTE. The study showed a higher risk among considerable evidence against each of these
women using third-generation oral contraceptives. suggestions (16, 17) but the debate has continued.

Current Topics WHO Drug Information Vol. 11, No. 2, 1997

A further objection levelled at the causal hypothesis Studies of the influence of third-generation oral
was the lack of a plausible biological explanation contraceptives on lipid metabolism (19) encouraged
(14). This objection is no longer valid, since the hope that these newer preparations might be
researchers in the Netherlands (18) have shown associated with a lower risk of other rare but
that women who use third-generation, monophasic serious cardiovascular complications of oral
oral contraceptives are significantly less sensitive to contraception — myocardial infarction and stroke.
activated protein C (APC) than women using There is no evidence of such a difference for stroke
second-generation oral contraceptives. Resistance (21) but for myocardial infarction, an international
to APC is known to be a feature of the most case-control study produced a lower estimate of
common type of hereditary thrombophilia due to the risk for third-generation compared with second-
factor V Leiden mutation. The laboratory work from generation oral contraceptives, although the
the Netherlands suggests that the increased risks difference was not statistically significant (22). The
of venous thrombosis in women using oral contra- WHO Collaborative Study of Cardiovascular
ceptives and in congenitally APC-resistant Disease and Steroid Hormone Contraception found
individuals originate from a defect in the same a difference in the same direction, based on small
physiological pathway. A previous Netherlands numbers of users of desogestrel or gestodene, but
case-control study (9) had shown that both carriers this difference disappeared when account was
and non-carriers of the factor V Leiden mutation taken of the fact that women receiving the oral
had a higher relative risk of deep vein thrombosis contraceptives containing these progestogens were
when using oral contraceptives containing more likely to have had their blood pressure
desogestrel rather than older progestogens. The checked (23).
absolute risk of thrombosis appeared to be
especially high in women who both carried the If third-generation oral contraceptives were shown
factor V Leiden mutation and used a third- to confer a lower risk of myocardial infarction or
generation oral contraceptive. There is a striking stroke, this would be mainly relevant to older
coherence between the predictions from the women (and especially those who are smokers).
laboratory and epidemiological data (17). For women under 30 years of age, who constitute
the majority of oral contraceptive users in many
The case fatality for VTE is believed to be low (1 to countries, the risk of myocardial infarction or stroke
2%) (7), but non-fatal deep vein thrombosis and is extremely small (1, 2).
especially pulmonary embolism can be distressing
and disabling for otherwise healthy young women. The outstanding benefit of oral contraception is its
Regulatory authorities have already issued advice prevention of unplanned pregnancy — with a high
about third-generation oral contraceptives in degree of effectiveness, convenience and rever-
several countries, including the United Kingdom, sibility. For most women, the non-contraceptive
Germany, Norway and New Zealand. Reasons for benefits of oral contraceptives also outweigh the
delay in other countries have included concern risks (24). Decisions about the choice of a particular
about possible sources of bias in the oral contraceptive formulation should be based on
epidemiological studies, the previous lack of a consideration of all the potential risks and benefits,
biological explanation, the fact that the absolute risk having regard to the circumstances of the individual
of VTE in women using third-generation oral woman. Women with a personal history of VTE or
contraceptives is low (unless they also have other with possible hereditary thrombophilia should not
risk factors such as hereditary thrombophilia), and use any combined oral contraceptive. There is now
the possibility that the extra risk of VTE may be sufficient evidence to recommend against pre-
outweighed by specific advantages of third- scribing oral contraceptives containing desogestrel
generation contraceptives. or gestodene for women who have other risk
factors for VTE — such as extensive varicose
What are these particular advantages? The contra- veins, obesity (defined as a body mass index of 30
ceptive efficacy of these products appears to be kg/m2 or over), the presence of lupus anti-coagulant
similar to that of other combined oral contra- or malignancy, or mechanical factors such as
ceptives (19). The new preparations are widely held immobility or trauma (25). For the majority of
to produce fewer minor side effects (especially women without risk factors for VTE, the choice of
androgenic effects) than oral contraceptives an oral contraceptive will depend on a variety of
containing levonorgestrel, although there are considerations including the risk of cardiovascular
surprisingly few well-designed clinical studies (20). disease. Contraceptives that may carry additional

WHO Drug Information Vol. 11, No. 2, 1997 Current Topics

risks should be recommended only when there is a 10. Jick, H., Jick, S.S., Gurewich, V. et al. Risk of
prospect of additional benefits. idiopathic cardiovascular death and nonfatal venous
thromboembolism in women using oral contraceptives
Clearly, such decisions would be assisted by reso- with differing progestagen components. Lancet, 346:
1589–1593 (1995).
lution of some of the issues discussed here. For
this reason, the World Health Organization will be 11. Farmer, R.D.T., Lawrenson, R.A., Thompson, C.R.
convening a Scientific Group in November 1997. It et al. Population-based study of risk of venous thrombo-
is expected that their report will provide Member embolism associated with various oral contraceptives.
States, scientists, and family-planning providers Lancet, 349: 83–88 (1997).
with an authoritative review of all the evidence con-
cerning the cardiovascular effects of oral contra- 12. World Health Organization Collaborative Study of
ceptives and the implications for family planning. Cardiovascular Disease and Steroid Hormone Contra-
ception. Effect of different progestagens in low oestrogen
References oral contraceptives on venous thromboembolic disease.
Lancet, 346: 1582–1588 (1995).
1. Stadel, B.V. Oral contraceptives and cardiovascular
disease. New England Journal of Medicine, 305: 612–618 13. Vandenbroucke, J.P., Helmerhorst, F.M., Bloemen-
& 672–677 (1981). kamp, K.W.M. et al. Third-generation oral contraceptives
and venous thrombosis. Lancet, 349: 731 (1997).
2. Sartwell, P.E., Stolley, P.D. Oral contraceptives and
vascular disease. Epidemiologic Reviews, 4: 95–109 14. Lidegaard, O., Milsom, I. Oral contraceptives and
(1982). thrombotic diseases: impact of new epidemiological
studies. Contraception, 53: 135–139 (1996).
3. Inman, W.H.W., Vessey, M.P., Westerholm, B. et al.
Thromboembolic disease and the steroidal content of oral 15. Lewis, M.A., Heinemann, L.A.J., MacRae, K.D. et al.
contraceptives. British Medical Journal, 2: 203–209 The increased risk of venous thromboembolism and the
(1970). use of third-generation progestogens: role of bias in
observational research. Contraception, 54: 5–13 (1996).
4. Gerstman, B.B., Piper, J.M., Tomita, D.K. , Ferguson,
W.J. et al. Oral contraceptive estrogen dose and the risk 16. Farley, T.M.M., Meirik, O, Poulter, N.R. et al. Oral
of deep venous thromboembolic disease. American contraceptives and thrombotic diseases: impact of new
Journal of Epidemiology, 133: 32–37 (1991). epidemiological studies. Contraception, 54: 193–195
5. Prentice, R.L., Thomas, D.B. On the epidemiology of
oral contraceptives and disease. Advances in Cancer 17. Vandenbroucke, J.P., Rosendaal, F.R. End of the line
Research, 49: 285–401 (1987). for "third-generation pill" controversy? Lancet, 349: 1113–
1114 (1997).
6. Gerstman, B.B., Piper, J.M., Freiman, J.P. et al. Oral
contraceptive oestrogen and progestin potencies and the 18. Rosing, J., Tans, G., Nicolaes, G.A.F. et al. Oral
incidence of deep venous thromboembolism. International contraceptives and venous thrombosis: different
Journal of Epidemiology, 19: 931–936 (1990). sensitivities to activated protein C in women using second
and third generation oral contraceptives. British Journal
7. World Health Organization Collaborative Study of of Haematology, 97: 233–238 (1997).
Cardiovascular Disease and Steroid Hormone Contra-
ception. Venous thromboembolic disease and combined 19. Speroff, L., DeCherney, A. and the Advisory Board for
oral contraceptives: results of international multicentre the New Progestins. Evaluation of a new generation of
case-control study. Lancet, 346: 1575–1582 (1995). oral contraceptives. Obstetrics and Gynecology, 81:
1034–1047 (1993).
8. Spitzer, W.O., Lewis, M.A., Heinemann, L.A.J. et al.
Third-generation oral contraceptives and risk of venous 20. Paul, C. Oral contraceptives and venous thrombo-
thromboembolic disorders: an international case-control embolism. New Zealand Medical Journal, 109: 413–415
study. British Medical Journal, 312: 83–88 (1996). (1996).

9. Bloemenkamp, K.W.M., Rosendaal, F.R., Helmerhorst, 21. World Health Organization Collaborative Study of
F.M. et al. Enhancement by factor V Leiden mutation of Cardiovascular Disease and Steroid Hormone
risk of deep-vein thrombosis associated with oral Contraception. Ischaemic stroke and combined oral
contraceptives containing a third-generation progestagen. contraceptives: results of an international, multicentre,
Lancet, 346: 1593–1596 (1995). case-control study. Lancet, 348; 498–505 (1996).

Current Topics WHO Drug Information Vol. 11, No. 2, 1997

22. Lewis, M.A., Spitzer, W.O., Heinemann, L.A.J. et al. 24. Vessey, M.P. An overview of the benefits and risks of
Third-generation oral contraceptives and risk of combined oral contraceptives. In: Oral contraceptives and
myocardial infarction: an international case-control study. breast cancer. Mann, R.D. ed. Carnforth, Parthenon,
British Medical Journal, 312: 88–90 (1996). 1990, pp. 121–132.

23. World Health Organization Collaborative Study of 25. Mills, A.M., Wilkinson, C.L., Bromham, D.R. et al.
Cardiovascular Disease and Steroid Hormone Contra- Guidelines for prescribing combined oral contraceptives.
ception. Acute myocardial infarction and combined oral British Medical Journal, 312: 121–122 (1996).
contraceptives: results of an international multicentre
case-control study. Lancet, 349: 1202–1209 (1997).

WHO Drug Information Vol. 11, No. 2, 1997

Personal Perspectives
Counterfeit medicines: ingredient or a subtherapeutic dose are not only a
hazard to the health of the individual and a waste of
a special case for concern money but, in the case of anti-infectives, a risk to
public health in encouraging bacterial and parasitic
Margaret Cone resistance when delivered in subtherapeutic doses.
Vice President for Scientific Affairs
International Federation of Pharmaceutical The pharmaceutical industry shares these concerns
Manufacturers Associations (IFPMA) and is well aware that health care and patient
confidence are eroded when counterfeits are
"Counterfeiting of pharmaceuticals is a particularly reported to be in circulation. Furthermore, losses in
serious criminal offence and handling such revenue as a result of counterfeiting are enormous,
counterfeits is an unethical practice because it and the damage inflicted on a company’s reputation
endangers human health." This was the principal is a serious matter.
message to emerge from the jointly sponsored
WHO/IFPMA workshop held in April 1992, and it Estimates of the level of counterfeiting vary. It is
retains its relevance as the main theme in a paper difficult to obtain a true figure, but this must run into
recently published by the International Federation billions of dollars and possibly involves organized
of Pharmaceutical Manufacturers Associations crime. The prevalence of counterfeits in developing
(IFPMA)*. countries has been acknowledged for some time as
a major threat to public health. However, the
The term counterfeit, as applied to medicines, can widespread circulation of seriously substandard
be used to cover many different circumstances. In products in a situation where there is also an
its strictest sense it means a product which is not inadequate product registration system will tend to
made by the legitimate manufacturer but which is “blur” the distinction between a deliberate counter-
an imitation of an original with the correct active feit and a poor quality product which does not
ingredient in the correct dosage, presented in a comply with the labelled claim. Reports of high
similar form and in an apparently identical pack with percentages of counterfeit products in developing
the same, copied, technical literature. There exists, countries may, therefore, be distorted by the
however, a wide spectrum of counterfeits ranging prevalence of very poor quality products. Further-
from the product containing the correct dose of more, in the more developed countries, there is a
active ingredient, to the extreme case of a dosage danger that the scale of the problem is masked
form which contains none of the correct active because the counterfeits are so similar to the
ingredient, the wrong ingredient or, possibly, a toxic original product that they are more likely to pass
substance. In all of these cases, however, the undetected. It must be emphasized here that all
intention is to deceive. counterfeit products, no matter how close a copy to
the original, can pose a serious hazard to health
There is a need for far greater awareness of the and constitute a “tragedy about to happen” because
hazards to health posed by counterfeit medicines they have escaped the regulatory controls which
and a far greater political commitment to interna- have been put in place precisely to protect public
tional cooperation to stop their commercialization. health.
The harm to patients from counterfeit medicines,
which are rarely effective and, in many cases, Medicines represent one of the most regulated
positively dangerous, results in both human products available, so why do they attract
suffering and an increased burden on health counterfeiters? There may be many reasons.
services. Moreover, medicines containing no active Firstly, medicines are high value items in relation to
their bulk, and ingredient costs can be low if cheap
* International Pharmaceutical Issues Handbook. Available from substitutes are used for active ingredients or if they
The International Federation of Pharmaceutical Manufacturers are omitted altogether. Manufacture is also cheap
Associations (IFPMA), 30 rue de St. Jean, P.O. Box 9, 1211 as there are no overheads to pay for quality
Geneva 18, Switzerland.

Personal Perspectives WHO Drug Information Vol. 11, No. 2, 1997

assurance or meeting GMP standards as would “provide for criminal procedures and penalties to be
normally be the case. Gross margins are therefore applied at least in cases of wilful trademark
very high. In addition, many countries, especially in counterfeiting or copyright piracy on a commercial
the developing world, are without adequate scale” (Article 61). The industry believes that these
regulation and enforcement and, even in the obligations should be implemented as a matter of
industrialized countries, the risk of prosecution and urgency by countries where weak legislation
penalties for counterfeiting provide a weak impedes action against counterfeiters.
The IFPMA has encouraged its constituents to
Another reason is the process by which a patient ensure transparency in the exchange of information
comes to take a medicine, which is different from on counterfeits with regulatory authorities and
other consumer goods, because the end user is within the industry. Companies are also expected to
unable to evaluate the product ingredients. The assist official laboratories with the analysis of
doctor prescribes the product but, in most cases, suspected counterfeit products. This cooperation
never sees it. The pharmacist usually buys the can only be realized, however, if all parties respect
product from one or more of a selection of the need to treat all information in a responsible
wholesalers. Parallel trading opens a door through manner, thereby avoiding damage to legitimate
which goods of indeterminate origin can enter the products and the reputation of the companies
distribution chain. The vulnerability of medicines to concerned.
counterfeiting is therefore increased because a
number of possible points of insertion of illicit Industry has developed anti-counterfeiting
material exist even when the system is highly measures such as the use of holograms, but
regulated, as is the case in the industrialized world. experience has shown that counterfeiters soon
copy the technology. Efforts to impede counter-
At the joint WHO/IFPMA meeting on counterfeit feiting through innovative special packaging need,
medicines in 1992, the view was expressed that therefore, to be pursued by industry. Individual
regulation and enforcement are necessary to deal companies also have a responsibility to ensure that
with counterfeiting of medicines, and that this security measures are in place to detect and
regulation was identified as inadequate in both prevent diversion of products and components,
developed and developing countries. Key factors in such as packaging, for illegal purposes.
preventing counterfeiting include: stronger and
more specific legislation to take action against Pharmaceutical companies are making increased
counterfeiters; cooperation and coordination efforts to monitor and investigate the nature and
between all parties concerned — regulatory possible sources of counterfeit and diverted
agencies, police, customs, private industry, products which are detected in circulation. By
pharmaceutical professions and WHO. Appropriate studying and learning lessons from case histories,
exchange of information and the development of especially those involving diverted ingredients and
mutual trust regarding use of such material is other materials, it is hoped to improve guidelines on
needed, as are tight security measures by good operating practices which can strengthen the
companies to ensure that products, and especially barriers against the illicit and criminal activities of
packaging material, are not diverted from legitimate the counterfeit traders.
distribution channels.
In conclusion, there is no such thing as a “good”
Counterfeit medicines can more easily be counterfeit medicine and it is quite unacceptable to
introduced into the distribution chain when this is “tolerate” counterfeiting where the products are
too long or where parallel or international trading of close copies of the original and do not appear to
pharmaceuticals as “commodities” by brokers takes pose a hazard to health. Any medicinal product
place. Ideally, there should never be more than which comes from an unauthorized source is a
three stages in the chain — from licensed potential hazard, as it is not subject to quality
manufacturer to reputable wholesaler to a assurance and regulatory control. To ignore this is
supervised dispensary or retail outlet. The TRIPS to deny the usefulness and responsibility of
agreement (see page 59) imposes obligations on regulatory authorities.
members of the World Trade Organization to

WHO Drug Information Vol. 11, No. 2, 1997 Personal Perspectives

Future challenges in biotechnology-derived products that will need

specialized knowledge in evaluating their quality,
regulatory control efficacy and safety prior to marketing.
Dr E. Fefer Paradoxically, in a growing market, and with greater
Pan American Health Organization/ knowledge of the disease process, the actual
WHO Regional Office for the Americas number of companies with innovative research and
Washington, DC, USA development capability and with international
marketing capacity has decreased. Since the late
Novel pharmaceutical products and technologies 1980s, there has been a veritable epidemic of
are being developed at an unprecedented rate in mergers, acquisitions and strategic alliances. This
response to the sophisticated health demands of process of consolidation has been accompanied by
populations that are pursuing economic growth. In a streamlining of operations which has led to the
such a rapidly changing environment, it is crucial for closure of many research and operational facilities,
drug regulators to be fully informed of the latest and a reduction in personnel. This trend is fuelled
pharmaceutical discoveries, while at the same time by open market policies that allow international
retaining critical oversight of the transformations companies to supply their markets from the most
that are taking place within the industry. The trends cost-effective locations, a situation which has led to
of broad national and global markets must be the closure of sites which are financially
evaluated as they relate to the task of regulation unattractive.
and their influence defined with regard to public
health objectives. The recent World Trade Organization agreement on
trade-related aspects of international property rights
As a general rule, pharmaceutical markets are (TRIPS) provides for patent protection worldwide.
expected to grow in both size and value as a result The research-based industry is hopeful that this will
of two major factors: the ageing of populations, further stimulate research, but local industries that
which will account for 1000 million people of 60 prospered under pre-TRIPS conditions feel that
years or older by the year 2020, and increased there will be a resulting restraint on competition
urbanization, where, for example, an estimated which will lead to higher prices for new drugs.
75% of Latin Americans will be living in cities by the Implementation of this agreement has been a
year 2000. In the Americas, almost all countries particularly contentious subject throughout Latin
now have a democratically elected government and America and a source of confrontation. Relevant
a similar movement can be seen in other areas in legislation has now been approved in many
the world. The opening up of societies has brought countries but this new situation will demand
with it a debate on the role of the state and a broad adaptability by locally owned companies obliged to
consensus supports a centralized national policy- look for alternative ways to compete in the
making and regulatory apparatus with relevant marketplace.
activities delegated to local governments. At the
same time, greater responsibility is being demand- Before the end of the present decade, protection of
ed of the private sector and local communities. patents will come to an end for many of the current
best-selling products. This has led to increased
In this situation, health remains an important factor. production capacity of generic products — a market
Much has recently been reported of emerging and area which ten years ago was of limited interest to
re-emerging infectious diseases, including the re- multinational corporations. Today, all the leading
appearance of cholera and the spread of dengue in companies have generic product lines, and
Latin America. Many problems also occur in other governments are finding generic drug policies to be
regions of the world and one particular concern is a valuable instrument in controlling costs.
the development of resistance to antimicrobials.
The new products and expensive treatments soon Free-market policies and the integration of regional
to be launched by the pharmaceutical research and world economies have together provided
industry in response to this situation will need impetus for regulatory harmonization. The
careful assessment and regulation in order to International Conference on Harmonization (ICH),
ensure rational and sustainable use. Similarly, new which has been established by drug regulatory and
understanding of biological processes at the cellular pharmaceutical industry representatives of the
and molecular levels has led to the development of European Union, Japan and the United States, is

Personal Perspectives WHO Drug Information Vol. 11, No. 2, 1997

the best known process, although harmonization policy, weak legislation and regulation, lack of
efforts are also under way in other parts of the political support and will, flawed information flow,
world. The market importance of the ICH member- lack of financing, absence of transparent
ship will mean that the standards for quality, safety procedures, corruption, poor attention to cultural
and efficacy which are agreed upon by the ICH may constraints, weak or nonexistent consumer and
become de facto standards for the rest of the world. professional associations, and an absence of
Pharmaceutical companies in countries outside the priorities.
ICH are concerned that they may not be able to
meet such standards which, they argue, are driven The day-to-day shortcomings of many regulatory
by what is technologically feasible rather than what agencies range from a scarcity of qualified staff for
is clinically necessary. the review of applications for drug approval, to a
lack of enforcement in removing from the market
The main impact of a market-driven environment is unsafe or ineffective products. However, the
the pressure to decrease or limit the regulatory role regulatory situation in any given country will not
of the government and, as some extreme groups improve unless there are fundamental changes in
say, to "let the market decide". Clearly this cannot the structure, staffing and operation of the agencies
be allowed for pharmaceuticals for obvious reasons and this requires a government willing to invest the
of safety and protection of public health. This pres- necessary political will and finances to bring about
sure is similarly reflected by proposed or actual the required changes. Unfortunately, the import-
legislation and regulations aimed at facilitating and ance of strengthening the regulatory role of a
expediting the approval of pharmaceutical products. government only seems to come about after a
Deregulation has been exaggerated by some major tragedy occurs, as we have seen this decade
governments that automatically approve products in Argentina and, more recently, in Haiti.
according to their approval status in selected
reference countries. A visible agency and
qualified regulatory officials
Drug regulatory essentials An effective regulatory agency cannot be buried in
What must a drug regulatory authority do to the Ministry — it needs to be visible and have an
function effectively under political conditions that identity. This can be achieved by upgrading the
give priority to economic considerations and tend to status of the responsible department within the
favour a diminished role for the central govern- official structure or, better still, by establishing a
ment? First and foremost, there is a need to focus semi-autonomous agency with authority and
on essentials. Governments should not lose sight of responsibility for all aspects of drug regulation while
the central mission of the drug regulatory authority avoiding dispersion of, and competition among, the
— which is to protect public health. There should be available personnel.
no compromising on this.
This ideal agency would have administrative and
Of course, the regulatory agency also contributes to financial flexibility to enable it to carry out its work.
promoting public health by approving in a timely This would include the authority to hire a core of
manner applications for new drugs, expediting qualified full-time staff at competitive salaries. Full-
access to those products that represent significant time regulatory personnel require a salary which is
contributions to health, and encouraging the reasonable enough to waylay corrupting influences
marketing of well-known essential drugs, as well as and conflicts of interest. This reality needs to be
orphan drugs. And, of course, the regulatory adequately addressed in many societies.
agency should also be responsive to the legitimate
needs of the industry by providing an efficient and Where agency staff and expertise are limited,
transparent service. Unfortunately, we are far from certain functions can be contracted out. Recent
these goals in many developing countries. legislation in Colombia allows inspections, analysis
of samples, and evaluation of drug applications to
During a recent working group of the World Bank, be carried out by accredited institutions, although
involving WHO, UNICEF and other interested final approval rests with the agency. Very clear and
organizations, this issue was discussed at length. transparent arrangements are obviously required
Many barriers to effective regulation were identified, when delegating such responsibilities. Most
such as insufficient human resources, absence of a importantly, the agency and its staff must be

WHO Drug Information Vol. 11, No. 2, 1997 Personal Perspectives

supported by adequate legislation and regulations Application of international standards

— although in reality this situation can often be the The capability to evaluate pharmaceuticals, both
other way round. Regulations abound but they are before and after they are allowed on the market,
not enforced, in part due to a lack of motivated and varies from country to country. However, at a time
qualified staff. when efficiency is demanded from the public sector,
it makes no sense to duplicate work and harmoni-
Financing regulatory activities zation efforts are welcomed both by industry and
Inadequate financing of regulatory agencies has regulators. The International Conference on
been a major factor in limiting their performance. It Harmonization (ICH) is expected to have a major
would not be realistic to expect that the regular impact on standard setting. Even though emphasis
government budget should be used to provide has been on harmonizing registration requirements
funding for the kind of agency described above. A of new drugs, many of the criteria which have been
viable alternative is the implementation of user established are applicable to other pharmaceutical
fees. This concept has been widely accepted in the products (see above pp. 59–60).
developed world, where significant fees are
charged for the registration of products and Harmonization efforts are also under way in Latin
inspection of plants. By contrast, in the developing America in response to the formation of free-trade
world the charges are very low. Such low fees are, zones in Central America, the Andean region and
in effect, an incentive to submit applications for the countries of MERCOSUR — Argentina, Brazil
products of little or no therapeutic significance. The Paraguay and Uruguay. The harmonization process
Pan American Health Organization has consistently requires countries to look beyond traditional ways
advised Member States to increase their fees to a of doing business and to examine what is happen-
degree that would significantly contribute towards ing in the rest of the world. As a result, there is a
financing regulatory activities for the duration of the growing understanding among regulatory officials
approval period. Brazil is following this advice with and forward-looking national companies that the
a recently established fee of $8000. Responsible acceptance of recognized international standards
pharmaceutical companies do not object to for drug quality and for the drug approval process
increased registration fees if these are used to are prerequisites to participation in the global
provide a more effective service. market.
WHO has developed useful instruments to assist
Transparency of the drug review process agencies in their work, such as the WHO Certifica-
The procedures and criteria for drug review and tion Scheme for pharmaceutical products moving in
approval should be made public, as well as the international commerce, good manufacturing
results of the process. This is an obvious but, in practices (GMP), good clinical practice for clinical
practice, frequently violated principle in many trials (GCP), and ethical criteria for medicinal drug
countries, especially where political pressure and promotion. These guidelines are particularly useful
personal favours influence the regulatory process. for developing countries engaged in harmonization
A computerized drug registration system developed efforts. As countries are bound to re-examine their
by WHO's Division of Drug Management and outdated and at times contradictory regulations,
Policies and the Pan American Health Organization they will find the WHO recommendations to be an
has now been installed in a number of Latin acceptable and useful guide for the different parties
American countries. Computerization will facilitate involved.
monitoring of the review process and the use of a
common software will enable the exchange of Interagency and international cooperation
information among countries. Consumers and, of The World Health Organization regularly provides
course, industry must be able to go to the agency information on drug safety, quality and regulation in
with their concerns and priorities and the agency order to assist authorities to regulate and monitor
must provide feedback on its operations and their domestic markets. In addition, the facilities
decisions. This should be done, to the extent provided by new communications technology can
possible, in an open manner through committees offer advantages to the work of regulatory agencies
and other processes accessible to the public worldwide. In principle, an electronic network can
although it is understandable that some data and now easily be put in place to disseminate informa-
documents will need to remain confidential. tion regarding approvals, withdrawals, warnings,
etc. Equally, agencies can post enquiries and

Personal Perspectives WHO Drug Information Vol. 11, No. 2, 1997

request assistance for specific problems from regulatory agencies, the funds required could be
colleagues. This network is within reach of many mobilized from international development agencies
agencies and would be cost effective. Why, then, or from the pharmaceutical industry, which has
has such a network not been established at global always expressed interest in strengthening drug
level? regulation in the developing world.

The reality is that many regulatory authorities have Numerous issues face regulators, but none is more
no direct access to a fax machine or to the Internet. important than ensuring that the public health
I believe that if priority is given to the establishment mission remains unchanged.
and maintenance of an electronic network for

WHO Drug Information Vol. 11, No. 2, 1997

Reports on Individual Drugs

still incomplete, and well-informed dialogue
Move to triple-drug therapy for HIV between the patient and physician is essential in
Since 1995, promising new developments in achieving a rational individualized treatment
research have altered the management of HIV regimen. The following broad principles are
infection and further expansion in the range and recommended:
complexity of treatment is expected to continue, as
will greater individualization in patient care. As a • Treatment should be offered before substantial
consequence of the promising results obtained with immunodeficiency occurs.
monotherapy using zidovudine and other first- • Initial treatment should include a combination of at
generation antiretrovirals such as didanosine, least two drugs.
zalcitabine, stavudine and lamivudine (1), five large
randomized clinical trials were launched to evaluate • Switches in therapy should involve the substitution
different combinations of antiretroviral therapy. or addition of at least two new agents.

The results of the trials are now available and • Measurement of viral load and the CD4 count is
indicate that combination therapy is superior to essential.
nucleoside analogue monotherapy (2–7). The • Reduction in viral load to below the detection level
CAESAR trial has demonstrated a highly significant of a sensitive assay represents the optimal
reduction in progression to AIDS or death for treatment response. Failure to achieve or sustain
patients receiving lamivudine added to zidovudine- this control should prompt consideration of
containing regimens, as compared to patients therapy modification. This response is achieved
maintained on zidovudine-containing regimens only most reliably by a combination of two nucleoside
(6). The relative reduction in disease progression to analogues plus a third agent — either a protease
AIDS or death was 57% over one year for the inhibitor, a non-nucleoside reverse transcriptase
lamivudine-zidovudine group compared with inhibitor, or a third nucleoside analogue — or two
placebo, and the study was terminated early. protease inhibitors.
However, the research team cautioned that the
regimen may not prove sufficient to achieve long- The rapid advancement of HIV treatment obliges
term suppression of the HIV-1 viral load below practitioners caring for HIV-infected persons to
currently detectable limits, which is now considered keep abreast of the developments in HIV therapy if
by many to be the ultimate goal of treatment (6–8). the safe and effective use of new drugs is to be
achieved. The guidelines will be updated and
In the interim, results have also been received from revised as necessary.
the ACTG 175 (3) and DELTA (4) trials which show
the clear superiority of two nucleoside analogues Antiretroviral agents
over zidovudine monotherapy. Results from the The following is a list of some of the antiretroviral
ACTG 320 (6), which compared a triple combina- drugs which are authorized for marketing in many
tion of zidovudine plus lamivudine plus indinavir countries or are in an advanced stage of clinical
with zidovudine plus lamivudine, confirm that the development.
addition of a potent protease inhibitor to zidovudine
Nucleoside analogues:
plus lamivudine delays disease progression and
zidovudine (ZDV, AZT), zalcitabine (ddC), didano-
increases survival (6).
sine (ddl), stavudine (d4T), lamivudine (3TC).
New guidelines Protease inhibitors:
Recent developments are reflected in guidelines saquinavir (SQV), ritonavir (RTV), indinavir (IDV),
issued by the British HIV Association (8). Those nelfinavir, cidofovir, droxinavir, lasinavir, palinavir,
currently under preparation by the United States telinavir.
Public Health Service (9) are likely to be similar.
The British guidelines warn that data available are Non-nucleoside reverse transcriptase inhibitors:
nevirapine (NVP), delavirdine, loviride, atevirdine.

Reports on Individual Drugs WHO Drug Information Vol. 11, No. 2, 1997

Can HIV be eliminated from Triple therapy — obstacles and problems

infection reservoirs? Although the results of triple antiretroviral therapy
In untreated HIV-infected individuals, a viral load provide the basis for some optimism, many
below detection limit is associated with either slow questions remain unanswered. For example, long-
progression of HIV or non-progression (10, 11). A term critical outcomes are unavailable, and
reduction in the viral load to very low levels such as resistance is known to have occurred with triple
those reported in most patients on triple-drug therapy. It is possible that the virus may remain
therapy, is therefore an attractive goal (12). hidden in the central nervous system or bone
marrow and, when treatment is interrupted, strong
In May 1997, three research groups published viral rebound may lead to rapid clinical deteriora-
findings suggesting that HIV could be totally tion. Recently, the United States Food and Drug
eradicated from CD4 T cells and lymphoid tissue by Administration has issued a warning that protease
a combination of antiretroviral drugs. One group inhibitors are associated with increases in blood
studied viral decay in 8 patients given nelfinavir, a sugar and even diabetes. Among the 83 cases so
protease inhibitor, and zidovudine and lamivudine, far reported of diabetes mellitus or hypoglycaemia
two nucleoside reverse transcriptase inhibitors (13). in HIV-infected patients on protease inhibitor
Patients had not received previous retroviral therapy, 27 required hospitalization, of which 6
therapy. After an initial drop of 99% in plasma were in a life-threatening condition (17, 18).
concentration of HIV within two weeks of treatment,
a slower second phase of 6–25 days was needed In addition, the regimen is complicated and ardu-
for elimination and, at 8 weeks, the virus was ous. Between fifteen and thirty tablets have to be
undetectable in plasma. By incorporating these taken daily, and failure to comply with a regular
phases into a mathematical model, the researchers schedule may lead to the emergence of drug
postulated that if antiretroviral drugs completely resistance. Side-effects, including nausea,
inhibit viral replication, then the stores of virus in diarrhoea and blood dyscrasia are common in the
blood and tissues could disappear within 3 years. initial months. Finally, clinical and laboratory
The authors warned, however, that viral DNA within monitoring is necessary to detect adverse
mononuclear cells will still be present for many reactions, determine safety of treatment, and follow
years — and perhaps for life — leaving the remote up the patient's progress. Interactions with other
possibility that infectious progeny can be necessary drugs such as rifampicin and other
reactivated or produced. antibiotics, or mefloquine, are common and not yet
completely understood.
These findings are broadly in line with another
research group that looked at how long infected The greatest obstacle to delivery of effective treat-
host cells can harbour the virus (14). Some infected ment is accessibility. Treatment is expensive —
cells linger in a resting state whereby HIV is in- somewhere in the region of US$ 1000 to US$ 1500
corporated into the host DNA but does not divide to a month — and requires a wide variety of health-
produce new viral particles. These infected cells are related support such as laboratory services and
neither detectable by the immune system nor technical expertise, in addition to administration of
susceptible to antiretroviral therapy. In the study, a complicated regimen. This puts treatment well
levels of HIV DNA were examined in resting CD4 beyond the reach of the vast majority of HIV-
cells in the blood and lymph of 14 asymptomatic infected people, and especially those living in
infected patients. Although fewer than 0.05% of the countries where resources for health care are
resting CD4 cells harboured HIV DNA, this was limited. To put the situation into perspective: 90%
enough to produce virus when stimulated to divide. of people with HIV infection worldwide live in
The third group reported that triple therapy with developing countries. Over 60% of these live in
ritonavir, zidovudine and lamivudine for 6 months sub-Saharan Africa, and many of these countries
cleared more than 99.9% of HIV from the second- have been hit by economic and political upheavals,
ary lymphoid tissue (tonsils) of 34 infected patients and the basic needs of food and shelter remain
(15). The researchers cautioned, however, that a unmet.
residue of virus could remain in a certain type of
lymph cell — the follicular dendritic cell. Although In conclusion, although the latest research results
lymphoid tissue is the main reservoir of infection, are impressive, this does not mean that AIDS will
there may be secondary sites in the brain and bone soon be regarded as a chronic, non-fatal disease.
marrow and the presence of one infected cell may No data as yet exist to suggest that even vigorous
be enough to reactivate replication. compliance with the new regimens could ensure

WHO Drug Information Vol. 11, No. 2, 1997 Reports on Individual Drugs

non-infectivity. Commitment to essential, long-term

activities such as prevention programmes and the 12. Feinberg, M. Hidden dangers of incompletely
search for vaccines and microbicides remains of suppressive antiretroviral therapy. Lancet, 349: 1408–
vital importance. 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).
1. Update on AIDS. WHO Drug Information, 9(4): 196–201
14. Chun, T.W., Carruth, L., Finzi, D. et al. Quantification
of latent tissue reservoirs and total body viral load in HIV-1
2. Saravolacz, L.D., Winslow, D.L., Collins, G. et al.
infection. Nature, 387: 183–187 (1997).
Zidovudine alone or in combination with didanosine or
zalcitabine in HIV-infected patients with the acquired
15. Cavert, W., Notermans, D.W., Staskus, K. Kinetics of
immune deficiency syndrome or fewer than 200 CD4 cells
response in lymphoid tissues to antiretroviral therapy of
per cubic millimetre. New England Journal of Medicine,
HIV-1 infection. Science, 276: 960–964 (1997).
335: 1099–1106 (1996).
16. De Cock, K. Great strides in antiviral therapy. AIDS
3. Hammer, S.M., Katzenstein, D.A., Hughes, M.D. et al.
Targeted Information, Volume 11, Number 1, 1997.
A trial comparing nucleoside monotherapy with
combination therapy in HIV-infected adults with CD4 cell
17. FDA Talk Paper, T97–23, June 1997.
counts from 200–500 per cubic millimeter. New England
Journal of Medicine, 335: 1081–1090 (1996). 18. WHO Drug Alert, Nummber 59, 13 June 1997.
4. DELTA coordinating committee. DELTA: a randomised
double-blind controlled trial comparing combination of
zidovudine plus didanosine or zalcitabine or zidovudine
Amiodarone and
alone in HIV infected individuals. Lancet, 348: 283 (1996). post-infarction arrhythmia
5. Lalezari, J., Haubrich, R., Burger, H.U. et al. Improved Patients surviving the acute phase of myocardial
survival and decreased disease progression of HIV in infarction have a mortality rate of about 10% during
patients treated with saquinavir plus HIVID. XI the year following the attack. The main cause of
International Conference on AIDS, Vancouver, July 1996.
LB.B. 6033.
death during this period is attributed to ventricular
arrhythmia (1, 2) which has provided the rationale
6. Katlama, C. on behalf of the CAESAR coordinating for use of anti-arrhythmic drugs during this period.
committee. Clinical and survival benefit of 3TC in However, the results of clinical trials set up to
combination with zidovudine-containing regimens in HIV-1 evaluate various anti-arrhythmic drugs have until
infection: interim results of CAESAR study. 3rd now been disappointing (3–6). Meta-analyses of
International Congress on drug therapy in HIV infections, various trials have shown calcium-channel blockers
Birmingham, November 1996. Abstract SS2.1. to be harmful and calcium-channel antagonists to
have few beneficial effects (7, 8).
7. Randomised trial of addition of lamivudine or
lamivudine plus loviride to zidovudine-containing regimens
for patients with HIV-1 infection: the CAESAR trial. Favourable results were demonstrated, however, in
Lancet, 349: 1413–1421 (1997). a pilot study on the use of amiodarone, although
definite conclusions could not be made on all-cause
8. BHIVA Guidelines Coordinating Committee. British HIV mortality (9). The beneficial effects of this treatment
Association guidelines for antiretroviral treatment of HIV have now been confirmed by the results of two
seropositive individuals. Lancet, 349: 1086–1092 (1997). large, long-term mortality trials of amiodarone
9. US Public Health Service. Guidelines for the treatment among survivors of myocardial infarction at high
of HIV. SCRIP, Number 2234, May 1997. risk of cardiac death (10–12).
10. Cao., Y., Qin, L., Zhang, L. et al. Virologic and
immunologic characterization of long-term survivors of Both studies — the European Myocardial Infarct
human immunodeficiency virus type 1 infection. New Amiodarone Trial, EMIAT, and the Canadian
England Journal of Medicine, 332: 201–208 (1995). Amiodarone Myocardial Infarction Arrhythmia Trial,
CAMIAT— were randomized, placebo-controlled
11. Pantaleo, G., Menzo, S., Vaccarezza, M. et al. trials. EMIAT enrolled 743 patients in the amioda-
Studies in subjects with long-term nonprogressive human rone and 747 patients in the placebo group to
immunodeficiency virus infection. New England Journal of assess whether amiodarone reduced all–cause
Medicine, 332: 209-216 (1995).

Reports on Individual Drugs WHO Drug Information Vol. 11, No. 2, 1997

mortality, cardiac mortality and arrhythmia death in 3. The Cardiac Arrhythmia Suppression Trial (CAST)
survivors of myocardial infarction with a left- investigators. Effect of encainide and flecainide on
ventricular ejection fraction of 40% or less. Such mortality in a randomized trial of arrhythmia suppression
after myocardial infarction. New England Journal of
patients are known to have a 2-year mortality of
Medicine, 321:406–412 (l989).
15%, of which the arrhythmic component is about
half. The median follow-up was 21 months. 4. The Cardiac Arrhythmia Suppression Trial investiga-
tors. Effect of the antiarrhythmic agent moricizine on
All-cause mortality and cardiac mortality did not survival after myocardial infarction. New England Journal
differ between the two groups, but there was a 35% of Medicine, 327: 227–235 (l992).
risk reduction in arrhythmia death in the amioda-
rone group. The systematic prophylactic use of 5. Waldo, A.L., Camm, A.J., de Ruyter, H. et al. The
amiodarone in all patients with depressed left- SWORD trial. Survival with oral d-sotalol in patients with
left ventricular dysfunction after myocardial infarction:
ventricular function after myocardial infarction was
rationale, design and methods. American Journal of
not supported, but the reduction noted in arrhythmia Cardiology, 75:1023–1027 (l995).
deaths does support the results of the CAMIAT
study, which assessed the effect of amiodarone 6. Waldo, A.L., Camm, A.J., de Ruyter, H. et al. Effect of
treatment on the risk of resuscitated ventricular d-sotalol on mortality in patients with left ventricular
fibrillation or arrhythmia deaths among survivors of dysfunction after recent and remote myocardial infarction.
myocardial infarction with frequent or repetitive Lancet, 348: 7–12 (l996).
ventricular premature depolarizations (VPDs).
Within this study, 606 patients were treated with 7. Yusuf, S. et al. Critical review of approaches to the
prevention of sudden death. American Journal of
amiodarone and 596 patients with placebo.
Cardiology, 72: 51F–58F (l993)
Amiodarone reduced the incidence of ventricular
fibrillation and arrhythmia deaths, and absolute-risk 8. Burkart, F., Pfisterer, M., Kiowski, W. et al. Effect of
reduction was greatest among patients with antiarrhythmic therapy on mortality in survivors of
congestive heart failure or a history of myocardial myocardial infarction with asymptomatic complex
infarction. ventricular arrhythmias. Basel Anti-arrhythmic Study of
Infarct Survival (BASIS). Journal of American College of
These trials have been helpful in clarifying pending Cardiologists, 16: 1711–1718 (l990).
questions on the use of anti-arrhythmic post-
9. Ceremuzynski, L., et al. Effect of amiodarone on
infarction treatment. Amiodarone should not be
mortality after myocardial infarction. A double-blind,
used routinely after myocardial infarction as the placebo controlled, pilot study. Journal of American
data do not demonstrate any improvement in total College of Cardiologists, 20: 1051–1062 (l992).
mortality. However, the clinician should be
encouraged to consider amiodarone for patients 10. Cairns, J.A., et al. Post-myocardial infarction mortality
with symptomatic or sustained and potentially in patients with ventricular premature depolarizations: the
dangerous arrhythmias after myocardial infarction, Canadian amiodarone myocardial infarction arrhythmia
and especially in patients with low ejection fraction trial. Circulation, 4: 550–557 (l991).
and congestive heart failure. Future results from
11 Julian, D. G., et al. Randomized trial of effect of
several ongoing trials will increase our knowledge
amiodarone on mortality in patients with left-ventricular
on the risk/benefit of anti-arrhythmia therapy in dysfunction after recent myocardial infarction: EMIAT.
these patients. Lancet, 349: 667–674 (l997).
References 12. Cairns, J.A., et al. Randomised trial of outcome after
myocardial infarction in patients with frequent or repetitive
1. Impact Research Group. Report on arrhythmic and
ventricular premature depolarisations: CAMIAT. Lancet,
other findings. Journal of American College of Cardio-
349: 675–682 (l997).
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).

WHO Drug Information Vol. 11, No. 2, 1997

Regulatory Matters
Update on risks of Concerns are still apparent regarding the potentially
life-threatening side-effects and drug interactions of
non-sedating antihistamines terfenadine use. The Committee now considers that
the risk/benefit ratio has moved in favour of restric-
Several countries have recently reconsidered the
tion of the supply of terfenadine on prescription
regulatory status of the non-sedating antihistamine,
only. This change will allow better assessment of
terfenadine, following its association with fatal
individual risks, and communication of such risks to
cardiac arrhythmias, as reported in the previous
the patient by the prescribing physician. The
number of this journal (1).
Committee will expedite the urgent safety review of
In a recent article in the Lancet, the WHO astemizole.
Collaborating Centre for International Drug Reference: Letter from the Therapeutic Goods
Monitoring in Uppsala, Sweden has analysed the Administration on Gazettal notice of 190th Australian Drug
reporting rate profile of five non-sedating anti- Evaluation Committee, April l997.
histamines: acrivastine, astemizole, cetirizine,
loratadine and terfenadine. Overall, they have many
similarities, but it would appear that terfenadine and Terfenadine: proposed
astemizole have a propensity to block cardiac
muscle potassium channels, which is linked with
change to prescription only
QT prolongation and cardiac arrhythmia. In United Kingdom — The Committee on Safety of
contrast, loratadine has been shown not to have Medicines has reviewed the safety profile of
this action. None the less, reporting of cardiac rate terfenadine in relation to cardiac arrhythmias and is
and rhythm disorders for the five antihistamines concerned that, despite the measures taken in
was of a similar order. 1992 and 1994, serious adverse reactions continue
The authors conclude that alternatives to terfena- to be reported. Because of the increasing
dine possess similar modes of action, and that complexity of the precautions needed for its safe
careful consideration of the comparative benefit-risk use, it is unlikely that terfenadine can be used as
profile of all non-sedating antihistamines is safely as alternative non-sedating antihistamines
essential. Such an assessment is currently under without medical supervision. For this reason the
way within Europe by the Committee for Proprietary Committee has recommended that steps be taken
Medicinal Products (CPMP). to revert terfenadine to prescription-only status. By
law, such a change of legal status can only be
References made after a period of formal consultation with a
1. WHO Drug Information, 11(1): 17 (1997). wide range of interested organizations, and this
process will take some months.
2. Lindquist, M., Edwards, I.R. Risks of non-sedating
antihistamines. Lancet, 349: 1322 (1997). Information on the safety of terfenadine, and
precautions needed for its use have meanwhile
been circulated to physicians and pharmacists and
Terfenadine to prescription-only an information sheet has been provided for
status — astemizole under critical patients. If there is any doubt as to whether
terfenadine can be used safely, the precautions
review must be consulted and an alternative non-sedating
antihistamine with a more suitable profile should be
Australia — The Australian Drug Evaluation considered. These alternative products, such as
Committee has considered the prescription status cetirizine and loratadine, are available from
of terfenadine now that fexofenidine, a new and pharmacies without prescription. The patient
safer alternative antihistamine has been registered information sheet also states that the third alterna-
as a nonprescription drug. tive, astemizole, is available without prescription.

Regulatory Matters WHO Drug Information Vol. 11, No. 2, 1997

Astemizole also has the potential to produce As already reported (2), a link between anorectic
serious cardiac arrhythmias in certain circum- use and primary pulmonary hypertension (PPH)
stances as described in the package insert, but has been demonstrated in a multinational case-
at present there is insufficient evidence to justify control study of 95 patients with this condition. This
switching prescription status. The situation is study indicated that patients taking anorectics were
consequently being kept under close review. 6 times more likely to suffer from PPH, and 23
times more likely if anorectics were taken for more
Reference: Terfenadine: UK Dear Doctor/Pharmacist
letters, April l997.
than three months.
These revised recommendations for anorectic
therapy, including restricted indications, contra-
Terfenadine: further reports indications, duration of treatment and requirements
Germany — The Federal Institute for Drugs and for supervision and monitoring of therapy, are
Medical Devices (BfArM) has received five reports consonant with previous recommendations issued
of "torsades de pointes" associated with the use of by the CPMP (2).
terfenadine and one report with astemizole in
addition to one report of death associated with each
drug. The agency has requested physicians to 1. Committee on Safety of Medicines. Current Problems in
monitor and report cardiovascular adverse drug Pharmacovigilance, No. 23 (1997).
reactions and, in particular, arrhythmias associated 2. WHO Drug Information, 10 (4): 187 (1996).
with use of the non-sedating antihistamines,
terfenadine and astemizole. 3. Guy-Grand, B., Apfelbaum, M., Crepaldi, G. et al.
International trial of long-term dexfenfluramine in obesity.
Reference: Communication to WHO of 3 June 1997 Lancet, 2: 1142–1145 (1989).
including text from Arzneimittel-Schnellinformationen of
March 1997.
Baclofen: withdrawal reactions
Anorectic agents: United Kingdom — The Medicines Control Agency
revised recommendations has received nine reports of serious psychiatric
reactions caused by abrupt withdrawal of oral
United Kingdom — The Medicines Control Agency baclofen. Baclofen, a gamma-aminobutyric acid
has issued recommendations on the use of fen- (GABA) derivative, is used to reduce spasticity in
fluramine, dexfenfluramine and phentermine based voluntary muscles. Withdrawal reactions include:
on a review carried out within the United Kingdom hallucinations, paranoia, delusions, psychosis,
by the Royal College of Physicians (1), and an confusion and agitation.
earlier risk-benefit evaluation made by the
European Committee for Proprietary Medicinal In order to prevent or minimize the risk of these
Products (CPMP) during 1995-1996 (2). reactions, baclofen therapy should always be
discontinued by gradual dose reduction over at
As many as 98 randomized controlled clinical trials least one or two weeks, although a longer period of
of at least six months duration have provided withdrawal may be necessary in certain cases.
evidence of the efficacy of anorectic agents in
terms of weight loss. In one such trial, carried out in Reference: Committee on Safety of Medicines. Current
800 obese patients, 35% of subjects treated with Problems in Pharmacovigilance, No. 23 (1997).
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
Fluvastatin and muscle
patients maintained this weight loss for up to 12 disorders: a class effect
months when treated with dexfenfluramine as
compared to placebo, and these results suggest Australia — During 1996, the Adverse Drug
that dexfenfluramine is effective in sustaining Reactions Advisory Committee received 85 reports
weight loss in selected patients with a body mass concerning fluvastatin. Of these, 30 describe
index of 30 kg/m2 or greater. However, no such muscle disorders such as myalgia, myopathy, myo-
evidence was demonstrated for other anorectic sitis, leg cramps and/or increased creatine kinase.
agents. Fluvastatin was the only drug suspected in all but

WHO Drug Information Vol. 11, No. 2, 1997 Regulatory Matters

two of these cases, and three reports documented systemic corticosteroid products has been
recurrence of symptoms on rechallenge. Similar amended to reflect more up-to-date knowledge on
problems were documented with previous use of safety. A patient information sheet is now provided
simvastatin or another “statin” in 13 of the cases. by manufacturers for all systemic corticosteroid
products, and pharmacists and physicians must
The Committee reminds prescribers that muscle ensure that the patient is supplied with a copy.
involvement is a class effect of all HMG-CoA
reductase inhibitors, and similar reports have been Special precautions describe certain situations
received in Australia concerning simvastatin (307 where diseases may be exacerbated by cortico-
reports) and pravastatin (29 reports). steroids and particular care and monitoring are
required in patients with, or having a history of,
Reference: Australian Adverse Drug Reactions Bulletin,
16: 3 (1997).
osteoporosis, hypertension, congestive heart
failure, severe affective disorders, diabetes mellitus,
tuberculosis, glaucoma, liver failure, renal in-
Abuse of gamma sufficiency, epilepsy or peptic ulceration.
hydroxybutyric acid (GHB) The section on use in pregnancy and during
lactation points to the possibility of growth
United States of America — The Food and Drug
retardation of the fetus and a small increased risk of
Administration has re-issued a warning against
cleft palate. Patients with pre-eclampsia or fluid
"recreational" (intoxicating) and body-building use
retention require close monitoring and infants of
of gamma hydroxybutyric acid (GHB). This drug
mothers taking systemic corticosteroids during
has not been authorized for marketing within the
lactation should be evaluated for signs of adrenal
United States and its use within the country is
suppression. Use in children may result in
considered as illegal.
irreversible dose-related growth retardation in
infancy, childhood and adolescence. Elderly
Gamma hydroxybutyric acid is a potentially danger-
patients require close supervision.
ous drug, and its use may result in vomiting, dizzi-
ness, tremors and seizures that could cause
Corticosteroid action may be reduced during
injuries requiring hospitalization. Some deaths have
concomitant use of rifampicin, carbamazepine,
already been linked with consumption of GHB
phenobarbital, phenytoin, primidone or amino-
glutethimide. The effects of hypoglycaemic agents,
The Food and Drug Administration and the Depart- antihypertensives and diuretics are antagonized by
ment of Justice have taken enforcement action corticosteroids, while the hypokalaemic effects of
against several firms and individuals involved in acetazolamide, diuretics and carbenoxolone may
manufacturing, distributing or promoting GHB. The be enhanced.
agency has also instituted an automatic detention
policy to prevent products containing GHB from Adverse reactions to corticosteroids are generally
being imported. These actions, along with related to dose and duration. Use of corticosteroids
embargoes, public education campaigns and other for less than 7 days (e.g. in acute asthma) is
measures taken by state and federal authorities unlikely to result in serious adverse reactions but
have reduced distribution and abuse. Recently, with longer courses many body systems and
however, there appears to have been an increase functions may be affected. Adverse reactions are
in the availability of GHB produced by clandestine listed in the product information while the serious
laboratories, and this has resulted in an increase in reactions are listed on the patient information card.
reports of GHB-related injuries and deaths. Patients should always be advised to take the
lowest effective dose for the minimum length of
Reference: FDA Talk Paper, T97-10, February 1997. time. This should be given either as a single
morning dose or on alternate days, with frequent
Instructions for safe use of patient review to titrate dose against disease
activity. Any intercurrent illness, trauma or surgical
systemic corticosteroids procedure may require a temporary increase in
dosage and re-introduction if corticosteroids have
United Kingdom — At the request of the Medi- recently been stopped.
cines Control Agency, the product information for

Regulatory Matters WHO Drug Information Vol. 11, No. 2, 1997

Withdrawal must be gradual because cortico- United Sates of America and United Kingdom —
steroids suppress adrenal production of endo- Glaxo Wellcome has issued “Dear Doctor” letters in
genous steroids. As a result, the dose should be the above-mentioned countries warning that
tapered off over weeks or months to enable the children aged 16 years and under treated with
adrenal glands to recover activity. Too rapid a lamotrigine are at a much higher risk of severe,
reduction of corticosteroid dosages may result in potentially life-threatening skin reactions than
acute adrenal insufficiency, which has a high previously thought.
mortality rate. Patients should carry a Steroid
Treatment Card with them containing any relevant The incidence of such reactions requiring hospital
information for use when consulting a physician. admission is estimated to be between 1 in 50 and 1
in 300 children. It was previously thought to be the
This comprehensive revision of product information same as that in adults, i.e. 1 in every 1000 patients.
for systemic corticosteroids, together with the The letter points out that concurrent administration
updated patient information provides a good of valproic acid may increase the risk of reactions
example for any drug regulatory authority in similar because it prolongs the mean half-life of lamotrigine
situations concerning corticosteroid products. twofold.
Reference: Committee on Safety of Medicines. Current
Problems in Pharmacovigilance, No. 23 (1997). 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
Update on lamotrigine reported after more prolonged use. All patients,
adults or children, who develop a rash should be
and severe skin reactions promptly evaluated and lamotrigine withdrawn
immediately unless the rash is clearly not drug-
Australia — Lamotrigine is an anticonvulsant used
for the treatment of epileptic seizures as add-on
therapy in children, and as either monotherapy or
Lamotrigine is marketed in over 25 countries. The
add-on therapy in adults.
experiences described above from Australia, the
United States and the United Kingdom may assist
The Adverse Drug Reactions Advisory Committee
drug regulators in other countries to take approp-
has received 111 adverse reaction reports involving
riate action.
lamotrigine. Of these, 36 describe skin reactions —
mostly rashes and often maculopapular, while 8 of Reference: Communication from Glaxo Wellcome dated
the reports describe severe skin reactions such as 30 April 1997 enclosing “Dear Doctor” letters.
erythema multiforme, Stevens Johnson syndrome,
toxic epidermal necrolysis and bullous eruption.
Of the serious cases, ages range from 3 to 35 Drug interactions
years, with five of the eight patients being under 18 with grapefruit juice
years of age. Onset occurred as early as the first
day and as late as 2 years after commencing United Kingdom — The Medicines Control Agency
therapy. Six of the eight reports also documented warns that ciclosporin, terfenadine and most cal-
concurrent administration of valproic acid — a drug cium channel blockers should not be taken at the
that may reduce the hepatic clearance of lamo- same time as grapefruit juice (1). It has become
trigine resulting in increased plasma concentrations apparent that the juice contains a psoralen which
of up to twofold. inhibits the metabolism of certain drugs by enzymes
of the CYP 3A subfamily of cytochrome P450 (2).
The Committee reminds prescribers that careful This effect reduces the metabolism of ciclosporin,
incremental titration of the dose, and lowering the terfenadine, and calcium channel blockers (other
dose of valproic acid if administered concomitantly than amlodipine and diltiazem), resulting in
may help to avoid reactions. Any patient who increased plasma concentrations which could be
develops a rash should be evaluated promptly and clinically important (3, 4). In recent studies,
consideration given to immediate withdrawal of the grapefruit juice was administered simultaneously
drug. with these drugs. However, the study did not
demonstrate how long patients should wait after
Reference: Australian Adverse Drug Reactions Bulletin, taking the juice and before taking the drugs and the
16: 3 (1997).

WHO Drug Information Vol. 11, No. 2, 1997 Regulatory Matters

duration of metabolic inhibition. There is no Ticlopidine has not been authorized for marketing in
evidence that eating grapefruit also causes inter- the United Kingdom but is used on a named-patient
actions. (compassionate use) basis and the manufacturer's
product information leaflet is directed both to
Patients are therefore advised to avoid drinking physicians and patients.
grapefruit juice when taking the drugs indicated
Reference: Committee on Safety of Medicines. Current
above. Product information to physicians and Problems in Pharmacovigilance, No. 23 (1997).
patients is to be amended accordingly.

References Selegiline-associated
1. Committee on Safety of Medicines. Current Problems hypertensive reactions
in Pharmacovigilance, No. 23 (1997).
United States of America —The product informa-
2. Edwards, D.J. et al. Drug metabolism and Disposition, tion of the monoamine oxidase inhibitor, selegiline,
24: 1287–1290 (l996).
which is used for Parkinson‘s disease, has been
3. Fuhr, U. et al. The fate of naringin in humans: a key to modified to note that rare hypertensive reactions
grapefruit juice – drug interactions? Clinical Pharma- associated with the ingestion of tyramine-containing
cology and Therapeutics, 58: 365–373 (1995). foods have occurred. The risk may increase if
selegiline is prescribed in doses exceeding 10 mg
4. Honing, P.K., Wortham, D.C., Lazarev, A. et al. per day. In addition to two reports received by the
Grapefruit juice alters the systemic bioavailability and Food and Drug Administration, one case of
cardiac repolarization of terfenadine in poor metabolizers hypertensive reaction has also been published.
of terfenadine. Journal of Clinical Pharmacology, 36:
345–351 (1996). Reference: FDA Medical Bulletin, 27: 5–6 (l997).

Triazolam and alprazolam Pemoline and liver failure

and interactions United States of America — The product labelling
for pemoline products has been modified to include
United States of America — The prescribing
a boxed warning describing the risk of liver failure
information on triazolam and alprazolam has been
and to indicate that the drug should not ordinarily
revised to indicate that both are metabolized via the
be considered as first-line therapy for attention
cytochrome P450 3A (CYP 3A) pathway, and
deficit hyperactivity disorder (ADHD).
consequently interact with other drugs and foods
that use this same pathway. Since marketing in 1975, 13 cases of acute hepatic
failure have been reported to the Food and Drug
Triazolam is contraindicated with ketoconazole, Administration, 11 of which have resulted in death
itraconazole and nefazodone, and alprazolam with or liver transplantation. It is not clear whether
ketoconazole and itraconazole. baseline and liver function tests are predictive of
Reference: FDA Medical Bulletin, 27: 7 (1997).
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
Ticlopidine and be conservative due to under-reporting and given
the long latency period before the appearance of an
white blood cell disorders association.
United Kingdom — Ticlopidine, an antiplatelet Reference: FDA Medical Bulletin, 27: 6 ( l997).
drug, is used for thrombosis prophylaxis. It causes
neutropenia in about 2.4% of patients and
agranulocytosis may occur within the first three Ritonavir and interactions
months of treatment. It is therefore important to
monitor differential white blood cell counts every 2 United States of America — Based on post-
weeks during this period and patients should be marketing experience, the product information of
requested to report any symptoms of fever, sore ritonavir, a protease inhibitor, now includes new
throat or mouth ulceration. information on drug interactions. Cardiac and
neurologic events have been reported when co-

Regulatory Matters WHO Drug Information Vol. 11, No. 2, 1997

administered with disopyramide, mexiletine, Reference: Information on Adverse Reactions to Drugs,

nefazodone or fluoxetine. Plasma concentrations of No.138, March 1997.
saquinavir increased more than 20-fold when
administered concomitantly. Contraindications have
been added concerning ergot alkaloid preparations Metformin and lactic acidosis
and pimozide. United States of America — The manufacturer of
metformin has emphasized the importance of
In addition, the sections dealing with warnings and appropriate patient selection in order to minimize
adverse reactions have been revised to include the risk of lactic acidosis in patients with a pre-
allergic reactions, hepatic transaminase elevation, disposition to significant drug accumulation and
hepatic dysfunction, seizure, hyperglycaemia, renal impairment, or in patients with impaired ability
syncope, orthostatic hypotension and renal to clear lactate (tissue hypoperfusion, hypoxia, or
insufficiency. liver impairment).
Reference: FDA Medical Bulletin, 27: 6 (l997).
Metformin should consequently be withheld or
discontinued in patients with evidence of renal
Cidofovir and renal impairment disease or dysfunction, unstable haemodynamic or
impaired hepatic function or excessive alcohol
United States of America — Following several intake, or who are undergoing procedures using
reports of severe renal impairment, a guideline intra-venous iodinated contrast media.
has been sent to physicians giving instructions on
appropriate patient selection, and emphasizing the Reference: FDA Medical Bulletin, 27: 7 ( l997).
importance of monitoring treatment to ensure that
cidofovir, an HIV protease inhibitor, is used
correctly. Cisapride and asthmatic attacks
Japan — Cisapride, a benzimidazole derivative
Prescribers are also alerted to two new contra- with prokinetic and antiemetic properties, has a
indications: pre-existing renal disease and similar action to metoclopramide and domperidone.
concomitant administration with agents having It is used in Japan to treat gastro-oesophageal
nephrotoxic potential. reflux disease caused or aggravated by broncho-
Reference: FDA Medical Bulletin, 27: 6 (l997). dilator therapy in chronic asthma patients.

The Pharmaceutical Affairs Bureau has received

Granulocyte macrophage colony- reports in which cisapride may have caused an
stimulating factor and interstitial asthmatic attack or has aggravated underlying
asthma or bronchospasm. Three cases have also
pneumonia been published in the scientific literature.
Japan — The recombinant granulocyte macro- Although the mechanism for this remains unclear,
phage colony-stimulating factor products filgrastim, cisapride may cause asthma through a hyper-
lenograstim and nartograstim have been approved sensitivity reaction or because of its pharmaco-
for the treatment of neutropenia caused by cancer logical action on the bronchial smooth muscles.
chemotherapy. Relevant precautions have been added to the
product information of these drugs in Japan.
The Pharmaceuticals Affairs Bureau has received
several reports of interstitial pneumonia associated Reference: Information on Adverse Reactions to Drugs,
with use of these drugs. All have a similar action in No.138, March 1997.
increasing neutrophils and macrophages and in
enhancing their function.
Withdrawal of fixed paracetamol-
The occurrence of excessive increases in neutro- methionine combination
phils, based on periodic blood testing, or the
appearance of early symptoms of pneumonia United Kingdom — SmithKline Beecham has
should be dealt with by a decrease in the dose, or decided to withdraw the fixed paracetamol-
discontinuation of treatment. 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

Regulatory Matters WHO Drug Information Vol. 11, No. 2, 1997

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

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

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

Essential Drugs WHO Drug Information Vol. 11, No. 2, 1997

Neurocysticercosis Hymenolepis nana infections

Adults: 15 mg/kg daily for 30 days. Recent data Adults: 2 g on day 1, followed by 1 g daily for 6
suggest that an 8-day course may be equally days.
For all other indications
Contraindications: Known hypersensitivity; first- Adults: 2 g as a single dose.
trimester pregnancy. Children <10 kg: 0.5 g as a single dose.
Children 10–35 kg: 1 g as a single dose.
Precautions: Liver function tests and blood counts
should be regularly monitored throughout treatment Precautions: Chronically constipated patients
when high doses are used. should receive a purgative before treatment.
Adverse effects: Occasionally, transient gastro-
intestinal discomfort and headache occur and, Adverse effects: Mild gastrointestinal disturb-
rarely, rash and fever, alopecia, reversible leuko- ances.
penia and reversible increases in serum levels of
hepatic enzymes.
Drug interactions : These will appear in tabulated Anthelminthic agent
form in the appendix of the published edition of the Tablet: 150 mg, 600 mg
WHO Model Formulary.
Uses: Infections due to Taenia saginata, T. solium,
Hymenolepis nana and Diphyllobothrium latum.
Anthelminthic agent Intestinal taeniasis
Chewable tablet: 100 mg, 500 mg Adults and children over 4 years: a single dose of
Uses: Echinococcus multilocularis and E. granulo- 5–10 mg/kg.
sus infections prior to surgery. Hymenolepiasis
Adults and children over 4 years: a single dose of
Dosage: Each dose should preferably be taken 15–25 mg/kg.
between meals. Adults: 4.5 g daily in three divided
doses for 6 months. Diphyllobothriasis
Adults and children over 4 years: a single dose of
Contraindications: Known hypersensitivity and 10–25 mg/kg.
Adverse effects: Occasionally, transient gastro- Adults and children over 4 years: a total of 50 mg/
intestinal discomfort and headaches occur and, kg daily in three divided doses for 14 days. A
rarely, hypersensitivity reactions and liver abnor- corticosteroid such as prednisolone should be
malities. administered for 2–3 days beforehand and then
throughout the period of treatment.
Drug interactions : These will appear in tabulated
form in the appendix of the published edition of the Because of the risk of pericystic oedema, patients
WHO Model Formulary. with neurocysticercosis should always be treated in
a hospital setting.

NICLOSAMIDE Dermal cysticercosis

Anthelminthic agent Adults and children over 4 years: a total of 60 mg/
kg in three divided doses for 6 days.
Chewable tablet: 500 mg
Uses: Infections due to Taenia saginata, T. solium, Contraindications: Ocular cysticercosis.
Hymenolepis nana and Diphyllobothrium latum. Adverse effects: Occasionally, abdominal dis-
Dosage : The tablets should be chewed thoroughly comfort, nausea, headache, dizziness and
before swallowing and washed down with 250 ml drowsiness. Rarely, pyrexia, urticaria and rectal
water. bleeding.

WHO Drug Information Vol. 11, No. 2, 1997 Essential Drugs

Drugs used for intestinal In symptomatic trichostrongyliasis, a single dose of

pyrantel or albendazole (400 mg) is effective.
nematode infections
In capillariasis, prolonged treatment with mebenda-
Intestinal nematode infections include ascariasis, zole or albendazole offers the only prospect of cure.
hookworm infection, strongyloidiasis, enterobiasis,
trichuriasis, trichostrongyliasis and capillariasis.
Ideally, all cases of hookworm infection should be ALBENDAZOLE
treated. However, when this is impracticable, Anthelminthic agent
priority should be given to women in second- and Chewable tablet: 200 mg, 400 mg
third-trimester pregnancy, children and debilitated
patients. In hookworm, broad-spectrum Uses: Ascariasis, hookworm infections, strongy-
anthelminthics should be preferred wherever other loidiasis, enterobiasis, trichuriasis, trichostrongy-
nematode infections are endemic. Both liasis and capillariasis.
mebendazole and albendazole are effective.
Dosage: Adults and children over 2 years: a single
Levamisole is effective in the treatment of mixed dose of 400 mg is sufficient to eliminate most cases
ascaris and hookworm infections and pyrantel has of ascariasis, hookworm infection, enterobiasis,
been highly effective in some community-based trichostrongyliasis, and moderate trichuriasis
control programmes, although several doses are infections. Strongyloidiasis and heavy trichuriasis
often needed to eliminate Necator americanus infections require a 3-day course of treatment. The
infection. Anaemic patients require supplementary dose should be continued for at least 10 days in
iron salts and should receive ferrous sulfate (200 capillariasis.
mg for adults daily) for at least 3 months after the
haemoglobin concentration has regained the Contraindications: Known hypersensitivity; first-
threshold of 12 g/100 ml. trimester pregnancy.
Adverse effects: Occasionally, transient gastro-
In strongyloidiasis, all infected patients should be intestinal discomfort and headache.
treated. Albendazole, 400 mg administered for 3
consecutive days, is well tolerated by both adults
and children over 2 years of age and reports LEVAMISOLE
suggest it may eradicate up to 80% of infections. Anthelminthic agent
Tablet: 40 mg, 50 mg (as hydrochloride)
Mebendazole has also been used but to be effec-
tive it must be administered for longer periods as it Uses: Ascariasis and mixed ascariasis/hookworm
has a limited effect on larvae and hence upon the infections.
cycle of autoinfection. Ivermectin is also effective
against strongyloidiasis. Dosage: Adults and children: a single dose of 2.5
mg/kg is used widely for both individual treatment
In enterobiasis, all household members should be and community-based campaigns. In cases of
treated concurrently with a single dose of mebend- severe hookworm infection, a second dose may be
azole, albendazole or pyrantel. Since reinfection given 7 days after the first.
readily occurs, at least one further dose is required
2–4 weeks later. Piperazine is also effective, but Adverse effects Occasionally abdominal pain,
must be taken regularly for at least 7 consecutive nausea, vomiting, dizziness and headache occur.

In trichuriasis, chemotherapy is required whenever MEBENDAZOLE

symptoms develop or when faecal samples are Anthelminthic agent
found to be heavily contaminated (over 10 000 Chewable tablet: 100 mg, 500 mg
eggs per gram). A single dose of albendazole (400
mg) or mebendazole (500 mg) is effective in mild to Uses: Hookworm infections, enterobiasis, ascaria-
moderate infections, but heavy infections require a sis, trichuriasis and capillariasis. Mass treatment
3-day course. control programmes.

Essential Drugs WHO Drug Information Vol. 11, No. 2, 1997

Dosage: Each dose should preferably be taken Contraindications: Known hypersensitivity.

between meals. All doses are suitable for adults
and children over 2 years. Precautions: Lower doses should be administered
to patients with hepatic function impairment.
A single dose of 500 mg. Adverse effects: Occasionally, mild gastro-
intestinal disturbance, headache, dizziness,
Hookworm infections and trichuriasis drowsiness, insomnia and rash have been reported.
A dose of 100 mg twice daily for 3 consecutive
days. A second course may be given after 3 to 4 Drug interactions: Pyrantel, piperazine and older
weeks if eggs persist in the faeces. Recently, a anthelminthics have antagonistic effects; they
single dose of 500 mg has been effective in mass should not be administered together.
treatment control programmes, and this will improve
compliance. Drugs used for tissue
Enterobiasis nematode infections
A single dose of 100 mg repeated at least once Tissue nematode infections include dracunculiasis,
after an interval of 2 to 4 weeks. All members of the trichinellosis, cutaneous larva migrans, visceral
household should be treated at the same time. larva migrans, anisakiasis and angiostrongyliasis.
In dracunculiasis, metronidazole (25 mg/kg daily for
Capillariasis 10 days, with a daily maximum of 750 mg for
A dose of 200 mg daily for 20–30 days. children) provides rapid symptomatic relief. It also
weakens the anchorage of the worms in the sub-
For mass treatment control programmes: A single cutaneous tissues, and they can then be removed
dose of 500 mg four times a year. by traction. However, since it has no effect on pre-
emergent worms, it does not immediately prevent
Contraindications: Known hypersensitivity; first- transmission.
trimester pregnancy.
Each case of confirmed or even suspected trichinel-
Adverse effects: Occasionally, transient gastro- losis infection should be treated in order to prevent
intestinal discomfort and headache. the continued production of larvae. In both adults
and children, mebendazole (200 mg for 5 days),
Drug interactions: These will appear in tabulated albendazole (400 mg for 3 days), and pyrantel (10
form in the appendix of the published edition of the mg/kg daily for 5 days) are each effective. Pred-
WHO Model Formulary. nisolone, 40–60 mg daily, may be needed to
alleviate allergic and inflammatory responses.
PYRANTEL In cutaneous larva migrans, albendazole in a single
Anthelminthic agent dose of 400 mg is effective. Calamine lotion
Chewable tablet: 250 mg (as embonate) provides symptomatic relief.
Oral suspension: 50 mg (as embonate)/ml
In visceral larva migrans caused by Toxocara canis
Uses: Hookworm infections, ascariasis, entero- and, less frequently, T. cati, treatment should be
biasis and trichostrongyliasis. reserved for symptomatic infections. A 3-week oral
course of diethylcarbamazine kills the larvae and
Dosage: Adults and children: A single dose of 10 arrests the disease, but established lesions are
mg/kg is sufficient to eliminate many cases of irreversible. To reduce the intensity of allergic
hookworm infection, ascariasis, enterobiasis and reactions induced by dying larvae, dosage is
trichostrongyliasis. Patients with enterobiasis, commonly commenced at 1 mg/kg twice daily and
however, should receive a second dose after 2–4 raised progressively to 3 mg/kg twice daily (adults
weeks. Heavy hookworm infections are relatively and children).
resistant and three further doses should be given
on consecutive days. In order to suppress allergic inflammatory
responses in patients with ophthalmic lesions,
Mass treatment control programmes: A single dose prednisolone should be administered concurrently,
of 2.5 mg/kg 3 or 4 times a year. either topically or systemically.

WHO Drug Information Vol. 11, No. 2, 1997 Essential Drugs

In anisakiasis, anthelminthic treatment is rarely The recommended dosage regimen should be

necessary. Prevention is dependent upon informing strictly followed to minimize allergic reactions to
communities of the hazards of eating raw or dying parasites.
inadequately prepared salt-water fish, and the need
for early evisceration of fish after capture, and Contraindications: During pregnancy, treatment
freezing of seafood at – 20 ° C for at least 60 hours should be delayed until after delivery. Dosage
before sale. should be reduced in patients with renal
impairment. Patients who are severely ill with other
In angiostrongyliasis, symptomatic treatment acute diseases should not receive diethylcarba-
pending spontaneous recovery is often all that is mazine until after recovery.
Adverse effects: Immunological disturbances
Antifilarials (similar to the Mazzotti reaction in onchocerciasis)
are induced by disintegrating microfilariae. Fever,
Infections caused by filaria include (1) loiasis, (2) headache, dizziness, anorexia, malaise, urticaria,
lymphatic filariasis and (3) onchocerciasis. vomiting and asthmatic attacks may occur within a
few hours of the first dose and usually subside by
1. Loiasis the fifth day of treatment. When microfilaraemia is
Diethylcarbamazine (DEC) is effective against both heavy, there is a risk of meningoencephalitis and
the adult worms and larvae of all forms of the para- the advantages of treatment must be weighed
site and a single weekly dose is normally effective against the possibility of life-threatening encepha-
as prophylaxis. During individual treatment, litis. Reversible proteinuria may occur.
particularly of persons with heavy microfilaraemia
(>50 000 microfilariae/ml blood), a condition
simulating meningoencephalitis can occasionally 2. Lymphatic filariasis
occur. This probably results from sludging of Diethylcarbamazine has both microfilaricidal and
moribund microfilariae within the cerebral capilla- macrofilaricidal activity, but some adult worms may
ries. The frequency of meningoencephalitis survive even after repeated courses of therapy.
associated with DEC therapy of loiasis is reported Total cumulative dosages of 72 mg/kg are generally
as 1.25%, with a mortality rate of about 50% in recommended for Wuchereria bancrofti infections,
affected patients. Permanent cerebral damage is with half this dose for Brugia malayi and B. timori
common among patients who survive and this infections. In all cases where microfilaraemia is
possibility should be considered when treatment is heavy, treatment is best initiated with smaller
decided upon. Treatment of heavily infected doses for 2–3 days in order to avoid the danger of
patients should thus begin at low dosage and immunological reactions.
corticosteroid and antihistamine cover should be
provided for the first 2–3 days. 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.
Antifilarial agent Mass treatment control programmes: A single
Tablet: 50 mg (dihydrogen citrate) yearly dose of 6 mg/kg diethylcarbamazine can be
used. The addition of DEC to table salt at a
Uses: Treatment of loiasis and prophylaxis against concentration of 0.1–0.3% is also effective.
loiasis in temporary residents of endemic areas.
Adults: 1 mg/kg as a single dose initially, doubled Antifilarial agent
on 2 successive days and then adjusted to 2–3 mg/ Tablet: 50 mg (dihydrogen citrate)
kg three times daily for a further 18 days. Uses: Individual and community treatment of
Prophylaxis systemic lymphatic filariasis and occult filariasis
Adults: 300 mg weekly for as long as exposure (tropical pulmonary eosinophilia).

Essential Drugs WHO Drug Information Vol. 11, No. 2, 1997

Dosage: The following dosage schedules are 3. Onchocerciasis

intended only as a guide since many countries have
Ivermectin has transformed the treatment of oncho-
developed their own specific treatment regimens.
cerciasis and it is now used extensively in control
The doses given are suitable for both adults and
programmes in many countries. Its microfilaricidal
children aged over 10 years. Children under 10
action is more persistent and less liable to provoke
years of age should be given half the total adult
adverse reactions than that of diethylcarbamazine.
A single oral dose reduces the microfilarial count to
W. bancrofti infections low levels for up to a year. It appears to kill both
6 mg/kg daily for 12 days administered orally, microfilariae and to inhibit their expulsion from the
preferably in divided doses after meals. uterus of female worms. Available data suggest that
a single annual dose will suppress microfilaraemia
Mass treatment control programmes: 6 mg/kg to a degree that prevents development of clinical
weekly, monthly or as a single annual dose. disease. Although the drug is generally well
tolerated, it is advisable to have medical support
B. malayi and B. timori infections available during treatment programmes. Patients
3–6 mg/kg daily for 6–12 days administered orally, with a heavy microfilarial load occasionally react
preferably in divided doses after meals. adversely and, rarely, transient severe postural
hypotension has occurred within 12–24 hours of
Mass treatment control programmes: 3–6 mg/kg, treatment.
6 times either weekly or monthly.
Treatment of pregnant women with ivermectin
In China and India several trials have shown that should be limited to those situations where the risk
when used consistently over a period of at least 6 of complications from untreated onchocerciasis
months, table salt fortified with diethyl-carbamazine exceeds the potential risk to the fetus from
at a concentration of 0.1% can eliminate W. treatment. Diethylcarbamazine is now largely
bancrofti lymphatic filariasis. A superseded as a microfilaricide in onchocerciasis
concentration of 0.3% for 3–4 months may be because of the frequency with which it induces
necessary where B. malayi is endemic. severe host (Mazzotti) reactions characterized by
itching, skin rash, oedema, pain and swelling of the
Occult filariasis lymph nodes, fever and severe eye lesions.
A dose of 8 mg/kg daily for 14 days repeated, as
necessary, if symptoms return. Suramin is the only macrofilaricide that is currently
available for use against Onchocerca volvulus .
Contraindications: During pregnancy, treatment Administered intravenously over a period of several
should be delayed until after delivery. Dosage weeks, suramin also kills microfilariae. It is,
should be reduced in patients with renal impair- however, one of the most toxic substances used in
ment. Patients who are severely ill with other acute clinical medicine and should always be given under
diseases should not receive diethylcarbamazine medical supervision in a hospital. A careful assess-
until after recovery. ment must always be made of the patient's capacity
to withstand the effects of suramin treatment both
Adverse effects: Immunological disturbances before and during administration.
(similar to the Mazzotti reaction in onchocerciasis)
are induced by disintegrating microfilariae. Fever,
headache, dizziness, anorexia, malaise, urticaria, IVERMECTIN
vomiting and asthmatic attacks may occur within a Antifilarial agent
few hours of the first dose and usually subside by
the fifth day of treatment. When microfilaraemia is
Scored tablet: 6 mg
heavy, there is a risk of meningoencephalitis and Uses: As a microfilaricide in the suppressive treat-
the advantages of treatment must be weighed ment of onchocerciasis. Although it may not be
against the possibility of life-threatening encepha- effective against immature larval stages of O.
litis. Reversible proteinuria may occur. Recently- volvulus, it seems to impair the fecundity of the
killed adult worms often form nodules which are adult worm.
palpable subcutaneously and along the spermatic
cord; their death may result in transient lymphan- Dosage: Effective suppression of microfilariae is
gitis and an exacerbation of lymphoedema. obtained by annual administration of a single oral

WHO Drug Information Vol. 11, No. 2, 1997 Essential Drugs

dose of 150 µg/kg (adults and children over 5 years patients with impaired liver or renal function; total
of age). blindness — unless required for relief from intense-
ly itchy lesions.
Contraindications: Known hypersensitivity.
Precautions: Suramin is extremely toxic and
Precautions: Breast-feeding mothers should not should always be given under medical supervision
be treated until the infant is at least 1 week old, by in a hospital. A satisfactory food and fluid intake
which time the blood-brain barrier should be fully should be maintained throughout treatment. Urine
developed. samples should be taken before and during treat-
ment to detect the presence of albumin. Moderate
Adverse effects: Mild ocular irritation may occur. albuminuria indicates that the dose should be
Somnolence has been reported as well as Mazzotti reduced but heavy albuminuria with the passage of
reactions. Transient symptoms that may occur casts indicates the need for immediate discontinu-
within 3 days of treatment include headache, ation of treatment.
pruritus, rash, arthralgia, myalgia, lymphadeno-
pathy, lymphadenitis, oedema, fever, weakness, Adverse effects: Direct toxic effects require
tachycardia, nausea, conjunctivitis, diarrhoea and immediate withdrawal. Rarely, potentially fatal loss
vomiting, including reactions resulting from a heavy of consciousness may occur during the first
microfilarial load. injection. Heavy albuminuria, stomal ulceration,
Drug interactions : These will appear in tabulated exfoliative dermatitis, severe diarrhoea, prolonged
form in the appendix of the published edition of the high fever and prostration may occur. Lesser, but
WHO Model Formulary. common, symptoms include tiredness, anorexia,
malaise, polyuria, increased thirst and tenderness
of the palms of the hands and soles of the feet.
SURAMIN SODIUM Indirect reactions due to the death of the parasites
Antifilarial agent including urticaria, swelling, tenderness and
Powder for injection: 1 g in vial abscess formation around adult worms, painful
immobilization of the hip, intensely itchy urtico-
Uses: As a macrofilaricide in the curative treatment papular rash, inflammatory and subsequent
of onchocerciasis. degenerative changes in the optic nerve and retina,
and swollen, painful joints particularly of the hands
Dosage: Suramin is administered by slow intra- and feet.
venous injection of a 10% solution in water for
injection. Drug interactions : These will appear in tabulated
form in the appendix of the published edition of the
Adults: a total of 66.0 mg/kg should be WHO Model Formulary.
administered in six incremental weekly doses
apportioned as follows.
Week 1 2 3 4 5 6 Schistosomiasis, a waterborne parasitic infection,
is caused by several species of trematode worms
Dose(mg/kg) 3.3 6.7 10.0 13.3 16.7 16.0 (blood flukes). Its socioeconomic impact as a
parasitic disease is outstripped only by that of
malaria. Intestinal schistosomiasis is caused
Because loss of consciousness has occasionally principally by Schistosoma mansoni, as well as
occurred, the first injection (0.2 g in 2 ml of water S. japonicum, S. mekongi, and S. intercalatum.
for injection for a 60 kg adult) should be Urinary schistosomiasis is caused by S. haema-
administered with particular caution. Wait at least tobium. The latter is an important predisposing
one minute after injecting the first few microlitres, cause of squamous-cell cancer of the bladder.
inject the next 0.5 ml over 30 seconds and wait one
more minute. Inject the remainder over several Praziquantel has transformed the treatment of
minutes. schistosomiasis and is often effective in a single
Contraindications: Previous anaphylactic dose against all species of the parasite. It can be of
reactions or sensitivity to suramin; pregnancy; particular value in patients with mixed infections
children less than 10 years old; elderly or infirm and those who do not respond adequately to other

Essential Drugs WHO Drug Information Vol. 11, No. 2, 1997

drugs. It is also extremely well tolerated and well infections unresponsive to oxamniquine, co-
suited for mass treatment control programmes. infections of S. haematobium and S. mansoni
Extensive use over several years has provided no otherwise requiring treatment with both metrifonate
evidence of serious adverse effects or long-term and oxamniquine.
toxicity, nor has mutagenic or carcinogenic activity
been shown in animals. Despite lack of terato- Dosage: The dosage for both adults and children is
genicity and embryotoxicity, however, it is given in the table below.
preferable to delay treatment during pregnancy until
after delivery, unless absolutely essential. Adverse effects: In patients with heavy worm
loads, these include abdominal discomfort, nausea,
Other drugs still widely used for schistosomiasis headache, dizziness, drowsiness and rarely,
include metrifonate, which is active against S. pyrexia, urticaria and rectal bleeding.
haematobium, and oxamniquine, which is effective
against S. mansoni. Drug interactions : These will appear in tabulated
Strains resistant to oxamniquine, which have been form in the appendix of the published edition of the
reported in South America, have been treated WHO Model Formulary.
effectively with praziquantel. Although neither metri-
fonate nor oxamniquine has been shown to be
teratogenic or embryotoxic, it is preferable to delay METRIFONATE
treatment during pregnancy until after delivery Anthelminthic agent
unless immediate intervention is essential. There is Tablet: 100 mg
no information on whether metrifonate or oxamni-
Uses: Urinary schistosomiasis.
quine is excreted in breast milk, and it is therefore
preferable not to administer these drugs to nursing
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
Anthelminthic agent undertaken in communities recently exposed to
Tablet: 600 mg insecticides or other agricultural chemicals with
Uses: Intestinal schistosomiasis due to S. anticholinesterase action. Treated patients should
japonicum, S. intercalatum or S. mekongi which is not receive depolarizing neuromuscular blocking
not responsive to oxamniquine. S. mansoni 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 “cure” is considered to be a complete absence of eggs from the urine or faeces 6 months after completion of
In patients who have not been cured.
In some areas dosage may be increased to 60 mg/kg.

WHO Drug Information Vol. 11, No. 2, 1997 Essential Drugs

Adverse effects: Abdominal pain, nausea, transient fever, peripheral blood eosinophilia and
vomiting, diarrhoea, headache and vertigo are scattered pulmonary infiltrates (Loeffler’s
common. Cholinergic symptoms very rarely occur syndrome) following a 3-day course of treatment.
with currently recommended dosages.
Drug interactions : These will appear in tabulated
Drug interactions : These will appear in tabulated form in the appendix of the published edition of the
form in the appendix of the published edition of the WHO Model Formulary.
WHO Model Formulary.

Drugs used in fluke infections

OXAMNIQUINE The intestinal flukes include Fasciolopsis buski,
Anthelminthic agent Metagonimus yokogawai, Heterophytes hetero-
Capsule: 250 mg phytes, Echinostoma spp and Gastrodiscoides
Syrup: 250 mg/5 ml hominis. The liver flukes include Clonorchis
sinensis, Opisthorchis viverrini, O. felineus and
Uses: Intestinal schistosomiasis (S. mansoni) both Fasciola hepatica. In some areas Clonorchis
in the acute stage and in patients with hepato- sinensis and Opisthorchis spp. infections are
splenic involvement. strongly associated with cholangiocarcinoma
(cancer of the bile duct). Lung flukes belong to the
Dosage: The effective dose varies. The following genus Paragonimus.
regimens provide general guidance but definitive
recommendations should be based on local Praziquantel has transformed the therapy of most
experience. fluke infections. Parasitological cure has been
obtained in virtually all cases (with the exception
West Africa, South America and the Caribbean of fasciola infections) without significant adverse
Adults: A single dose of 15 mg/kg. effects, but the drug should be taken for several
Children (less than 30 kg): 20 mg/kg in two divided days for treatment of paragonimus infections.
Evidence suggests that a single dose of tricla-
East and central Africa and the Arabian peninsula bendazole is effective and well tolerated in a high
Adults and children: 30 mg/kg in two divided doses proportion of cases of both fasciola and
paragonimus infections.
Egypt and southern Africa
Adults and children: 60 mg/kg administered over
2–3 days. The maximum single dose should not PRAZIQUANTEL
exceed 20 mg/kg. Anthelminthic agent
Tablet: 150mg, 600 mg
Precautions: Epileptic patients should remain
under observation for several hours following Uses: Intestinal, liver and lung fluke infections
treatment since seizures may be precipitated. including those due to Fasciolopsis buski, Meta-
Patients should be advised not to drive or operate gonimus yokogawai, Heterophytes heterophytes,
machinery for at least 24 hours, since drowsiness Echinostoma spp., Clonorchis sinensis, Opisthor-
may occur. chis viverrini, O. felineus and various species of
Adverse effects: Mild and transient dizziness and
drowsiness occur in about one-third of patients. Dosage:
Headache, vomiting and diarrhoea may also be Intestinal fluke infections
troublesome and intense orange-red discoloration Adults and children over 4 years: a single dose of
of the urine may occur. Rarely, hallucinations, 25 mg/kg is recommended.
excitation and epileptiform convulsions are report- Liver and lung fluke infections
ed; transient but inconsequential increases in levels Adults and children over 4 years: a dose of 25 mg/
of serum transaminases are sometimes detected. kg three times a day for 2 consecutive days
In Egypt and some other countries of the Eastern produces virtually 100% cure rates in the majority of
Mediterranean region many patients develop liver and lung fluke infections. A single dose of
40 mg/kg has also been shown to be effective.

Essential Drugs WHO Drug Information Vol. 11, No. 2, 1997

Precautions: Patients with paragonimus infections drowsiness. Rarely, pyrexia, urticaria and rectal
should always be treated in a hospital since flukes bleeding.
can invade the central nervous system.
Drug interactions: These will appear in tabulated
Adverse effects: Occasionally, abdominal form in the appendix of the published edition of the
discomfort, nausea, headache, dizziness and 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.

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

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

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

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]-

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

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

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

C1128H1702N269O336S20 182212-66-4

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

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

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


ceftizoximum alapivoxilum
ceftizoxime alapivoxil (+)-(pivaloyloxy)methyl (6R,7R)-7-[2-[2-(L-alanylamino)thiazol-
7 2 -(Z)-(O)-methyloxime)

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

carboxylate de [(2,2-diméthylpropanoyl)oxy]méthyle

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)-

C22H28N6O8S2 135821 -54-4

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

(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

clenoliximab immunoglobulin G 4 (human-Macaca monoclonal CE9γ4PE γ4-chain anti¬
human antigen CD 4), disulfide with human-Macaca monoclonal CE9γ4PE
κ-chain, dimer
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

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

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

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)

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)

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

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)
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

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)-


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
eplerenona éster metílico de la γ-lactona del ácido 9,11α-epoxi-17-hidroxi-3-oxo-
antagonista de los receptores

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

C24H30O6 107724-20-9

felvizumab immunoglobulin G 1 (human-mouse monoclonal, γ-chain anti-respiratory
syncytial virus), disulfide with human-mouse monoclonal κ-chain, dimer
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
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

fudosteine expectorant
(-)-acide (2R)-2-amino-3-[(3-hydroxypropyl)sulfanyl]propanoïque
fudostéine expectorant
fudosteína expectorante
C6H13NO3S 13189-98-5

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-
antagoniste des récepteurs du NMDA

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

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

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

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

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

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
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

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

interferonum alfacon-1
interferon alfacon-1 N-L-methionyl-22-L-arginine-76-L-alanine-78-L-aspartic acid-79-L-glutamic
158-L-leucineinterferon α1 (human lymphoblast reduced)
interféron alfacon-1 N-L-méthionyl-[22-L-arginine-76-L-alanine-78-L-acide aspartique-79-L-acide
158-L-leucine]interféron α1 (lymphoblastique humain réduit)
interferón alfacón-1 N-L-metionil-22-L-arginina-76-L-alanina-78-ácido L-aspártico-79-ácido
158-L-leucinainterferón α1(linfoblástico humano reducido)
C670H1366N236O259S9 118390-30-0



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

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

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

licostinel NMDA receptor antagonist
licostinel antagoniste des récepteurs du NMDA
licostinel antagonista de los receptores de NMDA
C8H3CI2N3O4 153504-81 -5

lumefantrine (±)-2,7-dichloro-9-[(Z)-p-chlorobenzylidene]-α[(dibutylamino)methyl]fluorene-
luméfantrine (1RS)-2-(dibutylamino)-1-[(Z)-2,7-dichloro-9-(4-chlorobenzylidène)-
lumefantrina (±)-2,7-dicloro-9-[(Z)-p-clorobencilideno]-α[(dibutilamino)metil]fluoreno-
C30H32CI3NO 82186-77-4

and enantiomer
et énantiomère
y enantiómero

milacainide antiarrhythmic
milacaïnide antiarythmique
milacainida antiarrítmico

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

C19H25N3O 141725-10-2

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

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

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

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

oberadilol (±)-4-chloro-2-[3-[[1,1-dimethyl-2-[p-(1,4,5,6-tetrahydro-4-methyl-6-oxo-
β-adrenoceptor antagonist
obéradilol 4-chloro-2-[3-[[1,1-diméthyl-2-[[4-(4-méthyl-6-oxo-1,4,5,6-tétrahydro=
antagoniste β-adrénergique
oberadilol (±)-4-cloro-2-[3-[[1,1-dimetil-2-[p-(1,4,5,6-tetrahidro-4-metil-6-oxo-
antagonista de los receptores β-adrenérgicos
C 2 5 H 3 0 CIN 5 O 3 114856-44-9

opanixil 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)-N-ethyl-α,α,α-trifluoro-
opanixil 4-amino-2-(4,4-diméthyl-2-oxoimidazolidin-1-yl)-N-éthyl-
opanixilo 4-amino-2-(4,4-dimetil-2-oxo-1-imidazolidinil)-N-etil-α,α,α-trifluoro-
C19H21F3N6O2 152939-42-9

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

orazipone immunosuppressant
orazipone immunosuppresseur
orazipona inmunosupresor
C13H14O4S 137109-78-5

pegmusirudin L-vaiyl-L-valyl-L-tyrosyl-L-threonyl- L-α-aspartyl-L-cysteinyl-threonyl-L-α-
L-glutamylglycyl- L-asparaginyl-N6-carboxy-L-lysyl-L-cysteinyl-L-isoleucyl-
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-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

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

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



pleconaril 3-[4-[3-(3-methyl-5-isoxazolyl)propoxy]-3,5-xylyl]-5-(trifluoromethyl)-
pléconaril 3-[3,5-diméthyl-4-[3-(3-méthylisoxazol-5-yl)propoxy]phényl]-
pleconarilo 3-[4-[3-(3-metil-5-isoxazolil)propoxi]-3,5-xilil]-5-(trifluorometil)-
C18H18F3N3O3 153168-05-9

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

pralmorelin D-alanyl-3-(2-naphthyl)-D-alanyl-L-alanyl-L-tryptophyl-D-phenylalanyl-
growth hormone release stimulating peptide
pralmoréline D-alanyl-[3-(naphtalén-2-yl)-D-alanyl]-L-alanyl-L-tryptophyl-D-phénylalanyl-
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

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
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
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

(-)-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

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

C14H22N2O2 123441-03-2

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

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-
antitrombótico, antagonista del receptor del fibrinógeno
C21H29N5O6 170902-47-3

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

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-

fixateur de phosphate

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

captador del fosfato


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

sibrafiban [[1-[(2S)-2-[[4-[(Z)-
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

tazomeline cholinergic

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

tazomelina colinérgico

C14H23N3S2 131987-54-7

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

trecovirsen P-thiothymidylyl-(5'→3')-2'-deoxy-P-thiocytidylyl-(5'→3')-P-thiothymidylyl-

trécovirsen P-thiothymidylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-P-thiathymidylyl-

trecovirseno P-tiotimidilil-(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-P-tiotimidilil-(5'→3')-P-

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

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

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

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

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

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

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

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


vatanidipine (±)-p-[4-(diphenylmethyl)-1-piperazinyl]phenethyl methyl 1,4-dihydro-2,6-
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

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


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

W H O Drug Information, Vol 11 No. 2, 1997 Proposed INN: List 77

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,
itamelina sustituyase el nombre químico por lo siguiente:
3-formil-5,6-dihidro-1 (2H)-piridinacarboxilato de (E)- p-clorofenilo,

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

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:


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:

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:

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

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:
palonosétron remplacer le nom chimique, la formule brute et la formule développée par :
palonosetrón sustituyanse el nombre quimico, la fórmula empírica y la fórmula empírica


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.

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:

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

lasinavir remplacer le nom chimique et la formule développée par:

2-méthylpropyl]amino]-5-oxo-4-(2,3,4-triméthoxybenzyl)pentyl]carbamate de

lasinavir sustituyase la fórmula desarrollada por:

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

teserstigminum terestigminum
teserstigmine terestigmine
téserstigmine térestigmine
teserstigmina terestigmina


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.

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

p. 18 nadroparinum calcicum remplacer la description par:

nadroparine calcique 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.

p. 29 enoxaparinum natricum remplacer la description par

énoxaparine sodique 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

Dénominations communes internationales proposées (DCI Prop.): Liste 65

(Informations pharmaceutiques OMS, Vol. 5, No, 2, 1991)

p. 13 tinzaparinum natricum remplacer la description par:

tinzaparine sodique 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

parnaparinum natricum remplacer la description par

parnaparine sodique 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

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.


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

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

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

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

Proposed INN: List 77 W H O Drug Information, Vol. 11, No. 2, 1997

Annex 1
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

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

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)
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

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
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.

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 )
-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- )

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

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

Annexe 1


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

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).
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

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

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,

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

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

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

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
-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

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.

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

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



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)
Denominada Crónica de la OMS desde enero de 1959. A partir de 1987, las listas de DCI se publican en Información Farmacéutica

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

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.

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

Anexo 2



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

* 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.
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).

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

Latin Español

-acum -aco antiinflamatorios del grupo del ibufenaco

-actidum -actida polipéptidos sintéticos de acción semejante a la corticotropina
-adolum -adol }
-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