International Nonproprietary Names for

Transcrição

World Health Organization
WHO Drug Information Vol 18, No. 1, 2004
WHO Drug Information
Contents
Regulatory Challenges
Drug regulatory authorities recommend
action
Herbal Medicines
3
Regulation of traditional medicines in Africa
Herbal medicines, patient safety and plant
conservation
27
29
Essential Medicines
Treating 3 million people living with HIV/AIDS
by 2005
AIDS medicines and diagnostics service
Fixed dose combination therapy
HIV antiretrovirals and diagnostics funding
World Bank ARV procurement manual
Research on new HIV microbicides
Regulatory and Safety Action
11
11
13
13
14
14
Nevirapine and hepatotoxicity
Antidepressants in adults and children
Recommended influenza vaccine
2004–2005
Olanzapine and cerebrovascular events
Olanzapine: hyperglycaemia and diabetes
Better labelling for ingredient sensitivities
31
31
32
32
32
33
Safety and Efficacy Issues
Safety of HIV therapies targeted by new
advisory committee
The risks and benefits of hormone
replacement therapy
Macrolides and warfarin interaction
Statin risk factors: myopathy and
rhabdomyolysis
Serotonin syndrome
Antidepressants: worsening depression
and suicidal behaviour
Use of SSRI antidepressants in children
and adolescents
Repaglinide and gemfibrozil interaction
Consultation Document
15
16
17
17
19
20
20
21
Vaccines and Biomedicines
World’s biological experts establish
standards
International reference materials
Quality, safety and efficacy of biological
medicines
22
23
The International Pharmacopoeia –
monographs for antiretrovirals
Indinavir sulfate
Nelfinavir mesilate
Nevirapine anhydrous
Proposed International
Nonproprietary Names:
List 90
Recommended International
Nonproprietary Names:
List 51
34
34
38
42
45
83
24
1
World Health Organization
WHO Drug Information
is now available at:
http://www.who.int/druginformation
2
Drug regulatory authorities recommend action
The Eleventh International Conference of Drug Regulatory Authorities (ICDRA) took place in Madrid,
Spain from 16 to 19 February 2004. The ICDRA was hosted by the Ministry of Health of Spain and the
Spanish Agency for Medicines and Health Products in collaboration with the World Health Organization (WHO). The Conference was opened by the Minister of Health of Spain, and the Director-General
of WHO. Over 240 participants from drug regulatory authorities in 113 countries were present.
Drug regulatory authorities are continually challenged by the rapid development and sophistication of
medicinal products, new technologies and health care techniques. Such developments pose a heavy
demand on regulatory control systems which are often unable to respond due to inadequate resources.
Together with enlargement of distribution and access channels, growing use of the Internet and
penetration of substandard and counterfeit medicines into many markets, the regulator’s task is becoming more and more daunting. One objective of the ICDRA is to give regulators the opportunity to
exchange information, leverage collaboration and strengthen vital links with other agencies experiencing similar problems.
During the conference, the four-day programme focused on presentation and discussion of many
important topics that have an impact on public health. A progress report on implementation of recommendations from the Tenth ICDRA held in Hong Kong in 2002 was introduced by Hong Kong SAR
China and presented by WHO. Participants appreciated progress made in many areas of medicines
regulation since the Tenth ICDRA in Hong Kong in 2002. As globalization continues and has a profound impact on the development and marketing of medicines, the need for strong international collaboration between regulatory authorities together with government commitment to strengthening regulatory systems and policies, and mechanisms to intensify international collaboration were highlighted
as the most effective means to safeguard public health. (http://www.who.int/medicines/organization/
qsm/activities/drugregul/icdra.shtml)
The ICDRA continues to be an important forum for WHO and drug regulatory authorities to meet and
discuss actual problems and latest developments in medicines regulation with the main objective of
improving safety, efficacy, quality and access of medicines. The ICDRA continues to support collaborative initiatives with a focus on harmonization of medicines control. The Twelfth ICDRA will be held in
the Republic of Korea in 2006
Recommendations
Recommendations from the Eleventh ICDRA will
form a basis for future collaboration among
Member States, drug regulatory authorities, WHO,
interested agencies and institutions, and set
priorities for WHO action and support.
Regulatory aspects
of access to medicines
The mission of regulatory authorities is to promote
and protect public health. The lack of access to
medicines remains a huge concern, whether
these are essential medicines, vaccines, orphan
drugs or drugs for tropical diseases. To facilitate
access, regulators and all other stakeholders
need to be actively involved in identifying difficulties and seeking solutions leading to balanced
approaches to access which do not compromise
public health safeguards.
Recommendations
• Regulators have a role and responsibility to
facilitate access to drugs of public health
importance including proposing changes to the
respective regulations in order to facilitate
access without compromising quality, safety and
efficacy.
3
• When considering marketing authorization
(registration) applications, regulators should
give priority to medicines of high public health
importance in their countries. Regulators should
consider mechanisms to facilitate registration,
such as reducing fees or other related costs.
• As part of the medicines approval process,
regulators should carry out an appropriate risk
benefit assessment to allow for adjustment to
the needs and profile of the anticipated patient
populations.
Strengthening of regulatory frameworks
for medicinal products
The establishment of a well-functioning national
regulatory system as an integral component of
effective public health leads to better patient
protection through provision of medicines which
are safe, efficacious and of good quality. Cooperation, communication and trust between
national regulatory authorities based on common
principles and harmonized approaches will
strengthen the effectiveness of national regulation
and international collaboration. Transparency is
an important aspect of regulatory systems and
helps to build public confidence, while facilitating
cooperation and information exchange among
regulators.
• Member States should strengthen their efforts to
increase transparency of the work of national
regulatory authorities. Regulatory guidelines,
procedures and criteria as well as data about
registered medicines should be made publicly
available to all stakeholders.
• National regulatory authorities should make
available to the public, in understandable
language, negative and positive assessment
reports (including pharmacovigilance reports).
• National regulatory authorities should provide
applicants for a marketing authorization with full
information on regulatory decisions and an
explanation of the reason for such decisions.
Pharmacovigilance Practices
Spontaneous reporting is the mechanism used for
compiling adverse drug reaction reports and
regulatory authorities take important decisions
based on these data. Pharmacovigilance is a
broad concept, and also includes the re-evaluation of marketed drugs, risk management,
communicating drug information, promoting
4
rational drug use and crisis preparedness. It is
becoming increasingly important to provide
training in all of these activity areas and to carry
out intensive monitoring of new drugs in order to
evaluate the risk/benefit. Increasingly, medicines
are being donated for off-label indications for
specific public health needs and it is important
that sufficient data is available to the national
regulatory authority on safety, efficacy and quality.
Recommendations
• Member States should be encouraged to involve
pharmacovigilance staff in public health risk
assessment, management and communication
for medicines safety activities including adverse
reactions monitoring, medicines re-evaluation,
drug information, rational drug use, lack of
efficacy and crisis preparedness.
• Increasingly, certain medicines are approved
based on special conditions, such as finalization
and reporting of Phase IV studies. National
regulatory authorities should collaborate on
harmonizing the terms of conditional approval,
and develop systems to allow sharing of
information on medicines in this category.
• All sponsors and donors of medicines should
provide sufficient data to allow the national drug
regulatory authority to be assured that the
product being donated, or recommended for
use, meets appropriate standards of safety,
quality and efficacy. Obligations to conduct postmarketing surveillance as a public health
protection measure should also lie with sponsors and donors, as appropriate. International
agencies and aid programmes should make
every effort to comply with these requirements
and provide the necessary data.
• Member States should be encouraged to
establish databases of clinical information
suitable for epidemiological studies to examine
and quantify signals of possible emerging risk.
• WHO should coordinate and develop training
resources in pharmacovigilance and pharmacoepidemiology and expand its commitment to
include training programmes in each of its
regions.
• WHO should provide, upon request, technical
advice and support to Member States on the
appropriateness of post-marketing surveillance
plans submitted by sponsors when a medicine
is being introduced to manage a specific public
health campaign in that country.
• WHO should investigate the feasibility and
potential utility of creating a database of “recommendations for action” arising from evaluations
made by national regulatory authorities of the
periodic safety update reports (PSURs) in order
to improve the usefulness of such information
by making this generally available.
Pharmacopoeias in a changing
regulatory environment
Pharmacopoeial standard-setting for starting
materials and finished dosage forms underpins
the work of drug regulatory authorities by providing the means of ensuring the quality of medicines, particularly multisource (generic) products.
Increased collaboration and coordination at
international level of pharmacopoeial bodies and
all related parties is needed: (i) for the development and analysis of quality control specifications;
(ii) to speed up development of pharmacopoeial
specifications; (iii) to address the increasing
diversity and complexity of impurity profiles and
limits set at international level, especially for
pharmaceutical starting materials; and (iv) to
promote independent and worldwide validation of
analytical methods to ensure the quality of traded
and sourced products internationally.
The promotion of good quality pharmaceutical
products, and the development of quality control
methods - in particular to detect counterfeit drugs
- is important for public health. Participants
agreed on the need for international harmonization of quality control specifications, and recognized WHO’s leadership role in providing normative guidance for quality control and quality
assurance of medicines, particularly in the
development and international harmonization of
pharmacopoeial specifications for new drug
entities, including antiretrovirals, anti-tuberculosis
and antimalarial medicines.
for medicines for neglected and emerging
diseases of high public health risk.
• WHO should continue to support the establishment of international chemical reference
substances (ICRS) and assist in their supply,
particularly for medicines used in the treatment
of diseases of high public health impact.
Regulatory assessment
of combination products
Combination products for various diseases have
always been used in medical practice. Today, HIV/
AIDS, tuberculosis and malaria are the major
infectious diseases threatening public health and
the focus of many national, regional and global
initiatives. Combination therapy is considered
essential for their treatment as well as for the
prevention of drug resistance. Attempts to
manage these diseases include the development
of fixed dose combinations (FDC) of individual
drugs to be administered together in one finished
dosage form. Well documented clinical evidence
of the efficacy and safety of the loose combination
is a key entry point for development of any FDC
drug. Currently, there are no uniform principles,
guidelines or international standards addressing
the development and regulatory assessment of
FDCs. Only a few countries have specific FDC
regulatory guidelines available and irrational
combinations are still common in several markets.
Recommendations
• In countries where specific guidelines do not
exist regulators need to establish clear quality,
safety and efficacy requirements for registering
fixed dose combination medicines, particularly
prescription-only drugs. Regulators should
critically review the existing fixed dose combination drugs on the market and withdraw those
which do not meet these requirements.
Recommendations
• Member States should encourage close collaboration between regulatory authorities and
pharmacopoeial secretariats/commissions.
• WHO is urged to create — as a matter of
urgency — model guidelines for regulatory
approval of prescription-only fixed dose combination drugs with special emphasis on drugs for
communicable diseases with high public health
impact.
• In collaboration with those concerned, WHO
should organize an international conference on
pharmacopoeial issues to exchange views and
experiences among pharmacopoeial bodies and
regulators.
Regulators, good clinical practice
and ethics
• In collaboration with parties concerned, WHO
should develop a harmonized approach to
providing internationally validated specifications
Application of good clinical practice (GCP)
guidelines assures that clinical studies on medicinal products meet scientific and ethical requirements. However, recent advances in medicine
may encompass areas of clinical research not
covered by existing GCP guidelines and this gap
5
should be filled since all clinical research, including research on gene therapy and biotechnology
products, should be conducted under rigorously
implemented GCP. Since data on the safety and
efficacy of innovative products may be limited, it is
important that national regulatory authorities
strengthen mechanisms to share knowledge and
experience. Given the increasing tendency to
involve vulnerable subjects in research, there is a
special need to strengthen the application of
ethical principles in research carried out in these
populations.
Recommendations
• Member States should implement good clinical
practice (GCP) guidelines to assure that clinical
studies follow scientific and ethical requirements. All clinical research, not only for medicinal products, needs to be regulated.
• Member States should ensure that informed
consent processes, particularly for vulnerable
populations and for obtaining biological samples
for genetic studies, meet all GCP, national and
ethical requirements.
• Member States should recognize that gene
therapy is a new complex area of medicine
needing rigorously implemented GCP and
ethical oversight.
• WHO is requested to gather existing knowledge
and experience of safety, efficacy and quality of
innovative biotechnology products and share
this information with Member States.
• WHO is requested to accelerate its work in
regulatory capacity building for assessment of
vaccines and medicines of public health importance and to explore options for providing
external regulatory expert support for assessment of clinical trial applications in countries
with limited resources.
Public health needs vs. the marketplace
Development of new drugs is often driven by
market forces. Some medicines for priority
disease of public health impact are commercially
unattractive, and this is often because they are
unaffordable by poor populations. Effective
mechanisms compensating for this market failure
are needed to bridge the gap. Regulators,
together with other stakeholders, can play an
important role in supporting initiatives aimed at
creating new drugs for diseases where there is no
market attractiveness by motivating investment
into research and development. However, there is
6
also a regulatory capacity gap to overcome, as
regulators from developing countries have limited
capacity to advise on drug development or assess
the safety, efficacy and quality of new drugs
created for diseases exclusively prevalent in
those settings.
Recommendations
• WHO is encouraged to continue cooperation
with Member States, industry and other
stakeholders in order to promote and facilitate
development of new treatments for diseases
that have little market potential, in particular for
diseases prevalent in developing countries
(neglected diseases). Mechanisms and incentives should be created for more proactive
involvement of national regulatory authorities in
all stages of research and development of these
products.
• WHO should continue facilitating regulatory
capacity building and networking among
regulators of different countries in order to
empower regulators in countries with limited
resources to take informed and evidence-based
decisions.
• WHO should explore the potential of creating
distance learning courses for regulators.
Safety of herbal medicines
The use of herbal medicines is increasing rapidly
worldwide. Although the reasons for this may vary
in different settings, the safety of herbal medicines is a common global concern. Both public
and national health authorities are committed to
making progress in ensuring the safe use of
herbal medicines. This is a very complicated and
complex issue because of differing regulatory
requirements, availability and suitability of
technical methods for quality control, postmarketing quality surveillance, and safety monitoring, the presence or absence of qualified
practitioners and consumer education. Major
issues concerning the safe use of herbal medicines are set out below.
Recommendations
• The safe use of herbal medicines requires
adequate regulation. Member States should
continue to adapt their national and/or regional
regulatory framework, including pharmacovigilance, to the specific requirements of herbal
medicines. WHO should continue to provide
support including guidance and training programmes.
• Quality assurance and quality control of herbal
medicines presents specific challenges. WHO
should continue to provide technical guidelines,
particularly for the quality control of combination
products and criteria for reference substances
and materials.
• Awareness amongst consumers on the benefits
and limitations of herbal medicines needs to be
strengthened. Member States should consider
preparing a policy on consumer information and
guidelines on the advertising of herbal medicines. WHO should provide general guidance to
support these activities.
• Providers of traditional/complementary health
care play an important role in the safe use of
herbal medicines. Member States should
explore appropriate mechanisms to ensure
adequate training and education of these health
care providers. WHO should provide policy and
technical guidance.
• Regulatory agencies should work together to
make the best use of scientific resources related
to herbal medicines. Sharing national experience and information is crucial. WHO should
facilitate these activities e.g. by providing
updated monographs on medicinal plants and
technical/regulatory guidance.
Assuring quality and safety
of blood products
Blood and blood products are essential for the
treatment of a number of life-threatening conditions. However, because blood may transmit
infectious agents this can also cause severe harm
to the recipients. During the Ninth and Tenth
ICDRAs, emphasis was therefore given to
procedures aimed at inactivating and removing
infectious agents. In order to avoid transmission
of infectious agents in a reliable manner, good
manufacturing practice (GMP) has to be implemented as an essential tool of quality assurance.
In addition, adherence to GMP at all levels of the
process, from donor to recipient, is a prerequisite
for consistent quality in the preparation of blood
and blood products.
Recommendations
• WHO’s policy to give high priority to the implementation of GMP in blood and plasma collection establishments is welcomed. Educational
programmes and training opportunities should
be continued and strengthened. Guidance
documents should be developed and/or updated.
• In order to facilitate the enforcement of GMP in
both blood/plasma collection and fractionation
facilities, WHO should promote joint inspections
between several countries under the guidance
of experienced inspectors.
• WHO should promote cooperation between
regulatory authorities with regard to GMP
compliance aimed at mutual agreements among
Member States.
• WHO should contribute to advancing the
technical expertise of regulatory authorities by
enabling the creation of regional networks to
facilitate their regulatory role in the area of blood
and blood products.
• WHO should facilitate the formation of a global
network of regulatory authorities for blood and
blood products.
Human tissue: problems
and challenges for regulators
The transplantation of human cells, tissues and
organs has become the treatment of choice for a
wide range of both fatal and non-fatal diseases.
The volume and complexity of activities relating to
transplantation is growing rapidly. The ethical and
safety risks of transplantation require effective
regulatory oversight at national level, and international cooperation.
Given the rapid global increase in the allogenic
transplantation of cells, tissues and organs, and
the associated ethical and safety risks this entails,
Member States should develop and implement
effective national regulation of procurement,
processing and transplantation of human cells,
tissues and organs.
Recommendations
• To facilitate this process, WHO is requested to
develop clear guidelines for the quality, safety
and efficacy of human cell, tissue and organ
transplantation.
• To complement the regulation of human cell,
tissue and organ transplantation, Member
States should develop and implement effective
surveillance after cell, tissue and organ transplantation.
• WHO should facilitate these surveillance
activities by development of appropriate written
standards and reference materials
7
Regulatory tools for providing
drug information
Accurate drug information is essential for the
rational use of medicines. Assessment of safety,
efficacy and quality of products includes also
assessment of product information provided by
the applicant of the marketing authorization.
Although national regulatory authorities have the
responsibility of validating the correctness and
appropriateness of the product information,
resource constraints may limit the capacity of
small regulatory authorities to be able to verify the
quality of information provided by the manufacturers.
Recommendations
• National regulatory authorities should establish
and implement requirements for product
information in line with the information provided
in the summary of product characteristics (SPC)
as part of their national drug registration
process.
• At national level, product information should be
harmonized for all products having the same
active ingredient.
• WHO should develop guidance and new tools to
control promotion and drug information.
• National regulatory authority-approved information should be the reference for providing
independent information and the benchmark for
controlling promotion. Approved information
should be made available on the regulatory
agency website.
Harmonization updates
Harmonization of technical requirements for the
registration of medicines can contribute to public
health by improving access to safe, effective and
good quality medicines. It can also facilitate
development of a fair and transparent regulatory
process, improve international collaboration,
reduce duplication of work by different regulatory
agencies and facilitate trade and competition.
Harmonization initiatives are ongoing in all WHO
regions. The major focus of many of those
initiatives is to first harmonize basic regulatory
requirements for generic drugs. In contrast, the
International Conference of Harmonization (ICH),
an initiative set up between the European Union,
Japan and USA, has been focusing on requirements to evaluate the quality, safety and efficacy
of new innovative drugs, thus avoiding the
necessity to duplicate many time-consuming and
8
expensive test procedures. ICH has established a
Global Cooperation Group for non-ICH harmonization initiatives to learn from ICH experience.
Recommendations
• WHO should continue to support regional and
sub-regional harmonization initiatives that
contribute to public health priorities. WHO
should facilitate information exchange between
different harmonization initiatives and report on
progress made in these initiatives through its
website.
• Regional harmonization initiatives should have
clear public health priorities according to local
needs, clear milestones to measure progress,
and appropriate resources to make progress
possible. Member states are encouraged to
facilitate harmonization which will increase
availability and accessibility of medicines.
• The ICH Global Cooperation Group should
continue to serve as a forum of discussion and
dialogue between ICH and non-ICH harmonization initiatives recognizing different regional
needs, priorities and capacity.
Promoting good regulatory practices
To meet the objectives of promoting and protecting public health, national regulatory authorities
need to carry out their functions effectively and
efficiently within a set of principles based on
transparency and good governance. The issues
that are necessary to promote good regulatory
practices nationally and internationally include
sustainability of resources, optimal structure,
effective cooperation within the agency and with
other agencies, transparency and accountability,
competence in evaluating efficacy, safety, and
quality, timeliness, independence, collaboration
as a service provider, sharing information,
harmonization, and mutual recognition. In many
cases, regulatory authorities do not have sufficient resources to carry out these activities. Most
importantly, regulatory agencies must be accountable and decision-making processes must be
transparent but this needs to be balanced against
the need for protecting the confidentiality of the
data that has been submitted by the manufacturer. Sources of information and the decision
process should be made publicly available
whenever possible.
Good regulatory practices thus cover an evolutionary process, with good practices built into the
systems which continuously reinforce collaboration and trust. Regulatory authorities should
establish mechanisms to ensure the quality of the
procedures they operate to.
Recommendations
• WHO should develop the tools and guidelines
needed to help national regulatory authorities
effectively implement the principles of good
regulatory practices.
• Member States should encourage interagency
cooperation for effective implementation of drug
regulation involving national regulatory authorities, customs, judiciary, police, civil society and
other relevant bodies set up to protect public
health.
• National regulatory authorities should formulate
a clear mission statement to reinforce effective
and efficient drug regulation and customer
satisfaction and make use of benchmarking to
improve their performance.
• National regulatory authorities should nurture
good regulatory governance (integrity, transparency, accountability, public service ethics) to
establish credibility and gain confidence. The
political governance responsible for national
regulatory authorities should promote teamwork,
overcome bureaucracy and streamline work.
• WHO should promote and provide technical
assistance for the evaluation of regulatory
capacity of national regulatory authorities in
order to analyse the situation and to undertake
necessary corrective measures.
Regulatory aspects of supply
of quality medicines
Access to quality medicines contributes to
improving human health and promoting wellbeing.
Rigorous implementation of good manufacturing
practices in the production of medicines will
ensure that only safe, quality products are
allowed on the market.
The importance of quality has been repeatedly
underlined by the occurrence in various countries
of counterfeit and substandard drugs. Evidence
shows an increase in production, distribution and
sale worldwide of counterfeit, spurious and
substandard medicines which do not comply with
any quality standards. Such products are a waste
of money for the people who buy them, prolong
treatment periods, exacerbate the conditions
being treated, increase the emergence of drug
resistance and can even cause death.
Special efforts have been undertaken to raise
awareness of the importance of regulatory
measures covering trade in products and starting
materials, including active pharmaceutical
ingredients and excipients, and implementation of
good manufacturing practices.
Recommendations
• Countries are encouraged to implement the new
WHO good trade and distribution practices,
intended to improve safety in the trade of
starting materials for pharmaceutical use.
• Member States are encouraged to implement a
pilot phase of the new WHO certification
scheme for pharmaceutical starting materials
which will give additional information on the
quality assurance system used in the production
of starting materials.
• WHO should continue the Pre-qualification
Project of medicines for priority diseases,
particularly HIV, malaria and tuberculosis.
• WHO should foster collaboration between
manufacturers and regulators in the implementation of GMP and provide training.
• WHO should continue to develop international
guidelines for registration of multisource
(generic) products.
Implications of regulatory decisions for
pharmacoeconomics
The mandate of regulatory agencies is to promote
and protect public health by ensuring that all
medicines entering the market meet quality
criteria, are safe and effective. The particular
expertise of national regulatory authorities may
make a valuable contribution to decisions on the
cost effectiveness and rational use of medicines
with regard to pharmacoeconomics and pricing.
In countries with limited resources it is difficult to
avoid direct involvement of national regulatory
authorities in pharmacoeconomics due to their
unique knowledge base.
Recommendations
• Where national regulatory agencies do not have
pricing responsibilities, they should ensure that
all information about safety and efficacy needed
to conduct economic evaluation is made
available to public bodies charged with reimbursement or pricing responsibilities.
9
• WHO should further support national regulatory
authorities in introducing, wherever needed,
elements which will contribute to pharmacoeconomic evaluation.
plored by countries. Countries should not
voluntarily exceed TRIPS obligations which
could limit flexibility and utility in protection of
national public health interests.
• WHO should carry out an analysis on the
affordability of medicines, particularly in developing countries experiencing such problems.
WHO should collect and make available to
Member States information on various pricing
options and mechanisms, examples of impact of
inadvertent marketing strategies to medicines
expenditure and potential public health implications of implementation of the TRIPS agreement.
• Member States should consider the potential
impact of usage patents on access and affordability of medicines.
• WHO should support pharmacoeconomic
studies based on scientific methodology in
countries and regions. Countries undertaking
pharmacoeconomic studies are encouraged to
present outcomes during the next ICDRA.
• Member States should study the potential of
using objective measurement units such as
defined daily doses (DDD) for monitoring drug
utilization and using these data for developing
rational national policies for pricing and increased access to essential medicines.
Current topics
The current topics session provides an opportunity to all regulators at the ICDRA to express their
views on the newly-emerging topics which have
not been reflected in the conference programme.
Often, the topics raised in this session lead to
substantial discussion during subsequent
ICDRAs.
Recommendations
• The full flexibility of the TRIPS agreement to
improve access to medicines should be ex-
• Countries should adopt the WHO Guidelines on
Developing Measures for Combating Counterfeit
Drugs, raise public and political awareness of
the problem of counterfeiting, increase national
and international cooperation, data exchange
between all stakeholders, including national
regulatory authorities, interested nongovernmental organizations, law enforcement agencies, industries, and relevant international
organizations.
• WHO, in collaboration with other stakeholders,
should develop a draft concept paper for an
international convention on counterfeit drugs.
WHO should convene a meeting of national
regulatory authorities to discuss further the
concept paper and related issues before the
next ICDRA.
• The comparator product for a multisource
(generic) medicine should be the first product
registered in the market with a complete data
file available. In case the originator is not
available on the market and there is no
multisource (generic) market leader, then other
appropriate solutions should be considered on
case by case basis.
• Doping in sports is a serious health problem and
is within the remit of drug regulation. National
regulatory authorities should remain vigilant and
provide the necessary resources to combat
such practices.
Associated events
Three meetings were held prior to the ICDRA. The Second Regional Workshop on Regulation of
Traditional Medicines (see page 28); the Pan American Drug Regulatory Harmonization Initiative
(PANDRH); and the pre-ICDRA Workshop on Counterfeit Drugs. This latter meeting was open to all
interested parties, with over 90 participants from major institutions and agencies, including regulators,
representatives of World Customs Organization, World Intellectual Property Organization and Interpol, industry representatives and NGOs. This workshop discussed the experience of various parties in
fighting counterfeit drugs and debated the feasibility of drawing up an International Framework Treaty
on Counterfeit Drugs.
10
Essential Medicines
Treating 3 million people
living with HIV/AIDS by 2005
The World Health Organization (WHO) has
launched a 3 by 5 strategy to treat three million
people with HIV by 2005. The strategy will reflect
the highest public health standards and will
leverage resources and synergize action among
interested stakeholders including Governments,
institutions, agencies and programmes working
with HIV-related activities at international, regional
and local levels.
The 3 by 5 strategy recommends simplified HIV
treatment regimens and expanded access to
medicines. The strategy will ensure the supply of
safe, effective and affordable medicines. WHO
will assess the quality, safety and clinical efficacy
of HIV medicines as single-drug, two-drug, and
three-drug combination treatment through the
WHO prequalification Project. A rigorous review
process and ongoing quality monitoring will limit
the entry of substandard and counterfeit medicines into the supply chain. In addition, the
strategy will help build local regulatory and
production capacity.
The current situation
HIV is rapidly spreading. It is on the rise again in
Western Europe because integrated prevention
and treatment programmes have not been
sustained. Countries in Eastern Europe are home
to the fastest-growing epidemic in the world which
is crippling social and economic development.
Over 1.5 million people are living with HIV in
Eastern Europe and Central Asia, compared to
only 30 000 in 1995. In Eastern Europe and
Central Asia, only 7000 people receive antiretroviral therapy for HIV, which is 9% of those in need
in the region. For many, the treatment is too
expensive or simply not available.
WHO has also recently announced a plan to
support the 3 by 5 strategy by expanding collaboration between national tuberculosis and HIV/
AIDS programmes to curb the growing pandemic
of TB/HIV co-infection, with a principal focus on
Africa where 70% of the world’s 14 million people
who are co-infected live. A key element will be to
rapidly expand voluntary HIV testing and counselling in TB programmes, with the aim of identifying
and referring more than half a million TB patients
who are HIV positive for treatment in the next two
years. With additional training for health workers,
TB programmes will also assist in HIV prevention,
treatment distribution and patient care. Forty
million people are currently infected with HIV, and
5 million more are infected every year. According
to WHO, one third of the world’s population is now
infected with the TB bacillus, with more than 8
million people developing the active disease and
2 million dying of it each year.
3 by 5 country support
The Initiative will provide assistance to all countries that are committed to scaling up treatment.
Ninety percent of those needing antiretroviral
medicines are found in just 34 high-burden
countries. Much of the work will focus on these
countries.
Following a formal request by national authorities
to the WHO Country Representative, an emergency fact-finding mission is made to each
country. The mission includes WHO and UNAIDS
staff, country and global partners. Planning will be
carried out through the WHO Country Office, with
support from HQ, the Regional Office and local
UNAIDS missions to gain country and partner
involvement and commitment.
Implementation of the strategy will immediately
follow the emergency mission and continue
through the years of the initiative and beyond
2005. Keeping 3 by 5 going will take perseverance, public support and international financial
aid. A situation room will be built in WHO headquarters to monitor all progress in all aspects of
implementation of 3 by 5.
Reference: Information obtained from various documents at http://www.who.int/3by5/en/ and www.who.int/
medicines
AIDS medicines
and diagnostics service
The AIDS medicines and diagnostics service
(AMDS) is a mechanism created to expand
access to quality, effective treatment for HIV/AIDS
11
Essential Medicines
by facilitating the increased supply of antiretrovirals (ARVs) and diagnostics in developing
countries. The AMDS represents the access and
supply arm of the 3 by 5 initiative, which aims to
multiply eightfold the number of people in developing countries receiving antiretroviral therapy by
2005.
The AMDS builds on years of work by UNAIDS,
WHO, UNICEF, the World Bank, and the global
health community, as well as on some recent
initiatives to address the AIDS treatment gap in
developing countries. It brings together
stakeholders and partners to maximize impact
towards meeting the 3 by 5 goal as rapidly as
possible.
What the AMDS will offer
Manufacturers currently have little idea of global
market demand and its development over time.
This situation affects both the price and volume of
medicine production. AMDS will provide the
necessary forecasting information to ensure that
volumes produced reflect the real need at an
affordable price.
The AMDS will offer technical support to countries
to improve drug procurement, in-country supply
management services, and local production
where applicable. The AMDS will assist buyers to
obtain best prices for individual or pooled demand
for core ARVs and diagnostics. Where necessary,
advice will be given on alternative sourcing
options and through existing procurement agencies.
The AMDS will provide a service to governments,
public interest and nongovernmental organizations (NGOs), health insurance and employerbenefit schemes, and other not-for-profit supply
channels.
Specific services provided to countries
• Selection of ARVs, guidance on simplified
treatment regimes, and selection of essential
HIV diagnostic tests; country-level technical
support to promote clinical guidelines and
update the national essential medicines list.
drug regulatory agencies in dealing with ARVs
(registration, inspection, importation, local
production and combination products).
• Global quality and product specifications for
ARVs to be used for procurement tenders and
contracts, including quality specifications for
new combination products.
• Information on prequalification of ARVs and
diagnostics, operational standards for evaluating supply agencies and quality control laboratories.
• Market intelligence on sources, prices, raw
materials. Access to information on sources and
prices of ARVs, other AIDS-related medicines
and diagnostics, price indicators for raw materials for local production.
• Procurement of core ARVs and diagnostics.
Global guidance and training programmes on
procurement; practical information for buyers;
access to the services of the WHO/UNAIDS
diagnostics buyers group; country assessments
and country-specific technical support to
improve procurement and distribution of ARVs;
access to global procedures to obtain economies of scale through international rate contracts; procurement services by or through
AMDS.
• Import taxes and margins. Information on tariffs,
taxes and margins in other countries; countryspecific technical and political support in efforts
to reduce them.
• Supply management and monitoring. Global
guidance and training programmes in drug
supply management and monitoring; country
assessments and consultant support in improving national supply systems; methods and
technical support in preparing institutional and
national estimates of ARV quantities needed;
full-time (inter)national technical staff to assist
national authorities.
• Patent status and licensing. Information on
patent status of ARVs in the country; global
guidance and country-specific support on the
legal importation of generic medicines and
voluntary/compulsory licensing.
• Local production and quality assurance (Global
guidance on good manufacturing practices
(GMP) standards; training courses on quality
assurance and GMP; technical support to the
national drug regulatory agency in inspecting
national production facilities.
• Registration and quality assurance. Global
guidance and information on regulatory matters
and registration status of ARVs; strengthening
Parallel to the medicines scheme (1), a project
run by WHO and UNAIDS assesses the quality,
safety and suitability of HIV diagnostics for use in
12
Essential Medicines
developing countries. Currently, 24 HIV test kits
that have met the criteria are available at reasonable cost. Four of these are produced in transition
economies. Information on the proprietary rights,
licensing and patent issues related to these
products is collected and made available.
cines into the supply channels. In addition, the
project helps build local regulatory and production
capacity by involving local experts in the evaluations. Prequalification also respects intellectual
property rights while reflecting the highest public
health standards.
WHO also evaluates CD4 and viral load tests to
monitor the efficacy of HIV drug treatment and is
helping countries to develop the skills to assess
the quality of diagnostic technologies. WHO also
provides training to health care workers to ensure
correct use of diagnostic tests (2).
Reference: http://www.who.int/3by5/en/ and
www.who.int/medicines0
References
1. http://www.who.int/medicines and http://www.who.int
3by5/en/
2. http://www.who.int/eht
Fixed-dose combination therapy
WHO’s Prequalification Project has added three
new generic products for first-line HIV treatment
to its list of medicines meeting WHO standards of
quality, safety and efficacy. The products are
fixed-dose triple therapy combinations containing
lamivudine, stavudine and nevirapine. Their
introduction in the list of prequalified medicines
will increase choice and competition, thus contributing to make HIV treatment progressively more
affordable.
The 3 by 5 strategy recommends simplified HIV
treatment regimens so that countries can quickly
expand access to antiretroviral medicines. These
new products will help countries which are
hardest-hit by the HIV epidemic get easy-to-take
medicines to the people who need them most
urgently. Single-pill combinations of antiretrovirals
are a major breakthrough for treatment in poor
countries as they improve the reliability and
security of supplies, which has so far been one of
the major obstacles to access. From a therapeutic
point of view, they reduce the number of pills, are
easier to take and promote greater patient
compliance. They also ensure that the right
dosage of each substance is given to the patient.
At present, the prequalification list contains over
50 single-drug, two-drug, and three-drug combinations, including the three newly qualified
products. In assessing products and their manufacturers, prequalification provides a rigorous
review process and ongoing quality monitoring.
One of the benefits of this initiative is that it limits
the entry of substandard and counterfeit medi-
HIV antiretrovirals and
diagnostics funding
The Global Fund to Fight AIDS, Tuberculosis and
Malaria, the World Bank, UNICEF and the Clinton
Foundation have announced agreements that will
make it possible for developing countries to
purchase high-quality AIDS medicines and
diagnostics at the lowest available prices, in many
cases for more than fifty percent less than is
currently available. Countries will be required to
provide guarantees of payment, to conduct long
term tenders and to ensure the security of drug
distribution.
The Global Fund and the World Bank are among
the world’s largest sources of funding commitments to AIDS treatment. The Global Fund
focuses more than 60 percent of the $US 2.1
billion committed for two years to 122 countries to
the fight against AIDS. The World Bank has
currently committed $US 1.6 billion to fight AIDS
through the Multi-country HIV/AIDS Programs
(MAP) and other AIDS operations, including
grants for the poorest countries. UNICEF spent
$US 111 million during 2003 in the fight against
AIDS and is rapidly accelerating the procurement
of antiretroviral medicines (ARVs) and AIDS
diagnostic equipment and tests for developing
countries.
The drugs in these agreements include individual
formulations and two- and three-drug fixed dose
combinations which have been prequalified by
WHO to assure quality and efficacy. These
medicines are critical components of the four
regimens recommended by WHO as “first line”
treatment for AIDS in its 3 by 5 initiative. In developing countries outside of Brazil, such lifesustaining therapy is available to fewer than
200 000 people living with HIV, although almost
six million require it.
The pharmaceutical manufacturers included in
these agreements are from South Africa and
India. The price for the most common first line
formulation under these agreements is as low as
13
Essential Medicines
$US 140 per person per year, one-third to onehalf of the lowest price otherwise available in
most settings. The diagnostic tests included in
these agreements are offered by five leading
medical technology companies and include CD4
tests and viral load tests. The prices available for
these tests under the agreement include machines, training, reagents and maintenance and
are up to 80% cheaper than otherwise available in
the market.
Reference: http://www.clintonpresidentialcenter.com
World Bank ARV
procurement manual
The Technical guide for HIV/AIDS medicines
and related supplies: Contemporary context and
procurement has been published by the World
Bank. The Technical Guide was developed to
address the specific requirements and unique
features of the medicines and supplies that are
part of the HIV/AIDS Care Package.
Project teams working on HIV/AIDS projects are
strongly encouraged to use and disseminate the
recommendations of the Guide. A dissemination
strategy is under preparation .
Reference: http://siteresources.worldbank.org/
intprocurement/Resources/Technical-Guide-HIVAIDS.pdf
14
Research on new
HIV microbicides
New antiviral agents are being developed by
scientists and HIV experts from the UK Medical
Research Council (MRC) and the Department for
International Development (DFID). The antiviral
properties of potential microbicides could work in
a number of ways. They could kill or otherwise
immobilize the virus, create a barrier to block
infection, or prevent the infection from taking hold
after it has entered the body. An effective microbicide would combine these mechanisms.
A large-scale trial is planned to evaluate the
effectiveness of two of the six vaginal microbicides that are now in the final stages of clinical
development. Updates on recent international
microbicide research and development, including
information on the first Phase III trials, will be
released shortly.
Microbicides are likely to be of particular benefit to
women who are increasingly bearing the brunt of
the HIV epidemic and now account for over 50
per cent of people newly infected with HIV.
Microbicides could potentially control the risk of
contracting HIV and other sexually transmitted
diseases.
Reference: http://www.mrc.ac.uk
Safety of HIV therapies targeted
by new advisory committee
An Advisory Committee on Medicinal Product
Safety has been established under the auspices
of WHO to respond promptly and efficiently to
medicines safety issues of potential global
importance. The first meeting of the Committee
was held from 20–22 October 2003. Members are
drawn from WHO Expert Advisory Panels and
selected with regard to their experience in clinical
pharmacology, pharmacovigilance, pharmacoepidemiology, clinical medicine, drug regulation,
international public health, and risk-assessment. A
report of the meeting is available on http://
www.who.int/medicines.
The Committee has been set up to provide advice
on policy and issues related to the safety and
effectiveness of medicinal products in general and
specific issues that:
• are important to national or international programmes;
• cannot be met by structures, institutions or
systems in place;
• respond to identified needs of a country that
may be beyond their capability; and
• advance and promote the future development of
pharmacovigilance as a discipline.
During the meeting, discussion focused on how
safety surveillance can strengthen the WHO 3 by
5 Initiative aimed to provide HIV treatment to
three million people by 2005. It was agreed that
patient safety issues should be integrated into
the 3 by 5 initiative from the outset to ensure the
most effective delivery of long-term benefits to
patients and ensure success.
In 2002, the World Health Assembly urged
Member States to establish and strengthen
science-based systems for quality of care and
patient safety, including the monitoring of medicines safety, using reporting systems and implementing measures to reduce risk.
The 3 by 5 initiative proposes the use of antiretroviral medicines (ARVs) for HIV treatment. There is
already considerable experience of ARV use in
industrialized countries and significant safety
issues have been reported. However, there are a
number of additional challenges facing developing
countries targeted to receive ARVs, including:
• lack of an adequate infrastructure and trained
health care professionals for monitoring of
safety and use;
• complex co-morbid conditions including malnutrition, tuberculosis and other infectious diseases specific to HIV populations;
• use of alternative therapies and medicines and
potential interactions;
• sociocultural and educational particularities and
vulnerable populations; and
• lack of adequate regulatory systems or capacity
to deal with safety outcomes.
Safety issues
Antiretrovirals have been associated with numerous adverse reactions, some of which may be
serious. The outcome of long-term adverse
effects is unknown. The reactions may be common or unusual, such as altered body fat distribution (lipodystrophy), hypersensitivity reactions, or
muscle damage (myopathy) of the newborn.
Besides causing harm to patients, these and
other reactions may damage confidence in HIV
treatment and reduce patient compliance and
patients may stop taking life-prolonging ARVs. In
the case of ARVs, poor compliance is known to
lead to the development of resistance as well as
therapeutic failure.
Contribution of patient safety strategies
to public health programmes
There is evidence that knowledge and understanding of medicines safety through provision of
public education improves patient compliance and
confidence in public health programmes such as
the 3 by 5 initiative. With efficient monitoring,
better understanding of the safety of antiretrovi-
15
rals will lead to the development of improved
treatment and a more rational use of existing
therapies. Furthermore, once a basic monitoring
infrastructure is in place, this can contribute to
improved strategies for other public health
programmes. The cost of a medicines safety
system is small compared to the benefits gained
in patient wellbeing and in reducing the costs of
treating adverse reactions. The ultimate contribution that safety monitoring systems would make to
international public health and clinical practice in
the treatment of HIV disease are thus of high
priority.
Resources a key to success
The following are a number of ways in which
patient safety programmes can be integrated into
the 3 by 5 initiative.
• Utilize the technical expertise of the WHO
International Drug Monitoring Programme.
• Collaborate with existing national pharmacovigilance centres in the targeted countries.
• Call on expert advice on causality assessment
and systematic data collection and sharing.
• Seek access to the WHO ADR database
including information on drug-drug interactions.
• Educate, train and empower health professionals by improving access to medicine information
resources.
• Use existing infrastructures for monitoring
patient safety, such as for the Roll Back Malaria
programme.
• Work with other organizations that have medicine safety experience in order to enhance
patient communication and information.
It was also recognized that the pharmaceutical
industry had a role to play by contributing experience and information on safety monitoring of HIV
products and in implementing fully their own
safety requirements.
There will be no delay in integrating a patient
safety component into the 3 by 5 initiative,
because it will build on existing medicines safety
experience and framework. Additionally, the
Advisory Committee will be available to advise on
patient safety issues and activate the required
support systems.
16
Conclusions
A well-defined patient safety programme is
essential to the overall success of the 3 by 5
initiative by ensuring positive treatment follow-up.
Medicines effectiveness and safety management
is an essential and cost-effective means of
maximizing the success of treatment interventions. Patients should be provided with health
programmes that are structured and planned and
that maximize health benefits while minimizing
risk.
The risks and benefits of HRT
The Women’s Health Initiative (WHI) study, a
large randomized trial comparing combination
hormone replacement therapy (HRT) to placebo,
found that the increase in risk associated with
long term therapy exceeded the benefits (1). In
particular the promise of cardiovascular benefit
from HRT was unfulfilled and therapy was found
to increase the risk of cardiovascular events.
A further surprising result of the WHI study was
an increase in the incidence of dementia with
HRT using estrogen plus progestogen, and a
failure to enhance cognitive function (2). The WHI
study did, however, demonstrate protection
against fracture with estrogen plus progestogen
(1, 3) but this protection, even in women with the
highest risk of fracture in the study, did not
outweigh the other negative effects (3).
The Million Women Study (MWS), which had a
prospective observational design, further emphasized the risks of HRT, indicating a higher risk of
breast cancer with estrogen plus progestogen
than with estrogen alone (4). The results indicated
that the increase in the incidence of breast cancer
with estrogen plus progestogen (compared to
estrogen alone) was greater than the reduction in
incidence of endometrial cancer associated with
adding progestogen to oestrogen therapy (4). The
MWS also reported a significant increase in the
incidence of breast cancer with tibolone and with
implanted and transdermal estrogen-only preparations.
Following its comprehensive review of these
studies and other available data, the Australian
Drug Evaluation Committee (ADRAC) has
recommended “The use of HRT for any long term
disease prevention cannot be generally justified
as the potential harm may outweigh potential
benefits. This concern also applies to the use of
HRT to prevent osteoporosis.
“HRT has an established place in the short term
management of symptoms of the menopause. For
treatment of established osteoporosis, the
selection of HRT by the patient and doctor should
be based on a careful consideration and discussion of risks and benefits for that individual.”
In addition, ADRAC advises that HRT use be for
as short a time as practical, and be reviewed
regularly.
Extracted from Australian Adverse Drug Reactions Bulletin, Volume 23, Number 2, April 2004
References
1. Writing Group for the Women’s Health Initiative
Investigators. Risks and benefits of estrogen plus
progestin in healthy postmenopausal women. Principal
results from the Women’s Health Initiative randomized
controlled trial. Journal of the American Medical
Association, 288: 321–333 (2002)
2. Shumaker, S.A., Legault, C., Rapp, S.R. et al.
Estrogen plus progestin and the incidence of dementia
and mild cognitive impairment in postmenopausal
women. The Women’s Health Initiative Memory Study: a
randomized controlled trial. Journal of the American
Medical Association, 289: 2651–2662 (2003).
3. Cauley, J.A., Robbins, J., Chen, Z. et al. Effects of
estrogen plus progestin on risk of fracture and bone
mineral density. The Women’s Health Initiative randomized trial. Journal of the American Medical Association, 290:1729–1738 (2003).
4. Million Women Study Collaborators. Breast cancer
and hormone-replacement therapy in the Million Women
Study. Lancet, 362: 419–427 (2003).
Macrolides and warfarin
interaction
The Australian Drug Evaluation Committee
(ADRAC) has received reports of interactions
between warfarin and all four macrolide antibiotics
(azithromycin, clarithromycin, erythromycin, and
roxithromycin) (see table below) (1). Although
most cases were asymptomatic, some reports
documented substantial increases in INR. The
haemorrhagic complications reported included
haematoma, haemoptysis, haematuria, melaena,
and retroperitoneal haemorrhage.
Close attention should be paid to INR monitoring
in patients taking warfarin who are commenced
on a macrolide antibiotic. Consideration could
also be given to the use of an alternative antibiotic
if possible. Azithromycin has a particularly long
half-life (around 68 hours), so that an interaction
with warfarin may theoretically persist for some
days after azithromycin has been ceased.
Extracted from Australian Adverse Drug Reactions Bulletin, Volume 23, Number 2, April 2004
Reference
1. Australian Adverse Drug Reactions Bulletin, 14: 11
(1995).
Statin risk factors: myopathy
and rhabdomyolysis
Four statins (HMG CoA inhibitors) are available in
Australia for the treatment of hypercholesterolaemia: simvastatin, atorvastatin, pravastatin and
fluvastatin. Each of the statins may cause myalgia
or rhabdomyolysis. Cerivastatin was removed
from the market worldwide because of an unacceptably high rate of rhabdomyolysis, including
fatal cases, particularly when used with gemfibrozil (1).
The rates of muscle disorders observed in clinical
trials of statins have not been significantly
different from those with placebo (2), but wider
clinical use involves individuals having multiple
disease states or taking potentially interacting
medication. Recent reviews indicate that factors
Table: ADRAC reports of macrolide-warfarin interaction
Drug
reports
(no. symptomatic)
onset in days
(median range)
INR (median)
azithromycin
clarithromycin
erythromycin*
roxithromycin
3 (0)
6 (2)
19 (4)
56 (27)
3; 2-5
7; 0-9
5; 0-18
6; 0-36#
9.6
7.6
9.7
8.8
* metronidazole was another potentially interacting agent in 2 cases. # onset > 1 year in a further patient.
17
which increase the plasma concentrations of
statins are associated with an increase in the risk
of myalgia, myopathy and, particularly,
rhabdomyo-lysis (3, 4). For simvastatin and
atorvastatin which are metabolized by the liver
enzyme CYP3A4 these factors are presented in
Table 1 below.
Over half of the simvastatin cases with rhabdomyolysis had more than one identified risk factor
(see Table 2). Individuals with several risk factors
may be at risk of developing rhabdo-myolysis,
rather than a less serious muscle disorder. A
feature of the cases of rhabdomyolysis is that
long-term statin therapy was well tolerated until
after a change in medication (e.g. increase in the
dose of statin, or addition of clarithromycin or
diltiazem).
Pravastatin and fluvastatin are not metabolized by
CYP3A4 and are less subject to increases in
plasma concentration by interaction with other
drugs. Reports of muscle disorders with these
statins are shown below. The dominant risk
factors for pravastatin and fluvastatin were
advanced age and high dose. The lower number
of cases of rhabdomyolysis with these statins is
probably associated with the lesser likelihood of
drug interaction, but is also related to the lower
usage in Australia (From 1992 to November 2003,
85% of statin prescriptions have been for simvastatin or atorvastatin).
High doses of statins should be used with caution
in the elderly, in patients with renal or hepatic
insufficiency, hypothyroidism or diabetes. Particular caution should be observed in patients taking
simvastatin or atorvastatin with these conditions,
if gemfibrozil, cyclosporine or diltiazem are being
taken concomitantly. Consideration should be
given to temporary discontinuation of simvastatin
or atorvastatin, if short-term macrolide antibiotic
or azole antifungal therapy is required. Patients
should be advised to report to their doctor if
muscle aches, pains or weakness develop.
Table 1: Factors increasing the risk of muscle disorders
with simvastatin and atorvastatin
Substances inhibiting metabolism
by CYP3A4
cyclosporin, diltiazem, verapamil, macrolide
antibiotics, azole antifungals, protease inhibitors,
grapefruit juice
Medicine inhibiting metabolism
by other means
gemfibrozil
Disease states
diabetes, hypothyroidism, renal and hepatic disease
Advanced age
≥ 70 years
High statin dose
≥ 40 mg/day
Table 2: Frequency of risk factors in ADRAC reports
of muscle disorders with the statins
Statin
Total reports
Myalgia/
myopathy/
CK increase
% with risk
factors
Rhabdomyolysis
% with risk
factors
Simvastatin
2493
518
37%
91
94%
Atorvastatin
1055
237
45%
26
73%
Pravastatin
442
99
41%
5
80%
Fluvastatin
248
68
4%
2
100%
18
Extracted from Australian Adverse Drug Reactions Bulletin, Volume 23, Number 1, February
2004
Previous information on statins in primary prevention has been presented in WHO Drug Information, Volume 17, No. 3, p.156
References
1. Australian Adverse Drug Reactions Bulletin, 20(1): 3
(2001).
2. Gotto, A.M. Safety and statin therapy. Archives of
Internal Medicine, 163: 657–659 (2003).
3. Thompson, P. D., Clarkson, P, Karas, R.H. Statinassociated myopathy. Journal of the American Medical
Association, 289: 1681–1690 (2003).
4. Ballantyne, C.M., Corsini, A., Davidson, M.H. et al.
Risk for myopathy with statin therapy in high risk
patients. Archives of Internal Medicine, 163: 553–564
(2003).
Serotonin syndrome
Serotonin syndrome is caused by excessive
central nervous system and peripheral serotonergic activity. It most commonly occurs with a
combination of serotonergic agents, but may also
occur with a single agent. A combination of agents
increasing serotonin by different mechanisms,
such as by inhibition of serotonin uptake and
serotonin metabolism, is associated with a high
risk of the syndrome (see Table 1) (1).
Serotonin syndrome is a clinical triad of cognitivebehavioural changes, autonomic dysfunction and
neuromuscular dysfunction. At least three of the
features listed in Table 2 must be present (1, 2).
There is no laboratory test to aid diagnosis. The
syndrome often occurs within a day of a change
in treatment (increase in dose or addition of
another serotonergic agent) and the evolution of
symptoms is rapid. It should not be confused with
neuroleptic malignant syndrome which is clinically
similar, but is an idiosyncratic response to
neuroleptic agents, usually occurs after longer
periods of treatment and develops over a period
of days or weeks (1).
The Australian Drug Evaluation Committee
(ADRAC) has received 161 reports of serotonin
syndrome. The majority describe the syndrome in
association with the concomitant use of two or
more serotonergic agents, in particular SSRIs
(68), tramadol (29), moclobemide (23), venlafaxine (18), tricyclic antidepressants (18) and St
John’s wort (8). In 61 reports, the serotonin
Table 1: Agents causing serotonin syndrome
Antidepressants
SSRIs, monoamine oxidase inhibitors (including moclobemide),
tricyclics, mirtazapine, venlafaxine
Antiparkinson
Amantadine, bromocriptine, levodopa, selegiline, carbergoline,
pergolide
Illicit drugs
Cocaine, hallucinogenic amphetamines such as MDMA (ecstasy),
LSD, etc.
Migraine therapy
Other agents
Dihydroergotamine, naratriptan, sumatriptan, zolmitriptan
Tramadol, carbamazepine, lithium, reserpine, sibutramine, St. John’s
wort, bupropion, pethidine, morphine
Table 2: Clinical features of serotonin syndrome
Cognitive-behavioural changes
agitation, mental status changes (confusion, hypomania)
Autonomic dysfunction
sweating, diarrhoea, fever, shivering, hypertension
Neuromuscular dysfunction
hyperreflexia, incoordination, myoclonus, tremor
19
syndrome developed in association with a single
agent: SSRIs (40), moclobemide (5), venlafaxine
(5) and tramadol (5 reports) (3).
Serotonin syndrome is potentially serious.
Reports to ADRAC have described confusion
(31), convulsions (23), hypertension (22), hallucinations (12) and delirium (7). In the majority of
reports, the signs and symptoms developed within
24 hours of the addition of another serotonergic
agent or an increase in dose of an agent. Patients
responded to withdrawal of the serotonergic
agent(s) and appropriate treatment. Recovery
was documented in 85% of the cases where the
outcome was known and the remainder of
patients had not recovered at the time of reporting.
Health professionals should note the drugs that
may cause serotonin syndrome, alone or in
combination with other serotonergic agents, and
be alert to the features of serotonin syndrome.
Patients should be informed of the risk and
symptoms of serotonin syndrome when serotonergic agents are prescribed.
Extracted from Australian Adverse Drug Reactions Bulletin, Volume 23, Number 1, February
2004
References
1. Langford N.J. Serotonin Syndrome. Adverse Drug
Reaction Bulletin, No. 217, December 2002.
2. Sternbach H. The serotonin syndrome. American
Journal of Psychiatry, 148: 705–713 (1991).
3. Tramadol and serotonin syndrome. Australian
Adverse Drug Reactions Bulletin, 21: 14 (1991).
Antidepressants: worsening
depression and suicidal
behaviour
The US Food and Drug Administration (FDA) has
asked manufacturers to include a warning
statement recommending close observation for
worsening depression or the emergence of
suicidality of adult and paediatric patients treated
with the following antidepressants: fluoxetine
(Prozac®); sertraline (Zoloft®); paroxetine
(Paxil®); fluvoxamine (Luvox®); citalopram
(Celexa®); escitalopram (Lexapro®); bupropion
(Wellbutrin®); venlafaxine (Effexor®); nefazodone
(Serzone®); and mirtazapine (Remeron®).
20
Warning Information
• Health care providers should carefully monitor
patients receiving antidepressants for possible
worsening of depression or suicidality, especially at the beginning of therapy or when the
dose either increases or decreases.
• Heath care providers should carefully evaluate
patients in whom depression persistently
worsens, or emergent suicidality is severe,
abrupt in onset, or was not part of the presenting symptoms, to determine what intervention,
including discontinuing or modifying the current
drug therapy, is indicated.
• There is concern that patients who experience
symptoms of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and
mania may be at increased risk for worsening
depression or suicidality. Therefore, therapy
should be evaluated and medications may need
to be discontinued when symptoms are severe,
abrupt in onset, or were not part of the patient’s
presenting symptoms.
• If a decision is made to discontinue treatment,
certain of these medications should be tapered
rather than stopped abruptly.
• Patients should be adequately screened to
determine if they are at risk for bipolar disorder
before initiating antidepressant treatment.
Among antidepressants, only fluoxetine is
approved for the treatment of paediatric major
depressive disorder. Fluoxetine, sertraline, and
fluvoxamine are approved for paediatric obsessive compulsive disorder. None of these drugs is
approved as monotherapy for use in treating
bipolar depression, either in adults or children.
Reference: FDA Public Health Advisory, 22 March
2004.
Use of SSRI antidepressants in
children and adolescents
The Australian Adverse Drug Reactions Advisory
Committee (ADRAC) has considered the safety
and efficacy of selective serotonin reuptake
inhibitor (SSRI) antidepressants in children and
adolescents. There is international concern about
a possibility of increased suicidal ideation and
self-harm behaviour provoked by the use of these
drugs for the treatment of major depressive
disorder (MDD).
It should be noted that none of the SSRIs is
approved for the treatment of MDD in children or
adolescents in Australia, but these drugs are
being used for this purpose. Two SSRIs (fluvoxamine and sertraline) are approved in Australia for
the treatment of obsessive-compulsive disorder
(OCD) in children and adolescents.
ADRAC considers that the current data are not
conclusive regarding the efficacy and safety of
SSRIs in MDD in children and adolescents. With
this in mind, ADRAC recommends:
1. Any SSRI use in children and adolescents with
MDD should be undertaken only within the
context of comprehensive management of the
patient. Such management should include careful
monitoring for the emergence of suicidal ideation
and behaviour.
2. The choice of an SSRI for children or adolescents with MDD should be made only after taking
into account the recent evaluations of clinical trial
data and the Product Information.
3. Children and adolescents who are currently
being treated for MDD with an SSRI should not
have their medication ceased abruptly.
Reference: Statement from the Adverse Drug Reactions
Advisory Committee, 11 March 2004 on http://
health.gov.au/tga/
Repaglinide and gemfibrozil
interaction
An interaction between repaglinide a short-acting
secretagogue and gemfibrozil a lipid-lowering
agent used to great dyslipidaemia has been
reported (1) in the Volume 29 of Current problems
in Pharmacovigilance (Committee on Safety of
medicines, United Kingdom). When administered
concomitantly, the blood glucose-lowering effect
of repaglinide may be markedly enhanced and
prolonged.
Worldwide, 5 spontaneous reports have been
received of serious hypoglycaemia episodes in
patients using repaglinide and gemfibrozil together. Three of these patients experienced
hypoglycaemic coma, one of whom died. In some
cases, the patients were also taking other drugs
and it is therefore not known whether the reactions can be solely attributed to an interaction with
gemfibrozil. There have been no reports of this
interaction in the United Kingdom.
Any change in repaglinide pharmacokinetics
caused by concomitant gemfibrozil administration
is likely to be via inhibition of cytochrome P450
2C8. Other inhibitors of this enzyme such as
trimethoprim, may also enhance the effect of
repaglinide.
Because of this interaction, co-administration of
repaglinide and gemfibrozil is contraindicated.
Based on known metabolism of lipid-lowering
agents, a similar interaction between repaglinide
and other lipid-lowering agents is not expected.
Reference
1. Niemi, N. Diabetologia, 46 (3): 347–351 (2003).
Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and unexpected
adverse drug reactions. A signal is defined as "reported information on a possible causal relationship
between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually, more than a single report is required to generate a signal, depending upon the seriousness
of the event and the quality of the information". All signals must be validated before any regulatory decision
can be made.
21
World’s biological experts
establish standards
The WHO Expert Committee on Biological
Standardization met in Geneva from 17 to 21
November 2003. The technical specifications and
reagents developed by the Committee define
international regulatory expectations for the
quality, safety and efficacy of biological pharmaceutical products, including vaccines, blood
products, biological therapeutics and in vitro
diagnostic devices. This information is targeted to
national regulatory authorities and manufacturers.
A full report of the Committee’s decisions is in
preparation and will be published in the WHO
Technical Report Series. In the meantime, a prepublication document has been posted onto the
WHO website to provide early notice of content
(1).
The Committee recommended establishment of
the following new documents.
Guidelines on nonclinical evaluation of
vaccines: regulatory expectations
A broad range of novel vaccines are under
development and there is a need for guidance on
the type and extent of their nonclinical evaluation
since this forms an essential part of the quality
assessment of a vaccine candidate. The guidelines are intended to set out principles for nonclinical evaluation of vaccines and provide
information and guidance to vaccine manufacturers, and recommendations for national regulatory
authorities concerning evaluation and assessment. The document is intended to complement
WHO Guidelines for clinical evaluation of
vaccines: regulatory expectations (2).
Recommendations for the production
and quality control of pneumococcal
conjugate vaccines
Infections caused by Streptococcus pneumoniae,
are responsible for substantial morbidity and
mortality, particularly in the very young and
elderly. Several pneumococcal vaccines containing polysaccharide conjugated to protein carriers
are now available or at an advanced stage of
development. Controlled clinical trials with these
vaccines have demonstrated that such conjugates
are both safe and highly immunogenic. Differences in the incidence of serotypes causing
disease from one continent to another has lead to
the development of pneumococcal vaccine
formulations consisting of increasing numbers of
conjugated components. Experience gained with
identification of reference levels of antibodies
supporting successful licensing of a product in a
number of countries will guide the review of
clinical trial data from other countries and with
other products.
Recommendations for the production and quality
control of pneumococcal conjugate vaccines
takes account of the large number of serotypes of
S. pneumoniae and the need to allow flexibility in
recommendations to cover different conjugation
chemistries and carrier proteins.
Production and quality control
of inactivated influenza vaccine
Guidelines on production and quality control
of inactivated influenza vaccine have been
updated following an informal WHO Consultation
in July 2003. Significant development in influenza
vaccines has taken place since the last revision of
the document. Subunit and split vaccines are now
widely used and the effective dose of haemag-
*Fifty-fourth meeting of the WHO Expert Committee on Biological Standardization, 17–21 November 2003, Geneva.
Participation included members from: Belgium, Canada, France, Indonesia, Republic of Korea, Mexico, Netherlands,
Russian Federation, Switzerland, United Kingdom, United States of America. Representatives from: Global Collaboration of Blood Safety, European Diagnostic Manufacturers Association, Council of Europe, Developing Country Vaccine
Manufacturers Network, European Plasma Fractionation Association, International Association of Biologicals, International Bureau of Weights and Measures, International Federation of Clinical Chemistry and Laboratory Medicine, International Federation of Pharmaceutical Manufacturers Associations, International Society on Thrombosis and
Haemostatis, Plasma Protein Therapeutics Association, United States Pharmacopeia.
22
glutinin has been established. In addition,
vaccines containing adjuvants have been developed and approved. The danger exists of pandemics caused by the appearance of novel and
highly pathogenic strains of virus and this danger
presents a number of challenges for production
and administration of suitable vaccines. The new
recommendations reflect these and other developments.
Diphtheria, tetanus, pertussis
and combination vaccines
Developments have taken place in methods of
assay of diphtheria and tetanus vaccines directed
to overcoming difficulties in potency testing
including a number of in vitro assays. A series of
reviews and meetings held during 1999–2000
resulted in proposals for amendment of the WHO
Requirements but the technical details could not
be finalized at that time. Further discussion
resulted in a recommendation to move to a
harmonized and simplified batch release assay
using guinea pigs. The main changes to the
present requirements constitute an updating of
the sections on reference materials and separation of sections on potency into two, addressing
licensing and batch release respectively.
Use of animal cells for the
in vitro production of biologicals
The WHO Requirements for the use of animal
cells as in vitro substrates for the production of
biologicals (3) provide information on a WHO cell
bank of Vero cells. These cells were designated
as a master cell bank in 1998 making cultures of
the cells available to manufacturers and national
control authorities. Possible deficiencies in the
records relating to the cell bank might have
regulatory implications for establishment of
master cell banks, and so a revision of the
requirements was proposed. The Committee
endorsed a recommendation from a WHO Cell
Bank Monitoring Group that the 10–87 Vero cell
bank should not be considered as a master cell
bank for direct use in manufacturing processes.
Rather, the 10–87 bank should be regarded as a
Cell Seed qualified by scientific analytical consensus from which master cell banks may be established for thorough re-qualification.
International Reference Materials
A list of new or replacement reference materials is
given in Table 1. Details of selected reference
materials are given below to illustrate the range of
issues considered by the Committee.
Yellow fever vaccine
Potency determination of yellow fever vaccines
has historically been based on mouse LD50
assays although in vitro plaque assays have been
available and in routine use for some years. The
need to improve standardization of yellow fever
potency determinations led to a collaborative
study performed by thirteen laboratories in eight
countries to assess the suitability of candidate
preparations for an International Standard and the
relationship between the two assay methods. On
the basis of the results of the collaborative study,
the Committee established a preparation, in
ampoules coded 99/616, as the First International
Standard for Yellow Fever Vaccine.
Data obtained in the study indicated that there
was a consistent relationship between mouse and
plaque assays. The Committee therefore supported a proposal to encourage manufacturers
and control laboratories to include the standard in
assays to evaluate its suitability for setting a
minimum potency of 104.0 IU for yellow fever
vaccines. Data should be collated by WHO and
analysed to determine whether the potency
specification given in the WHO Recommendations (4) should be amended.
Factor VIII, concentrate
Stocks of the current (recombinant) standard are
likely to be exhausted within 12 months and there
have been reports of difficulties in using recombinant material in assaying plasma-derived
concentrates. For these reasons, and after
extensive consultation, it has been decided that
plasma-derived factor VIII will be the replacement
material. A collaborative study among 38 laboratories in 21 countries to establish a common batch
reference preparation was conducted and the
Committee established the Seventh International
Standard for Factor VIII, Plasma-derived, Concentrate, in ampoules coded 99/678, and an
activity of 11.0 IU per ampoule.
Human interferon beta
The current International Standard for interferon
beta is an impure preparation derived from human
fibroblasts containing about 1% interferon. Other
cytokines present influence the results of some
assays. Accordingly, an extensive collaborative
study of new and existing reference preparations
for interferon beta has been performed by 16
laboratories in 8 countries. One candidate
preparation, consisting of glycosylated interferon
beta derived from Chinese hamster ovary (CHO)
cells, gave a smaller inter-laboratory variability,
23
compared with the current standard, with all but
one sample examined. The Committee established the Third International Standard for Interferon Beta, Human, Recombinant, Glycosylated,
in ampoules coded 00/572, and assigned a
potency to it of 40 000 International Units per
ampoule. Since stocks of the current standard
remain, the Committee formally disestablished the
Second International Standard for interferon beta,
fibroblast, human, code number Gb23-902-531.
The CHO-cell derived material is likely to continue
to be available and is more suitable for calibration
of future therapeutic products than the fibroblast
material. However, it is not suitable for assay of
the Ser-17 interferon beta analogue and the 1st
International Standard of interferon-beta Ser 17
mutein, Gxb02-901-535, will be retained.
Hepatitis B surface antigen
Because the current First International Standard
for hepatitis B surface antigen is in need of
replacement, a candidate and panel of dilutions
were proposed. The aim of these reference
materials is to aid regulatory authorities and
manufacturers of HBsAg test kits in measuring
analytical kit sensitivity by providing a standard
with an internationally accepted unitage.
WHO collaborative studies were conducted and
data demonstrated that the assigned values of the
different HBsAg reference preparations differ
considerably: 1 IU is equivalent to 0.58 PEI units
(primary) or 0.43 PEI units (current) or 1.9 French
‘ng’ or 5.6 Abbott ‘ng’. However, it is noteworthy
that in 1985, the relationship between IS and the
primary PEI was nearly the same as was found in
the current study: 1 IU = 0.55 PEI unit. This and
related biochemical data indicate that there has
been no drift in the IU over 18 years. Furthermore, the study showed that the prediluted panel
provides a convenient resource for authorities to
assess sensitivity, especially of rapid tests.
On the basis of the results obtained, the Committee established the candidate preparation as the
Second International Standard for Hepatitis B
surface antigen, in vials coded 00/588, with an
assigned value of 33 IU per vial. The Standard
contains antigen subtype adw2, genotype A. The
Committee also established panel members A to
D, in vials coded 01/400, 01/402, 01/404 and 01/
406, which are 1 in 4, 1 in 16, 1 in 64 and 1 in 256
dilutions of the International Standard respectively, and panel member E, in vials coded 00/
616, which consists of human re-calcified plasma,
24
as a reference panel for hepatitis B surface
antigen for use by national regulatory authorities
in the assessment of the sensitivity of assay kits
for the detection of the surface antigen.
Quality, safety and efficacy of
biological medicines
Wild poliovirus contamination of oral
poliomyelitis vaccine
In the period November 2002 to February 2003,
several cases of poliomyelitis were observed in
one country after vaccination and the MEF-1
reference wild-type poliovirus type 2 strain was
isolated in each case (5). Initial investigations
excluded cross-contamination within the diagnostic WHO polio laboratory network that cultured the
viruses as an explanation for the findings. Further
examination demonstrated the presence of MEF1 in vials of one vaccine batch that had been filled
locally from imported bulk material. Samples of
the batch that had been collected from the field,
from retained samples and from other bulks were
tested. Only samples from the field were positive
so that contamination had taken place downstream from manufacture although it could not be
established whether this was during storage or
distribution. Enhanced security measures have
now been put in place by the manufacturer
concerned.
The Committee was asked to consider the wider
implications of this episode; whether current WHO
GMP guidance is adequate and whether additional control measures on the final product
should be laid down. The Committee considered
that prevention of deliberate interference with a
product requires safeguards different to normal
GMP and that no changes to existing GMP
guidance for this reason were necessary. However, the Committee drew attention to measures
that ensure that vials are tamper-proof and to
procedures that are available to detect counterfeiting. In this context WHO was advised to obtain
additional specialist advice, and to make this
available to all vaccine manufacturers, their
distributors and national regulatory authorities.
References
1. http://www.who.int/biologicals
2. World Health Organization. Expert Committee on
Biological Standardization. Technical Report Series, No.
924 (in press)
Table 1. New or replacement International Standards established by
the Fifty-fourth WHO Expert Committee on Biological Standardization
ADDITIONS
Antibodies
anti-toxoplasma IgG,
human
20 IU/ampoule
First International
Standard 2003
This substance is held and distributed by the International Laboratory for Biological Standards,
National Institute for Biological Standards and Control, Potters Bar, Herts. EN6 3QG, England.
Antigens and related substances
yellow fever vaccine
104.5 IU/ampoule
First International
Standard 2003
pertussis toxin
10 000 IU/ampoule
First International
Standard 2003
These substances are held and distributed by the International Laboratory for Biological Standards,
Blood products and related substances
Factor VIII, concentrate,
plasma, human
11.0 IU/ampoule
Seventh International
Standard 2003
Factor VIII/von Willibrand Factor,
plasma, human
0.68 IU/ampoule
Factor VIII:C
0.94 IU/ampoule
Factor VIII:antigen
0.91 IU/ampoule
VWF:antigen
0.78 IU/ampoule
VMF:ristocetin cofactor
0.94 IU/ampoule
VWF: collagen binding
Fifth International
Standard 2003
prekallikrein activator, human
29 IU/ampoule
Second International
Standard 2003
low molecular weight heparin
1097 IU/ampoule
Anti-Xa
326 IU/ampoule
Anti-IIa
Standard 2003
25
Table 1. New or replacement International Standards Continued
Cytokines, growth factors and endocrinological substances
Interferon, beta, human, recombinant,
glycosylated
40 000 IU/ampoule
Third International
Standard 2003
tumour necrosis factor, Aapha,
human, recombinant
46 500 IU/ampoule
Standard 2003
luteinizing hormone, human
recombinant
189 IU/ampoule
First International
Standard 2003
thyroid-stimulating hormone,
human, for immunoassay
11.5 x 10-3 IU/ampoule
Third International
Standard 2003
Diagnostic reagents
hepatitis B surface antigen
33 IU/vial
Standard 2003
hepatitis B surface antigen panel
(set of 4 dilutions and control)
No assignment
First International
Reference Panel 2003
lipoprotein (a) for immunoassay
0.107 nanomoles/vial
First Reference
Reagent 2003
This substance is held and distributed by Northwest Lipid Research Laboratories,
University of Washington School of Medicine, 2121 North 35th Street, Seattle, WA 98103, USA.
Biological Standardization.Technical Report Series, No.
878, Annex 1 (1998).
Biological Standardization.Technical Report Series, No.
872, Annex 2 (1998).
26
5. Weekly Epidemiological Record, 78: 88 and 284
(2003)
Herbal Medicines
Regulation of traditional
medicines in Africa
The majority of African populations use traditional
medicine for their health care needs which is
often bought in places such as open markets and
local stores. Although many traditional medicines
are claimed to cure various diseases, scientific
evidence of safety, efficacy or quality is lacking
and most countries in sub-Saharan Africa have no
regulation, safety-monitoring or pharmacovigilance centres for the pharmaceuticals or
herbal products sold on their markets. As with
conventional medicines, this lack of regulatory
control will compound the risks to patients. In view
of this situation, the WHO Regional Committee for
Africa has adopted the Regional Strategy on
Traditional Medicine which urges Member States
to develop systems for the safety, efficacy and
quality of traditional medicines.
The purpose of the Second Regional Workshop
was to expand WHO’s support in building capacity to regulate herbal medicines in countries of the
WHO African Region, according to their national
situation. Guidelines on Registration of Traditional
Medicines in the WHO African Region were
presented at the workshop which brought together 15 invited national drug regulatory authorities and experts from Angola, Burkina Faso,
Cameroon, Congo, Ghana, Lesotho, Liberia,
Madagascar, Namibia, Niger, Nigeria, Sierra
Leone, Togo and Zimbabwe. This workshop also
provided an opportunity for participants to attend
the Eleventh International Conference of Drug
Regulatory Authorities (See page 3). Against this
framework, the workshop focused on three
themes:
• Regulation and registration of traditional medicines,
• Quality control of traditional medicines, and
In order to support Member States to facilitate the
evaluation of traditional medicines for registration
purposes, the WHO Regional Office for Africa,
organized the first Regional workshop on Regulation of Traditional Medicines in Johannesburg, in
April 2003 in collaboration with the Department of
Essential Drugs and Medicines Policy in WHO
Geneva. The workshop was attended by 18
national drug regulatory authorities and experts
from: Benin, Burkina Faso, Congo, Cote d’Ivoire,
Ghana, Ethiopia, Kenya, Madagascar, Mali,
Mozambique, Nigeria, South Africa, Swaziland,
United Republic of Tanzania, Uganda, Zambia
and Zimbabwe. The document Guidelines on
Registration of Traditional Medicines in the WHO
African Region was reviewed and adopted at that
workshop.
The Second Regional Workshop on Regulation
on Traditional Medicines has been organized in
Madrid, Spain, 13–14 February 2004, with the
objective of promoting the registration and
marketing of safe, effective and good quality
traditional medicines within the African Region.
The workshop was organized by WHO with
support from the Spanish Agency for Medicines
and Health Products in Madrid, Spain.
• Safety monitoring and pharmacovigilance of
traditional medicines.
Recommendations
The Workshop identified major challenges and
made recommendations for each of the three
themes as follows.
Major challenges include:
• Lack of national policies and legal framework on
traditional medicine in most countries of Africa.
• Lack of registration of herbal medicines.
• Difficulty in evaluating the safety and efficacy of
• Lack of minimum regulatory requirements for
safety and efficacy of traditional medicines.
• Lack of methodology and tools for evaluation of
traditional medicines particularly lack of information on clinical data.
• Lack of understanding by traditional health
practitioners on the need for regulation of
27
Herbal Medicines
• Lack of protection of medicinal plant and
traditional medical knowledge.
• Inadequate laboratories and equipment for
quality control of traditional medicines.
Recommendations for Member States
• Lack of pharmacopoeia of national medicinal
plants for quality control of traditional medicines.
1. Member States should adopt WHO guidelines
related to national policy, legal framework, and
code of ethics, regulation and registration of
herbal medicines and formulate appropriate
national policies.
2. Member States should establish/strengthen
legal frameworks to back up the national policy on
traditional medicine.
3. Member States should set up a communication
network between national drug regulatory authorities and associations of traditional health practitioners.
4. Member States should undertake a listing of
traditional medicines in circulation within their
countries.
5. Member States should adopt and implement a
WHO Regional framework on protection of
traditional medical knowledge and intellectual
property rights of traditional medicine.
6. Member States should develop a national
inventory of commonly used medicinal plants.
Recommendations to WHO and partners
WHO and partners should support Member
States to:
1. Member States should strengthen human
resources capacity to undertake quality control of
herbal medicines.
2. Member States should adopt and implement
WHO guidelines on Good Agricultural and
Collection Practices of Medicinal Plants and Good
Manufacturing Practices for Herbal Medicines.
3. Member States should develop national
monographs/pharmacopoeia of medicinal plants
and share this information. The use of WHO
monographs, African Pharmacopoeia and other
national monographs for quality control should
also be encouraged.
4. Member States should strengthen national
quality control laboratories to be able to control
the quality of herbal medicines or set up a
network with other domestic research institutes
which have a capacity to carry out quality control
of herbal medicines.
5. If needed, Member States could use Regional
quality control laboratories from neighbouring
countries through WHO country and Regional
Offices for Africa.
• formulate national policies on traditional medicine.
6. Member States should strengthen communication amongst national drug regulatory authorities
and between them and importing and exporting
countries of herbal medicines.
• develop strategy to implement the regulation of
traditional medicine.
• develop inventories of traditional medicinal
products in circulation within the countries.
Quality control of traditional medicines
Major challenges include:
• Lack of expertise in quality control of herbal
medicines among national drug regulatory
authorities.
28
1. WHO and partners should:
• support countries to strengthen the capacity of
countries for quality control.
• support countries to undertake an inventory of
medicinal plants commonly used in their
communities.
• support countries to develop their national
pharmacopoeia or monographs of medicinal
plants.
Herbal Medicines
Safety monitoring and pharmacoviglance
Major challenges:
Most countries in the WHO African Region have
no safety monitoring or pharmacovigilance
system for essential or herbal medicines.
medicines and national policy on TM/CAM at both
regional and global levels.
The Workshop also discussed the impact of the
WHO guidelines on Good Agricultural and
Collection Practices of Medicinal Plants and
Safety Monitoring and Pharmacovigilance of
Herbal Medicines (see below).
1. Member States should set up a safety monitoring and pharmacovigilance system and the
expand existing system to cover safety monitoring
and pharmacovigilance of herbal medicines.
2. Member States should control advertisements
of herbal medicines.
3. Member States should develop consumer
educational information on the proper use of
1. WHO and partners should
• support Member States to develop consumer
educational information on the proper use of
• facilitate communication between Member
States of the WHO African Region and WHO
Collaborating Centre for Safety Monitoring in
Uppsala, Sweden.
• support requests on human resource development in safety monitoring of herbal medicines.
Besides the above-mentioned recommendations,
Member States proposed that WHO organize an
African Conference of Drug Regulatory Authorities
on Herbal Medicines every two years.
Conclusion
The Regional workshop facilitated sharing of
information on the minimum regulatory requirements for the assessment of the quality, safety
and efficacy of traditional medicines with respect
to their registration as laid down in the Guidelines
for Registration of Traditional Medicines in the
WHO African Region; and
The Workshop also made a review of the regulatory status of traditional medicine including the
results of the global survey on regulation of herbal
Herbal medicines, patient safety
and plant conservation
WHO has published guidelines for good agricultural and collection practices for medicinal plants
intended for national governments, to ensure
production of herbal medicines is of good quality,
safe, sustainable and poses no threat to people or
the environment.
Herbal medicines are the natural answer to many
ailments and are often locally available. For this
reason, their use remains widespread and they
are popular in many countries. Because of
improved monitoring, reports of patients experiencing adverse reactions with use of herbal
medicines are on the rise. Major causes of
adverse events can be directly linked to poor
quality, particularly of raw medicinal plant materials, or to the wrong identification of plant species.
Cultivating, collecting and classifying plants
correctly is therefore important.
In addition to patient safety issues, there is the
risk that a growing herbal market might pose a
threat to biodiversity through over-harvesting of
raw materials needed in herbal and traditional
medicines and other natural health care products.
If not controlled, these practices may lead to the
extinction of endangered species and the destruction of natural habitats and resources.
The WHO guidelines on good agricultural and
collection practices (GACP) for medicinal plants
are an important initial step to ensuring provision
of good quality, safe herbal medicines and
ecologically sound cultivation practices for future
generations. The Guidelines cover the spectrum
of cultivation and collection activities, including
site selection, climate and soil considerations and
identification of seeds and plants. Guidance is
also given on the main post-harvest operations
and includes legal issues such as national and
regional laws on quality standards, patent status
and benefit sharing.
29
Herbal Medicines
The safety and quality of raw medicinal plant
materials and finished products depend on
genetic or external factors, including environment,
collection methods, cultivation, harvest, postharvest processing, transport and storage
practices. Inadvertent contamination by microbial
or chemical agents during any of the production
stages can also lead to deterioration in safety and
quality. Medicinal plants collected in the wild may
be contaminated by other species or plant parts
through misidentification, accidental contamination or intentional adulteration, all of which may
have unsafe consequences. Examples of this are:
Digitalis: Cases of serious cardiac arrhythmias
were reported in the USA in 1997 following the
accidental substitution of plantain as a dietary
supplement with Digitalis lanata, generally used
for heart conditions. Subsequent investigations
revealed that large quantities of mislabelled
plantain had been shipped to more than 150
manufacturers, distributors and retailers over a
two-year period.
Podophyllum: Fourteen cases of Podophyllum
poisoning were reported from Hong Kong, China
following the inadvertent use of Podophyllum
hexandrum root instead of Gentiana and Clematis
species, for their antiviral qualities. This accidental substitution arose through the apparent
similarity in morphology of the root.
Aconitum: Cases of cardiotoxicity resulting from
the ingestion of Aconitum species used in complementary medicine for acute infections and
panic attacks have been reported. Aconitum
rootstocks are processed by soaking or boiling in
water to hydrolyse the aconite alkaloids into a
less toxic, aconine derivative. Toxicity can result
when such processes are mismanaged. In the
United Kingdom, the internal use of aconite is
restricted to prescription only.
30
Endangered medicinal plants
The wild type of ginseng (Panax ginseng), used to
address digestive conditions resulting from
nervous disorders, is currently reported to be
rapidly declining due to increasing demand and
collection. While wild American ginseng,
goldenseal, echinacea, black cohosh, slippery
elm and kava kava top the “at-risk list” of endangered species of medicinal plants.
Cultivation has replaced wild collection for the
supply of some essential drugs used in modern
medicine. The Madagascar rosy periwinkle,
Catharanthus roseus, is widely cultivated in Spain
and the United States for its properties for treating
childhood leukaemia and Hodgkin disease.
Demand is also greater than supply for the bark of
Pygeum (Prunus africana), a popular natural
remedy for prostate disorders in European
countries which is harvested from wild trees
growing in the mountain forests of continental
Africa and Madagascar. Demand is currently
unsustainable.
Devil’s Claw (Harpagophytum procumbens) is
also unsustainably harvested and may become
extinct in the wild under current practices. It is
used as a tonic, treatment for arthritis and
rheumatism, to reduce fever, ease sore muscles,
reduce cholesterol, and externally the ointment is
used to treat sores, boils, and ulcers. It is also
used to cleanse the lymphatic system, and to
remove toxins from the blood.
Reference: WHO Note for the Press No. 3,10 February
2004
Nevirapine and hepatotoxicity
Canada — The manufacturer of nevirapine
(Viramune®) has provided new safety information
clarifying risk factors for severe, life-threatening
and fatal hepatotoxicity. Nevirapine, a nonnucleoside reverse transcriptase inhibitor, is
indicated for the treatment of HIV-1 infection in
combination with other antiretroviral agents.
New labelling information is being added concerning 200 mg tablets.
Women with CD4 counts >250 cells/mm3 at
initiation of therapy, including pregnant women
receiving chronic treatment for HIV infection, are
at considerably higher risk (12–fold) of hepatotoxicity, which in some cases has been fatal. This
subset of patients was identified by analyses of
CD4 count at the time of initiation of therapy.
The greatest risk of severe and potentially fatal
hepatic events (often associated with rash) occurs
in the first 6 weeks of treatment. However, the risk
continues after this time and patients should be
closely monitored for the first 18 weeks of treatment. In some cases, hepatic injury progresses
despite discontinuation of the drug.
This new information is the result of recent postmarketing surveillance data. Although this new
information describes patients at increased risk, it
is important to note that any patient can experience hepatic events and should be monitored
carefully. It may be prudent initially to conduct
clinical and laboratory monitoring more often than
once per month, for example, liver function tests
at baseline, prior to dose escalation and at two
weeks post dose escalation.
All patients developing a rash, at any time during
treatment, but particularly during the first 18
weeks, should have liver function tests performed
at that time. After the initial 18 week period,
frequent clinical and laboratory monitoring should
continue throughout treatment. Patients with rash
and moderate to severe elevations should be
permanently discontinued from nevirapine and in
any patient experiencing constitutional symptoms,
hepatitis, severe skin reactions or hypersensitivity
reactions.
Stevens-Johnson Syndrome and toxic epidermal
necrolysis may be preceded by a prodrome of flulike symptoms including fever, malaise, rhinitis,
nausea, chest pain, vomiting, sore throat, cough,
dizziness, diarrhoea, headache, myalgia and
arthralgia. Patients should be closely monitored if
flu-like symptoms and/or an isolated rash occurs.
Based upon Canadian post-marketing data, since
1998, there has been one reported case of life
threatening Stevens-Johnson Syndrome with
hepatitis (non fatal) in a woman treated with
Viramune® in combination with other antiretroviral
agents.
Reference: Important Safety Information on nevirapine.
20 February 2004. http://www.
Antidepressants in adults
and children
United States of America — The Food and Drug
Administration (FDA) has cautioned health care
professionals and patients about the need to
closely monitor adults and children treated for
depression following reports suggesting an
increased risk of suicidal thoughts and actions in
children given antidepressants.
FDA has initiated a full review and it is not yet
clear whether antidepressants contribute to the
emergence of suicidal thinking and behaviour. In
the meantime, the agency is advising clinicians,
patients, families and caregivers of adults and
children that they should closely monitor all
patients being placed on therapy with these drugs
for worsening depression and suicidal thinking,
which can occur during the early period of
treatment.
The agency is also advising that these patients be
observed for certain behaviours that are known to
be associated with these drugs, such as anxiety,
agitation, panic attacks, insomnia, irritability,
hostility, impulsivity, akathisia (severe restless-
31
ness), hypomania, and mania, and that physicians be particularly vigilant in patients who may
have bipolar disorder.
Olanzapine and
cerebrovascular events
The manufacturers of ten drugs will include
stronger cautions and warnings about the need to
monitor patients for the worsening of depression
and the emergence of suicidal ideation, regardless of the cause of such worsening. The drugs
under review include bupropion, citalopram,
fluoxetine, fluvoxamine, mirtazapine, nefazodone,
paroxetine, sertraline, escitalopram and venlafaxine.
Canada — The manufacturer of olanzapine
(Zyprexa®) has circulated information pertaining
to cerebrovascular adverse events that have
occurred in elderly patients with dementia-related
psychosis treated with olanzapine in clinical trials.
Olanzapine is not approved for use in elderly
patients with dementia-related psychosis.
The only drug that has received approval for use
in children with major depressive disorder is
fluoxetine (Prozac®). Several of these drugs are
approved for the treatment of obsessive-compulsive disorder in paediatric patients, i.e., sertraline
(Zoloft®), fluoxetine (Prozac®), and fluvoxamine
(Luvox®). Fluvoxamine is not approved as an
antidepressant in the United States.
Reference: FDA Talk paper, T04-08. 22 March 2004.
Recommended influenza
vaccines: 2004–2005
World Health Organization — The composition
of influenza vaccines for the Northern hemisphere
2004–2005 Winter season has been determined
as follows:
• an A/New Caledonia/20/99(H1N1)-like virus
• an A/Fjian/411/2002(H3N2)-like virus. (The
currently used vaccine virus is A/Wyoming/3/
2003 A/Kumamoto/102/2002 is also available.)
• a B/Shanghai/361/2002-like virus. (Candidate
vaccine viruses include B/Shanghai/361/2002
and B/Jilin/20/2003.)
The national control authorities should approve
the specific vaccine viruses used in each country.
National public health authorities are responsible
for recommendations regarding use of the
vaccine. Updated epidemiological information is
available on WHO’s website at http://who.int/
influenza.
Reference: Weekly Epidemiological Record, 79: 91
(2004)
32
Recent analysis of some clinical trials in elderly
patients with dementia suggests that the use of
olanzapine in these patients may be associated
with an increased incidence of cerebrovascular
adverse events (CVAEs) such as stroke and
transient ischemic attacks, including few fatalities.
While elderly patients are at increased risk of
CVAEs, the above clinical trial data reflect an
increased incidence of such adverse events in
patients taking olanzapine compared with placebo-treated dementia patients after adjusting for
age, gender, and type of dementia.
Physicians should counsel their patients/
caregivers to immediately report signs and
symptoms of potential CVAEs such as sudden
weakness or numbness in the face, arms or legs,
and speech or vision problems, so that diagnosis
can be made and treatment options considered,
including discontinuation, without delay.
The current prescribing information states that
olanzapine should be used with particular caution
in patients with known cardiovascular disease
(history of myocardial infarction or ischemia, heart
failure, or conduction abnormalities), cerebrovascular disease, and conditions which would
predispose patients to hypotension (dehydration,
hypovolaemia, and treatment with antihypertensive medications).
Reference: Health Canada, http://www.hc-sc.gc.ca10
March 2004.
Olanzapine: hyperglycaemia
and diabetes
United States of America — The Food and Drug
Administration (FDA) has asked all manufacturers
of atypical antipsychotic medications to add a
warning statement describing the increased risk
of hyperglycaemia and diabetes. The atypical
antipsychotic class includes olanzapine, clozapine, risperidone, quetiapine, ziprasidone, , and
aripiprazole.
The manufacturer of olanzapine (Zyprexa®) has
updated prescribing information as follows.
Hyperglycaemia, in some cases extreme and
associated with ketoacidosis or hyperosmolar
coma or death, has been reported in patients
treated with atypical antipsychotics including
olanzapine.
Patients with an established diagnosis of diabetes
mellitus who are started on atypical antipsychotics
should be monitored regularly for worsening of
glucose control. Patients with risk factors for
diabetes mellitus (e.g. obesity, family history of
diabetes) who are starting treatment with atypical
antipsychotics should undergo fasting blood
glucose testing at the beginning of treatment and
periodically during treatment. Any patient treated
with atypical antipsychotics should be monitored
for symptoms of hyperglycaemia including
polydipsia, polyuria, polyphagia, and weakness.
Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics
should undergo fasting blood glucose testing. In
some cases, hyperglycaemia has resolved when
the atypical antipsychotic was discontinued;
however, some patients required continuation of
antidiabetic treatment despite discontinuation of
the suspect drug.
Reference: http://www.fda.gov/medwatch. 1 March
2004.
Better labelling
for ingredient sensitivities
United States of America —The Food and Drug
Administration (FDA) has published new rules on
content labeling (amount present per dosage unit)
and warning labeling for over-the-counter (OTC)
drugs that contain levels of calcium, magnesium,
sodium, or potassium that might be harmful to
people with certain underlying medical conditions.
The rules require uniform content and warning
labeling for oral OTC drug products containing
levels of these substances that exceed specific
thresholds. In addition, the agency is proposing to
extend sodium content labeling requirements to
OTC rectal drug products containing sodium
phosphates. FDA is taking this action because
people with certain medical conditions may be at
risk for serious or life-threatening electrolyte
imbalances when using these products.
Under the new rules, the labeling of oral OTC
drugs containing sodium, calcium, magnesium, or
potassium must state the amount of a particular
ingredient in each dose if they contain:
• 5 milligrams (mg) or more of sodium in a single
dose;
• 20 mg or more of calcium in a single dose;
• 8 mg or more of magnesium in a single dose; or
• 5 mg or more of potassium in a single dose.
The new rules also require new warnings on the
label to alert people with kidney stones, decreased kidney function due to kidney disease, or
people who are on sodium, calcium, magnesium,
or potassium-restricted diets to consult their
doctors before using products for oral ingestion
that contain:
• more than 140 mg of sodium as the maximum
daily dose.
• more than 3.2 grams of calcium as the maximum daily dose,
• more than 600 mg of magnesium as the maximum daily dose, or
• more than 975 mg potassium as the maximum
daily dose.
Sodium may be related to high blood pressure
and is a concern for individuals with congestive
heart failure. In people with kidney disease, blood
levels of calcium, magnesium, and potassium can
reach potentially dangerous levels due to their
decreased elimination. People with kidney stones
need to carefully monitor their calcium intake.
Reference: FDA News, P04-35 25 March 2004
33
The International Pharmacopoeia — monographs for antiretrovirals
Within the framework of the Pilot Procurement Project for Quality and Sourcing of HIV Drugs (http:/
/www.who.int/medicines), the International Pharmacopoeia is collaborating with manufacturers, independent analytical drug quality control laboratories, national and regional pharmacopoeial bodies,
research, governments, and regulatory bodies to provide specifications and monographs for the
following antiretroviral agents:
abacavir, didanosine, efavirenz, indinavir, lamivudine, nelfinavir,
nevirapine, ritonavir, saquinavir, stavudine, zidovudine
Specifications for the respective dosage forms will be developed during a second phase of the
project. The draft monographs, Indinavir sulfate, nelfinavir mesilate, and nevirapine are now available for consultation and are presented below. Comments should be sent to: Quality and Safety:
Medicines, World Health Organization, 1211 Geneva 27, Switzerland or [email protected].
Indinaviri sulfas
Indinavir sulfate
Molecular formula: C36H49N5O8S or C36H47N5O4,H2O4S
Relative molecular mass. 711.9
Graphic formula:
Chemical name: (2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1yl]amino]-5-oxopentyl]-N-(1,1-dimethylethyl)-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide sulfate
CAS Reg. No. 157810-81-6
34
Description: White or almost white powder.
Solubility: Freely soluble in water, soluble in methanol.
Category: Antiretroviral (protease inhibitor).
Storage: Indinavir sulfate should be kept in a tightly closed container, protected from light.
Additional information: Indinavir sulfate is hygroscopic in nature and occurs as monoethanolate.
Converts to hydrate upon loss of ethanol and exposure to moist air.
REQUIREMENTS
Indinavir sulfate contains not less than 98.5% and not more than 101.0 % of C36H47N5O4.H2SO4 calculated on anhydrous, ethanol free basis.
Identity tests
Either tests A and B, or test C alone may be applied.
A. TLC: to be added.
B. The absorption spectrum of a 0.100 mg/ml solution in water, when observed between 220 nm and
280 nm, exhibits one maximum at about 260 nm; the specific absorbance (A 1%1cm) is 56 to 62.
C. Carry out the examination as described under “Spectrophotometry in the infrared region”
(Vol. 1, p. 401 ). The infrared absorption spectrum is concordant with the reference spectrum
of indinavir sulfate.
Specific optical rotation. Use a 10.0 mg/ml solution in water and calculate with reference to the
anhydrous and ethanol free substance; [α ]D 20 °C = +27° to +31°.
Heavy metals. Use 1.0 g for the preparation of the test solution as described under “Limit test for
heavy metals”, Procedure 1 (Vol. 1, p. 1181 ); determine the heavy metals content according to method
A (Vol. 1, p. 1181 ); not more than 10 µg/g.
Sulfated ash. Not more than 1.0 mg/g (Vol. 1, p. 1231 ).
Water. Determine as described under “Determination of water by the Karl Fischer method”, Method A
(Vol. 1, p. 1351 ), using 0.5 g of the substance; the water content is not more than 15 mg/g.
pH value. pH of a 10 mg/ml solution in carbon dioxide free water R, 2.8-3.2.
Ethanol content. Determine by “Gas chromatography with static head-space injection”. Use a fusedsilica capillary or wide bore column 30 m long and 0.32 mm or 0.53 mm in internal diameter coated with
macrogol 20 000 R (film thickness: 0.25 µm).
As detector use a flame ionization detector.
Use nitrogen for chromatography R or helium for chromatography R as the carrier gas at an appropriate pressure and a split ratio 1:5 with a linear velocity of about 35 cm/sec.
1
Refers to The International Pharmacopoeia.
35
The following head-space injection conditions may be used:
Equilibration temperature (°C)
Equilibration time (min)
Transfer line temperature (°C)
Pressurization time (s)
Injection volume (ml)
80
60
85
30
1
Maintain the temperature of the column at 30 °C for 10 min, then raise the temperature at a rate of
5 °C per min to 70 °C, then raise the temperature at a rate of 15 °C per min to 180 °C and maintain for
10 min, maintaining the temperature of the injection port at 140 °C and that of the flame ionization
detector at 250 °C.
Test solution. Dissolve 0.200 g of indinavir sulfate in purified water and dilute to 20.0 ml with the same
solvent. Introduce 5.0 ml of this solution and 1.0 ml of purified water into an injection vial.
Reference solutions. Add 0.200 g of ethanol R to purified water and dilute to 200.0 ml with the same
solvent. Transfer respectively 2.0 ml, 3.0 ml and 4.0 ml in separate injection vials and bring the volume
to 6.0 ml with purified water.
Blank solution: Introduce 6.0 ml of purified water into an injection vial.
Analyse the blank vial and then alternatively test vials and reference vials.
The test is not valid unless the relative standard deviation on the areas of the peaks obtained from the
test vials is not more than 15%.
Calculate the ethanol content by using the results obtained with the test vials and with the reference
vials; the ethanol content is not less than 50 mg/g and not more than 80 mg/g.
Related substances.
Carry out the test as described under “High–performance liquid chromatography” (Vol. 5, p. 2571), using a stainless steel column (25 cm x 4.6 mm) packed with basedeactivated octadecylsilyl silica gel for chromatography R (5 µm).
Use the following conditions for gradient elution:
Mobile phase A: 30 volumes of acetonitrile, 5 volumes of phosphate buffer pH 7.5 and
65 volumes of purified water.
Mobile phase B: 70 volumes of acetonitrile, 5 volumes of phosphate buffer pH 7.5 and
25 volumes of purified water.
Prepare the phosphate buffer pH 7.5 by dissolving 1.4 g of disodium hydrogen phosphate in 50 ml of purified water, adjust the pH to 7.5 by adding phosphoric acid (105 g/l)
and dilute it to 100 ml with purified water.
1
Time
(min)
Mobile
phase A (%)
Mobile
phase B (%)
0-5
5-25
25-30
30-35
35-45
93
93 to 20
20
20 to 93
93
7
7 to 80
80
80 to 7
7
36
Comments
isocratic
linear gradient
isocratic
return to the initial conditions
isocratic re-equilibration
Prepare the following solutions. For solution (1) use 2.0 mg of Indinavir sulfate per ml. For solution (2)
dilute a suitable volume of solution (1) to obtain a concentration equivalent to 2 µg of Indinavir sulfate
per ml.
For the system suitability test: prepare solution (3) using 2 ml of solution (1) and 2 ml of sulfuric acid
(190 g/l), heat in a water bath at 80 °C for 60 minutes.
Operate with a flow rate of 1 ml per minute. As a detector use an ultraviolet spectrophotometer set at a
wavelength of 220 nm.
Maintain the column at 40 °C.
Inject solution (3). The test is not valid unless the resolution factor between the principal peak and the
peak which is coming after the principal peak is not less than 3.5. If necessary adjust the amount of
acetonitrile in mobile phase A.
Inject alternatively 20 µl each of solution (1) and (2).
Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2). In
the chromatograms obtained with solution (1), the area of any peak, other than the principal peak, is
not greater than that obtained with solution (2) (0.10 %). The sum of the areas of all peaks, other than
the principal peak, is not greater than five times the area of the principal peak obtained with
solution (2) (0.50 %). Disregard any peak with an area less than 0.2 times the area of the principal
peak in the chromatogram obtained with the solution (2) (0.02%).
Assay: Dissolve 0.30 g, accurately weighed, in 50 ml of water and titrate with sodium hydroxide (0.1
mol/l) VS, determine the end point potentiometrically. Each ml of sodium hydroxide (0.1 mol/l) VS is
equivalent to 35.59 mg of C36H47N5O4.H2SO4; calculate with reference to the anhydrous and ethanol
free substance.
Reagents
Silica gel for chromatography, octadecylsilyl, base deactivated
A very finely divided silica gel, pretreated before the bonding of octadecylsilyl groups to minimize the interaction with basic compounds.
Macrogol 20 000 R. Polyethyleneglycol 20 000
Description. White or almost white solid with a waxy or paraffin-like appearance.
Solubility. Very soluble in water and methylene chloride R. Practically insoluble in alcohol and in
fatty oils and mineral oils.
Nitrogen for chromatography.
Contains not less than 99.95% V/V of N2.
Helium for chromatography.
Contains not less than 99.995% V/V of He.
37
Nelfinavir mesilas
Nelfinavir mesilate
Molecular formula: C32H45N3O4S,CH4O3S
Relative molecular mass: 663.9
Graphic formula:
Chemical name: (3S,4aS,8aS)-N-(1,1-dimethylethyl)-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2methylbenzoyl)amino]-4-(phenylsulfanyl)butyl]decahydroisoquinoline-3-carboxamide methanesulfonate
CAS Reg. No. 159989-65-8.
Description: White or almost white powder.
Solubility: Practically insoluble in water and soluble in methanol R.
Category: Antiretroviral (protease inhibitor).
Storage: Nelfinavir mesilate should be kept in a tightly closed container, protected from light.
Additional information: Nelfinavir mesilate is hygroscopic.
REQUIREMENTS
General requirement: Nelfinavir mesilate contains not less than 98.0 % and not more than 101.0 % of
C32H45N3O4S.CH4O3S, calculated with reference to the dried substance.
Identity tests
Either tests A and B or test C may be applied.
A. TLC: to be done.
B. The absorption spectrum of a 40 µg/ml solution in methanol R, when observed between 220 nm and
280 nm, exhibits one maximum at about 253 nm; the specific absorbance (A 1% 1cm) calculated with
reference to the dried substance is 124 to136.
38
C. Carry out the examination as described under “Spectrophotometry in the infrared region” (Vol. 1, p.
401). The infrared absorption spectrum is concordant with the reference spectrum of nelfinavir mesilate.
Specific optical rotation: Use 10.0 mg/ml solution in methanol R and calculate with reference to the
dried substance; [α ]D 20 °C = –110 ° to –125 °.
Heavy metals: Use 1.0 g in 30 ml of methanol R for the preparation of the test solution as described
under “Limit test for heavy metals”, Procedure 2, (Vol. 1, p.1181); determine the heavy metals content
according to method A (Vol. 1, p.1181); not more than 20 µg/g.
Sulfated ash: Not more than 1.0 mg/g. (Vol. 1, p.1231).
Loss on drying: Weigh 1.000 g, dry to constant mass at 100 °C; it loses not more than 30 mg/g.
Related substances: Carry out the test as described under “High–performance liquid chromatography”
(Vol. 5, p. 2571), using a stainless steel column (25 cm x 4.6 mm) packed with base-deactivated
octadecylsilyl silica gel for chromatography R (5µm) (Note: Hypersil BDS C18 is suitable.)
Use the following conditions for gradient elution:
Mobile phase A: 27 volumes of acetonitrile R, 20 volumes of methanol R, 28
volumes of phosphate buffer pH 3.4 and 25 volumes of purified water.
Mobile phase B: 41 volumes of acetonitrile R, 31 volumes of methanol R and
28 volumes of phosphate buffer pH 3.4.
Prepare the phosphate buffer pH 3.4 by dissolving 4.88 g of anhydrous sodium dihydrogenphosphate
in 800 ml of purified water, adjust the pH to 3.4 by adding phosphoric acid (105 g/l) and dilute it to
1000 ml with purified water.
Time
(min)
Mobile
phase A (%)
Mobile
phase B (%)
0–27
27–60
60–75
75–80
80–90
100
100 – 0
0
0 – 100
100
0
0 – 100
100
100 – 0
0
Comments
isocratic
linear gradient
isocratic
return to the initial conditions
isocratic re-equilibration
Prepare the following solutions using mobile phase A as diluent. For solution (1) use 2.0 mg of
nelfinavir mesilate per ml. For solution (2) dilute a suitable volume of solution (1) to obtain a concentration equivalent to 10.0 µg of nelfinavir mesilate per ml. For solution (3) use 100 µg of methanesulfonic
acid per ml.
For the system suitability test: prepare solution (4) using 2 ml of solution (1) and 5 ml of sulfuric acid
(475 g/l), heat carefully in a water bath at 90 °C for 110 minutes.
Operate with a flow rate of 1 ml per minute. As a detector use an ultraviolet spectrophotometer set at a
wavelength of about 225 nm.
Maintain the column at 35 °C.
1
39
Inject 20 µl of solution (4). The test is not valid unless the resolution factor between the principal peak
and the peak with a retention time relative to the principal peak of about 0.2 is not less than 15. The
test is also not valid unless the resolution factor between the last two peaks out of three peaks, which
are growing during decomposition, is not less than 4.0. The ratio of the retention times of these two
peaks relative to the principal peak is about 1.8 and 1.9 respectively. If necessary adjust the amount of
acetonitrile in both mobile phases A and B.
Inject 20 µl of solution (3).
Inject alternatively 20 µl each of solutions (1) and (2).
Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2)
and calculate the content of related substances as a percentage. In the chromatograms obtained with
solution (1), the area of any peak, other than the principal peak, is not greater than that obtained with
solution (2) (0.5 %). The sum of the areas of all peaks, other than the principal peak, is not greater than
two times the area of the principal peak obtained with solution (2) (1.0 %). Disregard any peak with an
area less than 0.04 times the area of the principal peak in the chromatogram obtained with solution (2)
(0.02%). Ignore any peak due to methanesulfonic acid, corresponding to the principal peak in the
chromatogram obtained with solution (3).
Assay: Dissolve about 0.50 g, accurately weighed, in 50 ml of methanol R and titrate with sodium
hydroxide (0.1 mol/l) VS, determine the end point potentiometrically. Perform a blank determination and
make the necessary correction. Each ml of sodium hydroxide (0.1 mol/l) VS is equivalent to 66.39 mg
of C32H45N3O4S.CH3SO3H.
Reagents
Silica gel for chromatography, octadecylsilyl, base-deactivated
A very finely divided silica gel, pre-treated before the bonding of octadecylsilyl groups to
minimize the interaction with basic compounds.
Methanesulfonic acid R
Molecular formula. CH4O3S
Description. Colourless and corrosive liquid.
Solubility. Miscible with water.
Density (d). ~1.48.
Melting point. About 20 °C.
A typical chromatogram obtained for nelfinavir mesilate (Refer to the monograph text for chromatographic conditions in “Related substances” 1)
1
40
A typical chromatogram obtained for blank (Refer to the monograph text for chromatographic conditions in “Related substances”)
A typical chromatogram obtained for system suitability (Refer to the monograph text for system suitability conditions in “Related substances”)
41
Nevirapinum anhydricum
Nevirapine anhydrous
Molecular formula: C15H14N4O
Relative molecular mass: 266.30
Graphic formula:
Chemical name: 11-cyclopropyl-4-methyl-5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one
CAS Reg. No. 129618-40-2.
Description: White to almost white powder.
Solubility: Very slightly soluble in water and soluble in acidic solution.
Melting point: 242 – 246 °C.
Category: Antiretroviral (non-nucleoside reverse transcriptase inhibitor).
Storage: Nevirapine should be kept in a well closed container.
REQUIREMENTS
Nevirapine contains not less than 99.0 % and not more than 101.0 % of C15H14N4O, calculated with
reference to the dried substance.
Identity test
Carry out the examination as described under “Spectrophotometry in the infrared region” (Vol. 1, p.
401). The infrared absorption spectrum is concordant with the spectrum obtained from nevirapine RS.
Sulfated ash. Not more than 1.0 mg/g.
Loss on drying. Dry for 4 hours at 105 °C; it loses not more than 10 mg/g.
1
42
Related Substances
Note: Prepare fresh solutions and perform the tests without delay
Carry out the test as described under “High-performance liquid chromatography” (Vol. 5, p. 2571 ),
using a stainless steel column (15cm x 4.6mm), packed with hexadecylamidylsilyl silica gel for chromatography (5 µm). (Supelcosil LC-ABZ is suitable.)
Maintain the column temperature at 35 °C.
The mobile phase consists of a filtered and degassed mixture of 20 volumes of acetonitrile R and 80
volumes of a buffer of 25 mM ammonium dihydrogen phosphate adjusted to pH 5.0 using a 20 % w/w
ammonia solution.
Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at
a wavelength of about 220 nm.
Prepare the following solutions in the mobile phase (dissolution solvent).
For solution (1) dissolve 25 mg of nevirapine in 4 ml of acetonitrile R and dilute to 100.0 ml with the
dissolution solvent. For solution (2) dilute 5.0 ml of solution (1) to 50.0 ml with the dissolution solvent.
Then dilute 5.0 ml of this solution to 50.0 ml with the same solvent.
Inject separately 50 µl of solution (2) in replicate injections in the chromatographic system. The relative
standard deviation for peak areas of Nevirapine in replicate injections of solution (2) is not more than
5.0%.
Inject separately 50 µl each of solution (1) and of mobile phase in the chromatographic system.
Continue the chromatography for 5 times the retention time of nevirapine. Examine the mobile phase
chromatogram for any extraneous peaks and disregard the corresponding peaks observed in the
chromatogram obtained with solution (1).
The test is not valid unless the column efficiency determined from the solution (2) is not less than
10000. The peak symmetry should be between 0.8 and 1.2 .
In the chromatogram obtained with solution (1), the following impurity peaks are eluted at the following
relative retention time with reference to nevirapine: (A) = about 0.7; (B) = about 1.5 and (C) = about
2.8.
Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2),
and calculate the content of related substances as a percentage.
In the chromatogram obtained with solution (1) the area of any individual peaks corresponding to
impurity peaks A, B and C is not greater than 0.2 times the area of the principal peak obtained with
solution (2) (0.2%). Any other impurity peak is not greater than 0.1 times the area of the principal peak
obtained with solution (2) (0.1%). The sum of the areas of all peaks, other than the principal peak, is
not greater than the area of the principal peak obtained with solution (2) (1.0%). Disregard any peak
with an area less than 0.05 times the area of the principal peak obtained with solution (2) (0.05%).
Assay
Dissolve about 0.200 g, accurately weighed, in 50 ml of acetic anhydride R and titrate with perchloric
acid (0.1 mol/l) VS as described under “Non-aqueous titration”; Method A (Vol. 1, p.1311) determining
the end point potentiometrically.
1
43
Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 26.63 mg of C15H14N4O.
Tested impurities
A. 5,11-Dihydro-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][1,4]diazepin-6-one
1
B.
11-Ethyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][1,4]diazepin-6-one
C.
11-Propyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][1,4]diazepin-6-one
Reagents
Silica gel for chromatography, hexadecylamidylsilyl
Particles of silica gel, the surface of which has been modified with chemically bonded
hexadecylamidylsilyl groups.
1
44
WHO Drug Information, Vol. 18, No. 1, 2004
Proposed INN: List 90
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 (1–85) and Recommended (1–45) International Nonproprietary Names can be found in Cumulative List
No. 10, 2002 (available in CD-ROM only). 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 (1–85) et recommandées (1–45) dans
la Liste récapitulative No. 10, 2002 (disponible sur CD-ROM seulement). 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 de 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 (1–85) y Recomendadas (1–45) se encuentran
reunidas en Cumulative List No. 10, 2002 (disponible sólo en CD-ROM). 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 al producto. Debido a su carácter provisional, esos datos descriptivos no deben incluirse en las listas
recapitulativas de DCI.
45
Proposed International Nonproprietary Names: List 90
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 90
Proposed INN not later than 30 September 2004.
Dénominations communes internationales proposées: Liste 90
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 90 de
DCI Proposées le 30 septembre 2004 au plus tard.
Denominaciones Comunes Internacionales Propuestas: Lista 90
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 90 de DCI Propuestas el 30 de
septiembre de 2004 a más tardar.
Proposed INN
(Latin, English, French, Spanish)
Chemical name or description: Action and use: Molecular formula
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
adecatumumabum
adecatumumab
Immunoglobulin G1, anti-(human antigen 17-1A) (human monoclonal
MT201 γ1-chain), disulfide with human monoclonal MT201 κ-chain,
dimer
immunomodulator
adécatumumab
immunoglobuline G1, anti-(antigène 17-1A de la molécule
d'adhésion de la cellule épithéliale humain) ; dimère du disulfure
entre la chaîne γ1 et la chaîne κ de l'anticorps monoclonal humain
MT201
immunomodulateur
adecatumumab
Inmunoglobulina G1, anti-( antígeno humano 17-1A) dímero del
disulfuro entre la cadena γ1 y la cadena κ del anticuerpo
monoclonal humano MT201
inmunomodulador
C6552H10080N1740O2052S46
46
503605-66-1
arformoterolum
arformoterol
N-{2-hydroxy-5-[(1R)-1-hydroxy-2-{[(2R)-1-(4-methoxyphenyl)=
propan-2-yl]amino}ethyl)phenyl]formamide
bronchodilator
arformotérol
(-)-N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-méthoxyphényl)1-méthyléthyl]amino]éthyl]phényl]formamide
bronchodilatateur
arformoterol
(-)-N-[2-hidroxi-5-[(1R)-1-hidroxi-2-[[(1R)-2-(4-metoxifenil)1-metiletil]amino]etil]fenil]formamida
bronchodilatador
67346-49-0
C19H24N2O4
H OH H
N
H CH3
HO
HN
OCH3
H
O
banoxantronum
banoxantrone
1,4-bis{[2-(dimethylazinoyl)ethyl]amino}-5,8-dihydroxy9,10-anthraquinone
antineoplastic
banoxantrone
1,4-bis[[2-(diméthyloxydoamino)éthyl]amino]5,8-dihydroxyanthracène-9,10-dione
antinéoplasique
banoxantrona
1,4-bis[[2-(dimetiloxidoamino)etil]amino]-5,8-dihidroxiantraceno9,10-diona
antineoplàsico
136470-65-0
C22H28N4O6
O
-
OH
O
HN
N+ CH3
CH3
OH
O
HN
CH3
N+ CH3
O-
47
batabulinum
batabulin
2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)=
benzenesulfonamide
antineoplastic
batabuline
2,3,4,5,6-pentafluoro-N-(3-fluoro-4-méthoxyphényl)=
benzènesulfonamide
antinéoplasique
batabulina
2,3,4,5,6-pentafluoro-N-(3-fluoro-4-metoxifenil)bencenosulfonamida
antineoplásico
195533-53-0
C13H7F6NO3S
F
F
F
F
S
F
becampanelum
becampanel
H
N
F
O O
OCH3
[(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)methylamino]=
methylphosphonic acid
AMPA receptor antagonist
bécampanel
acide [[[(7-nitro-2,3-dioxo-1,2,3,4-tétrahydroquinoxalin-5-yl)méthyl]=
amino]méthyl]phosphonique
antagoniste des récepteurs de l'AMPA
becampanel
ácido [[[(7-nitro-2,3-dioxo-1,2,3,4-tetrahidroquinoxalin-5-il)metil]=
amino]metil]fosfónico
antagonista de los receptores del AMPA
188696-80-2
C10H11N4O7P
O
HO P
HO
O 2N
beminafilum
beminafil
H
N
H
N
N
H
O
O
trans-4-{4-[(3-chloro-4-methoxybenzyl)amino][1]benzothieno=
[2,3-d]pyrimidin-2-yl}cyclohexanecarboxylic acid
vasodilator
béminafil
acide trans-4-[4-[(3-chloro-4-méthoxybenzyl)amino]benzo=
[4,5]thiéno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylique
vasodilatateur
beminafilo
ácido trans-4-{4-[(3-cloro-4-metoxibencil)amino][1]benzotieno=
[2,3-d]pirimidin-2-il}ciclohexanocarboxílico
vasodilatador
48
566906-50-1
C25H24ClN3O3S
H
H
H
O
N
H
O
H
H
N
N
N S
binodenosonum
binodenoson
2-[(E)-(cyclohexylmethylene)hydrazino]adenosine
adenosine receptor A agonist
binodénoson
2-[(E)-2-(cyclohexylméthylène)diazanyl]-9-β-D-ribofuranosyl9H-purin-6-amine
agoniste du récepteur A de l'adénosine
binodenosón
2-[(E)-2-(ciclohexilmetileno)diazanil]-9-β-D-ribofuranosil-9H-purin6-amina
agonista del receptor A de adenosina
144348-08-3
C17H25N7O4
NH2
N
N
N
HO
N
H
N
N
O
OH
certolizumabum pegolum
certolizumab pegol
OH
Immunoglobulin, anti-(human tumor necrosis factor α) Fab' fragment
(human-mouse monoclonal CDP870 heavy chain), disulfide with
human-mouse monoclonal CDP870 light chain, pegylated at Cys221
immunomodulator
certolizumab pégol
immunoglobuline, anti-(facteur α de nécrose tumorale humain) ;
disulfure entre le fragment Fab' de la chaîne lourde et la chaîne
légère de l'anticorps monoclonal de souris CDP870 humanisé
pégylé
immunomodulateur
certolizumab pegol
inmunoglobulina, anti-(factor α de necrosis tumoral humano)
fragmento Fab' (cadena pesada del anticuerpo monoclonal
humanizado de ratón CDP870), disulfuro con la cadena ligera del
anticuerpo monoclonal humanizado de ratón CDP870, pegilado
inmunomodulador
C2115H3252N556O673S16 (peptide)
428863-50-7
49
ciluprevirum
ciluprevir
(2R,6S,12Z,13aS,14aR,16aS)-6-[(cyclopentyloxycarbonyl)amino]2-({7-methoxy-2-[(propan-2-ylamino)-1,3-thiazol-4-yl]quinolin4-yl}oxy)-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16atetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]=
diazacyclopentadecine-14a(5H)-carboxylic acid
antiviral (HCV)
ciluprévir
acide (2R,6S,12Z,13aS,14aR,16aS)-6-[[(cyclopentyloxy)carbonyl]=
amino]-2-[[7-méthoxy-2-[2-[(1-méthyléthyl)amino]thiazol4-yl]quinoléin-4-yl]oxy]-5,16-dioxo1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tétradécahydrocyclopropa=
[e]pyrrolo[1,2-a][1,4]diazacyclopentadécine-14a(5H)-carboxylique
antiviral (VHC)
ciluprevir
ácido (2R,6S,12Z,13aS,14aR,16aS)-6[[(ciclopentiloxi)carbonil]amino]-2-[[2-[2-[(1-metiletil)amino]tiazol-4-il]7-metoxi-quinolin-4-il] oxi]-5,16-dioxo1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahidrociclopropa=
[e]pirrolo[1,2-a][1,4]diazaciclopentadecina-14a(5H)-carboxílico
antiviral (HCV)
300832-84-2
C40H50N6O8S
OCH3
CO2H O
H
N
H
O
H
H
O
N
H O
HN
O
clazosentanum
clazosentan
N
S
N
HN
CH3
CH3
N-{6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazol5-yl)pyridin-4-yl]pyrimidin-4-yl}-5-methylpyridine-2-sulfonamide
endothelin receptor antagonist
clazosentan
N-[6-(2-hydroxyéthoxy)-5-(2-méthoxyphénoxy)-2-[2-(1H-tétrazol5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-méthylpyridine-2-sulfonamide
antagoniste du récepteur de l'endothéline
clazosentán
N-[6-(2-hidroxietoxi)-5-metil-2-[2-(1H-tetrazol-5-il)piridin-4-il]pirimidin4-il]-5-(2-metoxifenoxi)piridina-2-sulfonamida
antagonista del receptor de endotelina
50
180384-56-9
C25H23N9O6S
O O
S
NH
N
H 3C
OCH3
O
N
N
O
N
N
OH
NH
N N
clofarabinum
clofarabine
2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine
antineoplastic
clofarabine
2-chloro-9-(2-désoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin6-amine
antinéoplasique
clofarabina
2-cloro-9-(2-desoxi-2-fluoro-β-D-arabinofuranosil)-9H-purin-6-amina
antineoplásico
123318-82-1
C10H11ClFN5O3
NH2
N
N
Cl
HO
N
N
O
F
OH
daglutrilum
daglutril
[(3S)-3-{1-[(2R)-2-ethoxycarbonyl-4-phenylbutyl]=
cyclopentanecarboxamido}-2-oxo-2,3,4,5-tetrahydro1H-1-benzazepin-1-yl]acetic acid
antihypertensive (neutral endopeptidase inhibitor)
daglutril
acide [(3S)-3-[[[1-[(2R)-2-(éthoxycarbonyl)-4-phénylbutyl]=
cyclopentyl]carbonyl]amino]-2-oxo-2,3,4,5-tétrahydro1H-1-benzazépin-1-yl]acétique
antihypertenseur (inhibiteur de l'endopeptidase neutre)
daglutrilo
ácido [(3S)-3-[[[1-[(2R)-2-(etoxicarbonil)-4-fenilbutil]ciclopentil]=
carbonil]amino]-2-oxo-2,3,4,5-tetrahidro-1H-1-benzazepin-1-il]=
acético
antihipertensivo (inhibidor de la endopeptidasa neutra)
51
182821-27-8
C31H38N2O6
O
N
O
H
H3C
dextofisopamum
dextofisopam
N
H H
CO2H
O
O
(5R)-1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl5H-2,3-benzodiazepine
anxiolytic
dextofisopam
(+)-(5R)-1-(3,4-diméthoxyphényl)-5-éthyl-7,8-diméthoxy-4-méthyl5H-2,3-benzodiazépine
anxiolytique
dextofisopam
(+)-(5R)-1-(3,4-dimetoxifenil)-5-etil-7,8-dimetoxi-4-metil5H-2,3-benzodiazepina
ansiolítico
C22H26N2O4
82059-50-5
CH3
H
CH3
H3CO
N
N
H3CO
OCH3
H3CO
doranidazolum
doranidazole
(2RS,3SR)-3-{[2-nitroimidazol-1-yl]methoxy}butane-1,2,4-triol
radiosensitizing agent
doranidazole
(2RS,3SR)-3-[(2-nitro-1H-imidazol-1-yl)méthyl]butane-1,2,4-triol
radiosensibilisateur
doranidazol
(2RS,3SR)-3-[(2-nitro-1H-imidazol-1-il)metil]butano-1,2,4-triol
agente radiosensibilizante
149838-23-3
C8H13N3O6
N
O2N
52
HO
N
O
H
OH
H
OH and enantiomer
et énantiomère
y enantiómero
ecopladibum
ecopladib
4-(2-{5-chloro-2-[2-(3,4-dichlorobenzylsulfonamido)ethyl]1-(diphenylmethyl)-1H-indol-3-yl}ethoxy)benzoic acid
cytosolic phospholipase A2 inhibitor
écopladib
acide 4-[2-[5-chloro-2-[2-[[(3,4-dichlorobenzyl)sulfonyl]amino]éthyl]1-(diphénylméthyl)-1H-indol-3-yl]éthoxy]benzoïque
inhibiteur de la phospholipase A2 cytosolique
ecopladib
ácido 4-[2-[5-cloro-2-[2-[[(3,4-diclorobencil)sulfonil]amino]etil]1-(difenilmetil)-1H-indol-3-il]etoxi]benzoico
inhibidor de la fosfolipasa A2 citosólica
C39H33Cl3N2O5S
381683-92-7
Cl
O
O S
NH
Cl
CO2H
N
O
Cl
emapunilum
emapunil
N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin9-yl)acetamide
mitochondrial benzodiazepine receptor agonist
émapunil
N-benzyl-N-éthyl-2-(7-méthyl-8-oxo-2-phényl-7,8-dihydro-9H-purin9-yl)acétamide
agoniste du récepteur mitochondrial des benzodiazépines
emapunilo
N-bencil-N-etil-2-(2-fenil-7-metil-8-oxo-7,8-dihidro-9H-purin9-il)acetamida
agonista del receptor mitocondrial de benzodiazepinas
226954-04-7
C23H23N5O2
CH3
N
N
O
N
N
N
CH3
O
53
enzastaurinum
enzastaurin
3-(1-methyl-1H-indol-3-yl)-4-{1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]1H-indol-3-yl}pyrrole-2,5-dione
antineoplastic
enzastaurine
3-(1-méthyl-1H-indol-3-yl)-4-[1-[1-(pyridin-2-ylméthyl)pipéridin-4-yl]1H-indol-3-yl]-1H-pyrrole-2,5-dione
antinéoplasique
enzastaurina
3-(1-metil-1H-indol-3-il)-4-[1-[1-(piridin-2-ilmetil)piperidin-4-il]1H-indol-3-il]-1H-pirrol-2,5-diona
antineoplásico
170364-57-5
C32H29N5O2
H
N
O
N
O
N
CH3
N
N
eslicarbazepinum
eslicarbazepine
(10S)-10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepin5-carboxamide
anticonvulsant
eslicarbazépine
(10S)-10-hydroxy-10,11-dihydro-5H-dibenzo[b,f]azépin5-carboxamide
anticonvulsivant
eslicarbazepina
(10S)-10-hidroxi-10,11-dihidro-5H-dibenzo[b,f]azepin-5-carboxamida
anticonvulsivo
104746-04-5
C17H16N2O3
O
N
HO
54
H
NH2
esoxybutyninum
esoxybutynin
4-(diethylamino)but-2-yn-1-yl (2S)-cyclohexyl(hydroxy)phenylacetate
antispasmodic
ésoxybutynine
(2S)-cyclohexylhydroxyphénylacétate de 4-(diéthylamino)but-2-ynyle
anticholinergique (antispasmodique)
esoxybutynina
(2S)-ciclohexilhidroxifenilacetato de 4-(dietilamino)but-2-inilo
antiespasmódico
119618-22-3
C22H31NO3
O
CH3
O
N
OH
hormonum parathyroidum
parathyroid hormone
CH3
non glycosylated human parathyroid hormone, the origin should be
indicated between brackets after the INN, for example (r. E.coli) for
recombinant produced by Escherichia coli
hormone
hormone parathyroïde
hormone parathyroide humaine nonglycosylée, l'origine doit être
indiquée entre parenthèses après la DCI, par exemple (r. E. coli)
pour recombinante produite par Escherichia coli
hormone
hormona paratiroidea
hormona paratiroidea humana no glicosilada, el origen deberá,
indicarse entre paréntesis después de la DCI, por ejemplo (r. E. coli)
para la recombinante producida por Escherichia coli
hormona
345663-45-8
C408H674N126O126S2
H Ser
Val Ser
Glu
Ile
Gln
Leu
Met
His
Asn
Leu Gly
10
Lys
His
Leu
Asn Ser
Met
Glu
Arg
Val
Glu Trp Leu
20
Arg Lys Lys
Leu
Gln
Asp Val His
Asn
Phe
Val
Ala
30
Leu Gly
Ala
Pro Leu
Ala
Pro
Arg
Asp
Ala Gly
Ser
Pro
Arg Lys Lys
Glu
Asp
Asn
Val Leu
Val
Ser
His
Glu Lys
Ser
Leu
Gly
Glu
Ala
Asp
Lys
Ala Asp
Val
Asn Val
Leu Thr
Lys
Ala
Lys
Ser
Gln OH
40
Gln
Arg
50
Glu
60
70
80
55
imidafenacinum
imidafenacin
4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide
muscarin receptor antagonist
imidafénacine
4-(2-méthyl-1H-imidazol-1-yl)-2,2-diphénylbutanamide
antagoniste des récepteurs muscariniques
imidafenacina
2,2-difenil-4-(2-metil-1H-imidazol-1-il)butanamida
antagonista de los receptores muscarínicos
170105-16-5
C20H21N3O
H3C
N
N
NH2
O
lumiliximabum
lumiliximab
immunoglobulin G1, anti-(human immunoglobulin E receptor type II)
(human-Macaca irus monoclonal IDEC-152 γ1-chain), disulfide with
human-Macaca irus monoclonal IDEC-152 κ-chain, dimer
immunomodulator
lumiliximab
Immunoglobuline G1, anti-(récepteur de type II humain de
l'immunoglobuline E) ; dimère du disulfure entre la chaîne γ1 et la
chaîne κ de l'anticorps monoclonal chimérique homme-Macaca irus
IDEC-152
inmunomodulateur
lumiliximab
inmunoglobulina G1, anti-(receptor de tipo II humano de la
inmunoglobulina E) ; dímero del disulfuro entre la cadena γ1 y la
cadena κ del anticuerpo monoclonal quimérico hombre-Macaca irus
IDEC-152
inmunomodulador
C6850H10656N1824O2106S50
maropitantum
maropitant
357613-86-6
(2S,3S)-N-(5-tert-butyl-2-methoxybenzyl)-2-(diphenylmethyl)1-azabicyclo[2.2.2]octan-3-amine
neurokinin NK1 receptor antagonist
maropitant
(2S,3S)-N-[5-(1,1-diméthyléthyl)-2-méthoxybenzyl]2-(diphénylméthyl)-1-azabicyclo[2.2.2]octan-3-amine
antagoniste des récepteurs NK1 de la neurokinine
maropitant
(2S,3S)-N-[5-(1,1-dimetiletil)-2-metoxibencil]-2-(difenilmetil)1-azabiciclo[2.2.2]octan-3-amina
antagonista de los receptores NK1 de la neurokinina
56
147116-67-4
C32H40N2O
H3CO
H H H
N
CH3
N
mubritinibum
mubritinib
H3C
CH3
1-(4-{4-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol4-yl)methoxy]phenyl}butyl)-1H-1,2,3-triazole
antineoplastic
mubritinib
1-[4-[4-[[2-[(E)-2-[4-(trifluorométhyl)phényl]éthényl]oxazol4-yl]méthoxy]phényl]butyl]-1H-1,2,3-triazole
antinéoplasique
mubritinib
1-[4-[4-[[2-[(E)-2-[4-(trifluorometil)fenil]etenil]oxazol4-il]metoxi]fenil]butil]-1H-1,2,3-triazol
antineoplásico
366017-09-6
C25H23F3N4O2
N N
N
F 3C
N
O
O
muraglitazarum
muraglitazar
([(4-methoxyphenoxy)carbonyl]{4-[2-(5-methyl-2-phenyl-1,3-oxazol4-yl)ethoxy]benzyl}amino)acetic acid
antidiabetic
muraglitazar
acide [[(4-méthoxyphénoxy)carbonyl][4-[2-(5-méthyl-2-phényloxazol4-yl)éthoxy]benzyl]amino]acétique
antidiabétique
muraglitazar
ácido [[(4-metoxifenoxi)carbonil][4-[2-(2-fenil-5-metiloxazol4-il)etoxi]bencil]amino]acético
antidiabético
331741-94-7
C29H28N2O7
O
CO2H
O
N
CH3
N
O
O
OCH3
57
nebentanum
nebentan
(E)-N-[6-methoxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]2-phenylethenesulfonamide
endothelin receptor antagonist
nébentan
(1E)-N-[6-méthoxy-5-(2-méthoxyphénoxy)-2,2'-bipyrimidyl-4-yl]2-phényléthènesulfonamide
antagoniste des récepteurs de l'endothéline
nebentán
(1E)-2-fenil-N-[6-metoxi-5-(2-metoxifenoxi)-2,2'-bipirimidil-4-il]=
etenosulfonamida
antagonista de los receptores de endotelina
403604-85-3
C24H21N5O5S
O O
S
NH
N
N
N
N
netupitant
netupitant
OCH3
O
O
CH3
2-[3,5-bis(trifluoromethyl)phenyl]-N-methyl-N-[4-(2-methylphenyl)6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2-methylpropanamide
neurokinin NK1 receptor antagonist
nétupitant
2-[3,5-bis(trifluométhyl)phényl]-N,2-diméthyl-N-[4-(2-méthylphényl)6-(4-méthylpipérazin-1-yl)pyridin-3-yl]propanamide
antagoniste des récepteurs NK1 de la neurokinine
netupitant
2-[3,5-bis(trifluometil)fenil]-N,2-dimetil-N-[4-(2-metilfenil)6-(4-metilpiperazin-1-il)piridin-3-il]propanamida
antagonista de los receptores NK1 de la neurokinina
C30H32F6N4O
H3C
290297-26-6
N
CF3
N
N
O
N
H3C
omigapilum
omigapil
CH3
CH3
CH3
CF3
(dibenzo[b,f]oxepin-5-ylmethyl)(methyl)prop-2-yn-1-amine
neuroprotective agent
omigapil
N-[(dibenzo[b,f]oxépin-10-yl)méthyl]-N-méthylprop-2-ynamine
neuroprotecteur
omigapilo
N-[(dibenzo[b,f]oxepin-10-il)metil]-N-metilprop-2-inamina
neuroprotector
58
181296-84-4
C19H17NO
N
O
paclitaxelum poliglumexum
paclitaxel poliglumex
CH
CH3
poly(L-glutamic acid) partly γ-esterified by (2R,3S)-3-benzamido1-{[4,10β-bis(acetoxy)-2α-(benzoyloxy)-1,7β-dihydroxy-9-oxo5,20-epoxytax-11-en-13α-yl]oxy}-1-oxo-3-phenylpropan-2-yl
antineoplastic
poly(acide L-glutamique) partiellement γ-estérifié par du (1R)-1-[(S)(benzoylamino)phénylméthyl]-2[[(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-bis(acétyloxy)12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tétraméthyl-5-oxo2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodécahydro-7,11-méthano1H-cyclodéca[3,4]benzo[1,2-b]oxét-9-yl]oxy]-2-oxoéthyle
antinéoplasique
poli(ácido L-glutámico) parcialmente γ-esterificado por
(1R)-1-[(S)-(benzoilamino)fenilmetil]-2[[(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-bis(acetiloxi)12-(benzoiloxi)-4,11-dihidroxi-4a,8,13,13-tetrametil-5-oxo2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahidro-7,11-metano1H-ciclodeca[3,4]benzo[1,2-b]oxet-9-il]oxi]-2-oxoetilo
antineoplásico
263351-82-2
(C52H56N2O16)n . (C5H7NO3)x
HO
H
H
N
H
OH
HO
O
O
O
H
N
O
z
H
N
H
H
O
O
O
O
HN
H
H
O
O
H3C
y
CH3
O
H
O
O
CH3
H
CH3
OH
H
O O
O
OH
CH3 H
H
H
O
O
CH3
n
59
pasireotidum
pasireotide
cyclo[(4R)-4-(2-aminoethylcarbamoyloxy)-L-prolyl-L-phenylglycylD-tryptophyl-L-lysyl-4-O-benzyl-L-tyrosyl-L-phenylalanyl-)
inhibition of growth hormone release
pasiréotide
cyclo[-(4R)-4-[[(2-aminoéthyl)carbamoyl]oxy]-L-prolyl-(2S)2-phénylglycyl-D-tryptophyl-L-lysyl-O-benzyl-L-tyrosylL-phénylalanyl-]
inhibiteur de libération de l'hormone de croissance
pasireotida
ciclo[-(4R)-4-[[(2-aminoetil)carbamoil]oxi]-L-prolil-(2S)-2-fenilglicilD-triptofil-L-lisil-O-bencil-L-tirosil-L-fenilalanil-]
inhibidor de la liberación de la hormona de crecimiento
396091-73-9
C58H66N10O9
H
N
H2N
O
H
H
O
N
2
Gly
D-Trp
Lys
O
Tyr
Phe
O
pelitrexolum
pelitrexol
(2S)-2-(5-{2-[(6S)-2-amino-4-oxo-1,4,5,6,7,8-hexahydropyrido=
[2,3-d]pyrimidin-6-yl]ethyl}-4-methylthiophene-2-carboxamido)=
pentanedioic acid
antineoplastic
pélitrexol
acide (2S)-2-[[[5-[2-[(6S)-2-amino-4-oxo-1,4,5,6,7,8hexahydropyrido[2,3-d]pyrimidin-6-yl]éthyl]-4-méthylthiophén2-yl]carbonyl]amino]pentanedioïque
antinéoplasique
pelitrexol
ácido (2S)-2-[[[5-[2-[(6S)-2-amino-4-oxo-1,4,5,6,7,8-hexahidropirido=
[2,3-d]pirimidin-6-il]etil]-4-metiltiofen-2-il]carbonil]amino]=
pentanodioico
antineoplásico
C20H25N5O6S
446022-33-9
O
H2N
60
O
H
N
S
N
H
N
H
H CO2H
N
H
CO 2H
H3C
pruvanserinum
pruvanserin
7-{4-[2-(4-fluorophenyl)ethyl]piperazine-1-carbonyl}-1H-indole3-carbonitrile
serotonin receptor antagonist
pruvansérine
1-[(3-cyano-1H-indol-7-yl)carbonyl]-4-[2-(4-fluorophényl)éthyl]=
pipérazine
antagoniste de récepteurs de la sérotonine
pruvanserina
1-[(3-ciano-1H-indol-7-il)carbonil]-4-[2-(4-fluorofenil)etil]piperazina
antagonista de los receptores de serotonina
443144-26-1
C22H21FN4O
F
N
N
NC
NH
ramelteonum
ramelteon
O
N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}=
propanamide
selective melatonin receptor agonist
rameltéon
(-)-N-[2-[(8S)-1,6,7,8-tétrahydro-2H-indéno[5,4-b]furan-8-yl]éthyl]=
propanamide
agoniste des récepteurs de la mélatonine
ramelteòn
N-[2-[(8S)-1,6,7,8-tetrahidro-2H-indeno[5,4-b]furan-8-il]etil]=
propanamida
agonista de los receptores selectivos de melatonina
196597-26-9
C16H21NO2
O
O
ranibizumabum
ranibizumab
H
N
H
CH3
immunoglobulin G1, anti-(human vascular endothelial growth
factor) Fab fragment (human-mouse monoclonal rhuFAB V2 γ1chain), disulfide with human-mouse monoclonal rhuFAB V2 κ-chain
immunomodulator
ranibizumab
immunoglobuline G1, anti-(facteur de croissance endothelial
vasculaire humain) ; disulfure entre le fragment Fab de la chaîne γ1
et la chaîne κ de l'anticorps monoclonal de souris rhuFAB V2
humanisé
immunomodulateur
ranibizumab
inmunoglobulina G1, anti-(factor de crecimiento endotelial vascular
humano) fragmento Fab (cadena γ1 del anticuerpo monoclonal
humanizado de ratón rhuFAB V2), disulfuro con la cadena κ del
anticuerpo monoclonal humanizado de ratón rhuFAB V2
inmunomodulador
61
C2158H3282N562O681S12
razaxabanum
razaxaban
347396-82-1
1-(3-amino-1,2-benzoxazol-5-yl)-N-{4-[2-(dimethylaminomethyl)1H-imidazol-1-yl]-2-fluorophenyl}-3-(trifluoromethyl)-1H-pyrazole5-carboxamide
anticoagulant
razaxaban
1-(3-amino-1,2-benzisoxazol-5-yl)-N-[4-[2-[(diméthylamino)méthyl]1H-imidazol-1-yl]-2-fluorophényl]-3-(trifluorométhyl)-1H-pyrazole5-carboxamide
anticoagulant
razaxabán
1-(3-amino-1,2-bencisoxazol-5-il)-N-[4-[2-[(dimetilamino)metil]1H-imidazol-1-il]-2-fluorofenil]-3-(trifluorometil)-1H-pirazol5-carboxamida
anticoagulante
218298-21-6
C24H20F4N8O2
F3C
H
N
N
N
F
CH3
N
CH3
O
N
H2N
N
N O
resequinilum
resequinil
5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)1,6-naphthyridin-2(1H)-one
psychostimulant
réséquinil
5-(3-méthoxyphényl)-3-(5-méthyl-1,2,4-oxadiazol-3-yl)1,6-naphtyridin-2(1H)-one
psychostimulant
resequinilo
5-(3-metoxifenil)-3-(5-metil-1,2,4-oxadiazol-3-il)-1,6-naftiridin2(1H)-ona
psicoestimulante
219846-31-8
C18H14N4O3
H
N
N
O
N
N O
OCH3
62
CH3
rivaroxabanum
rivaroxaban
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide
blood-coagulation factor Xa inhibitor
rivaroxaban
5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phényl]oxazolidin5-yl]méthyl]thiophène-2-carboxamide
inhibiteur du facteur Xa de coagulation
rivaroxabán
5-cloro-N-[[(5S)-2-oxo-3-[4-(3-oxomorfolin-4-il)fenil]oxazolidin5-il]metil]tiofeno-2-carboxamida
inhibidor del factor Xa de coagulación
366789-02-8
C19H18ClN3O5S
O
O
N
H H
N
N
O
sabarubicinum
sabarubicin
S
O
Cl
O
(7S,9S)-7-{[4-O-(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)2,6-dideoxy-α-L-lyxo-hexopyranosyl]oxy}-6,9,11-trihydroxy9-(hydroxyacetyl)-7,8,9,10-tetrahydrotetracene-5,12-dione
antineoplastic, antibiotic
sabarubicine
(7S,9S)-7-[[4-O-(3-amino-2,3,6-tridésoxy-α-L-lyxo-hexopyranosyl)2,6-didésoxy-α-L-lyxo-hexopyranosyl]oxy]-6,9,11-trihydroxy9-(hydroxyacétyl)-7,8,9,10-tétrahydrotétracène-5,12-dione
antineoplasique, antibiotique
sabarubicina
(7S,9S)-7-[[4-O-(3-amino-2,3,6-tridesoxi-α-L-lixo-hexopiranosil)2,6-didesoxi-α-L-lixo-hexopiranosil]oxi]-6,9,11-trihidroxi9-(hidroxiacetil)-7,8,9,10-tetrahidrotetraceno-5,12-diona
antibiótico, antineoplásico
C32H37NO13
O
211100-13-9
OH
O
OH
OH
O
OH
H
O O
CH3
O O
CH3
OH
HO
NH2
63
solabegronum
solabegron
3'-[(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}ethyl)=
amino]biphenyl-3-carboxylic acid
β3-adrenoreceptor agonist
solabégron
acide 3'-[[2-[[(2R)-2-(3-chlorophényl)-2-hydroxyéthyl]amino]éthyl]=
amino]biphényle-3-carboxylique
agoniste des récepteurs β3 adrénergiques
solabegrón
ácido 3'-[[2-[[(2R)-2-(3-clorofenil)-2-hidroxietil]amino]etil]=
amino]bifenilo-3-carboxílico
agonista de los receptores β3-adrenérgicos
C23H23ClN2O3
H OH H
N
252920-94-8
N
H
CO 2H
Cl
tadekinigum alfa
tadekinig alfa
interleukin-18 binding protein (human gene IL18BP isoform a
precursor)
anti-inflammatory
tadékinig alfa
partie extracellulaire du récepteur de l'interleukine 18 humain
anti-inflammatoire
tadekinig alfa
fracción extracelular del receptor de la interleukina 18 humana
antiinflammatorio
C781H1230N216O237S6 (protein)
TPVSQTTTAA
220712-29-8
TASVRSTKDPH CPSQPPVFPA
WPEVEVPLNG TLSLSCVACS
RFPNFSILYW
AKQCPALEVT
LGNGSFIEHL
PGRLWEGSTS
RERGSTGTQL
CKALVLEQLT
PALHSTNFSC
VLVDPEQVVQ
RHVVLAQLWA
GLRATLPPTQ
EALPSSHSSP
QQQG
tanaprogetum
tanaproget
5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)1-methyl-1H-pyrrole-2-carbonitrile
non-steroidal progesterone receptor agonist
tanaproget
5-(4,4-diméthyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)1-méthyl-1H-pyrrole-2-carbonitrile
progestagène non stéroïdien (contraceptif)
tanaproget
5-(4,4-dimetil-2-tioxo-1,4-dihidro-2H-3,1-benzoxazin-6-il)-1-metil1H-pirrol-2-carbonitrilo
agonista no esteroidico del receptor de progesterona
64
304853-42-7
C16H15N3OS
H
N
S
O
H3C
N
NC
taneptacoginum alfa
taneptacogin alfa
CH3
CH3
344
.193
344
.193
344
.193
O ,Nτ - cyclic hemiacetal obtained by the action of
L-phenylalanyl L-phenylalanyl-L-arginine chloromethane on the blood
coagulation factor VII (eptacog alfa) activated
anticoagulant
taneptacogin alfa
O ,Nτ -hemiacétal cyclique obtenu par action du
L-phénylalanyl-L-phénylalanyl-L-arginylchlorométhane sur le facteur
VIIa de coagulation humain (eptacog alfa) activé
anticoagulant
taneptacogina alfa
O ,Nτ -hemiacetal cíclico obtenido por acción del L-fenilalanilL-fenilalanil-L-arginilclorometano sobre el factor VIIa de coagulación
humano (eptacog alfa) activado
anticoagulante
465540-87-8
taprizosinum
taprizosin
N-{2-[4-amino-6,7-dimethoxy-5-(pyridin-2-yl)quinazolin-2-yl]1,2,3,4-tetrahydroisoquinolin-5-yl}methanesulfonamide
α1-adrenoreceptor antagonist
taprizosine
N-[2-[4-amino-6,7-diméthoxy-5-(pyridin-2-yl)quinazolin-2-yl]1,2,3,4-tétrahydroisoquinoléin-5-yl]méthanesulfonamide
antagoniste des récepteurs α 1 adrénergiques
taprizosina
N-[2-[4-amino-6,7-dimetoxi-5-(piridin-2-il)quinazolin-2-il]1,2,3,4-tetrahidroisoquinolin-5-il]metanosulfonamida
antagonista del receptor α1-adrenérgico
210538-44-6
C25H26N6O4S
O O
S
HN
CH3
H3CO
N
N
N
H3CO
N
NH2
65
teduglutidum
teduglutide
[2-glycine](1-33)-Peptide 2 analogue of human glucagon (GLP-2)
gastrointestinal functions normalizing agent
téduglutide
[2-glycine](1-33)-peptide du Peptide 2 Analogue du Glucagon
humain (GLP-2)
traitement de lésions de la paroi intestinale
teduglutida
[2-glicina]péptido(1-33) del péptido-2 análogo del glucagón humano
normalizador de la función intestinal
C164H252N44O55S
H His Gly
287714-30-1
Asp Gly
Ser
Phe
Ser
Asp Glu Met
Asn Thr
10
Ile
Leu
Asp
Asn
Leu
Ala
Ala
Arg
Asp Phe
Ile
Asn
20
Trp
Leu
Ile
Gln Thr
Lys
Ile Thr
Asp OH
30
tocilizumabum
tocilizumab
Immunoglobulin G1, anti-(human interleukin 6 receptor) (humanmouse monoclonal MRA heavy chain), disulfide with human-mouse
monoclonal MRA κ-chain, dimer
immunomodulator
tocilizumab
immunoglobuline G1, anti-(récepteur de l'interleukine 6 humaine) ;
dimère du disulfure entre la chaîne lourde et la chaîne-κ de
l'anticorps monoclonal de souris MRA humanisé
immunomodulateur
tocilizumab
inmunoglobulina G1, anti-(receptor de la interleukina 6 humana) ;
dímero del disulfuro entre la cadena pesada y la cadena -κ del
anticuerpo monoclonal humanizado de ratón MRA
inmunomodulador
C6428H9976N1720O2018S42
uliprisnilum
uliprisnil
375823-41-9
11β-[4-(dimethylamino)phenyl]-17-hydroxy-19-norpregna-4,9-diene3,20-dione
progesterone receptor modulator
uliprisnil
11β-[4-(diméthylamino)phényl]-17-hydroxy-19-norprégna-4,9-diène3,20-dione
modulateur du récepteur de la progestérone
uliprisnilo
11β-[4-(dimetilamino)fenil]-17-hidroxi-19-norpregna-4,9-dieno3,20-diona
modulador del receptor de progesterona
66
159811-51-5
C28H35NO3
CH3
H3C
N
O
CH3
H
CH3
OH
H
H
O
urtoxazumabum
urtoxazumab
immunogobulin, anti-(Escherichia coli Shiga-like toxin II B subunit)
(human-mouse hybridoma HuVTm1.1 γ−chain V-D-J region),
disulfur with human-mouse hybridoma HuVTm1.1 κ-chain V-J
region, dimer
immunomodulator
urtoxazumab
immunogobuline G1, anti-(sous-unité B de la toxine II analogue à la
Shiga d'Escherichia coli) ; dimère du disulfure entre la chaîne γ et la
chaîne κ de l'anticorps monoclonal de souris HuVTm1.1 humanisé
immunomodulateur
urtoxazumab
inmunogobulina G1, anti-(subunidad B de la toxina II análoga de la
Shiga de Escherichia coli), dímero del disulfuro entre la cadena γ y
la cadena κ del anticuerpo monoclonal de ratón HuVTm1.1
humanizado
inmunomodulador
502496-16-4
C6414H9934N1718O2010S40
valtorcitabinum
valtorcitabine
4-amino-1-(3-O-L-valyl-2-deoxy-β-L-erythro-pentofuranosyl)pyrimidin-2(1H)-one
antiviral
valtorcitabine
4-amino-1-[3-O-[(2S)-2-amino-3-méthylbutanoyl]-2-désoxyβ-L-érythro-pentofuranosyl]pyrimidin-2(1H)-one
antiviral
valtorcitabina
4-amino-1-(3-O -L-valil-2-desoxi-β-L-eritro-pentofuranosil)-pirimidin2(1H)-ona
antiviral
380886-95-3
C14H22N4O5
CH3
O
H3C
O
O
H2N
HO
H
N
O
N
NH2
67
vildagliptinum
vildagliptin
(2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine2-carbonitrile
antidiabetic agent
3,7
vildagliptine
(2S)-1-[[(3-hydroxytricyclo[3.3.1.1 ]déc-1-yl)amino]acétyl]=
pyrrolidine-2-carbonitrile
antidiabétique
vildagliptina
(2S)-1-[[(3-hidroxitriciclo[3.3.1.1 ]dec-1-il)amino]acetil]pirrolidina2-carbonitrilo
antidiabético
3,7
274901-16-5
C17H25N3O2
O
H
N
H CN
N
OH
zanolimumabum
zanolimumab
immunoglobulin G1, anti-(human antigen CD4), heavy chain disulfide
with the κ−chain of human monoclonal antibody 6G5.2, dimer
immunomodulator
zanolimumab
immunoglobuline G1, anti-(antigène CD4 humain) ; dimère du
disulfure entre la chaîne lourde et la chaîne κ de l'anticorps
monoclonal humain 6G5.2
immunomodulateur
zanolimumab
inmunoglobulina G1, anti-(antígeno CD4 humano) ; dímero del
disulfuro entre la cadena pesada y la cadena κ del anticuerpo
monoclonal humano 6G5.2
inmunomodulador
652153-01-0
H
H
H
O
N
H
O
H
H
N
N
N S
68
AMENDMENTS TO PREVIOUS LISTS
MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES
MODIFICACIONES A LAS LISTAS ANTERIORES
Proposed International Non Proprietary Names (Prop. INN): List 10
Dénominations communes internationales proposées (DCI Prop.): Liste 10
Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 10
(Crónica de la OMS, Vol. 14, N° 6, Junio de 1960, págs. 265-272)
p. 268
suprimase
metodilazina
insértese
metdilazina
(WHO Chronicle, Vol. 18, No. 11, November 1964, pp 433-444)
p. 437
lauromacrogolum 400
lauromacrogol 400
lauromacrogol 400
replace the description by the following:
polyethylene glycol monododecyl ether, the name is followed by a number (400)
corresponding approximately to the average molecular mass of the polyethylene
glycol portion
remplacer la description par la suivante:
α-dodécyl-ω-hydroxypoly(oxyéthylène), la masse moyenne de la partie macrogol
(#44n+18) est indiquée entre parenthèses après la dénomination
lauromacrogol 400
sustitúyase la descripción por la siguiente:
éter monododecílico del polietilen glicol, al nombre le sigue un número (400) que
corresponde aproximadamente a la masa molecular media de la fracción
polietilenglicol
(WHO Drug Information, Vol. 11, No. 4, 1997)
p. 289
p. 287
robalzotanum
robalzotan
replace the action and use by the following:
serotonin receptor antagonist
robalzotan
remplacer la propriété et l'indication par la suivante:
antagoniste des récepteurs de la sérotonine
robalzotan
sustitúyase la acción y el uso por los siguientes:
antagonista de los receptores de la serotonina
supprimer
pregabaline
insérer
prégabaline
69
p. 107
delete / supprimer / suprimase :
erlosamidum
erlosamide
erlosamide
erlosamida
insert / insérer / insértese :
lacosamidum
lacosamide
lacosamide
lacosamida
p. 67
70
dalbavancinum
dalbavancin
5,31-dichloro-38-de(methoxycarbonyl)-7-demethyl-19-deoxy-56-O-[2-deoxy2-[(10-methylundecanoyl)amino]-β-D-glucopyranuronosyl]38-[[3-(dimethylamino)propyl]carbamoyl]-42-O- α-D-mannopyranosyl-15-N-methyl
(ristomycin A aglicone) (main component)
dalbavancine
acide 2-désoxy-1-O-[(3S,15R,18R,34R,35S,38S,48R,50aR)-5,31-dichloro38-[[3-(diméthylamino)propyl]carbamoyl]-6,11,34,40,44-pentahydroxy42-(α-D-mannopyranosyloxy)-15-(méthylamino)-2,16,36,50,51,59-hexaoxo2,3,16,17,18,19,35,36,37,38,48,49,50,50a-tétradécahydro-20,23:30,33diéthéno-3,18:35,48-bis(iminométhano)-1H,15H-4,8:10,14:25,28:43,47tétraméthéno-34H-[1,14,6,22]dioxadiazacyclooctacosino[4,5-m][10,2,16]=
benzoxadiazacyclotétracosén-56-yl]-2-[(10-méthylundécanoyl)amino]β-D-glucopyranuronique (composant majeur)
dalbavancina
sustitúyase la descrpción por la siguiente:
ácido 1-O-[(3S,15R,18R,34R,35S,38S,48R,50aR)-5,31-dicloro-38[[3-(dimetilamino)propil]carbamoil]-6,11,34,40,44-pentahidroxi-42(α-D-manopiranosiloxi)-15-(metilamino)-2,16,36,50,51,59-hexaoxo2,3,16,17,18,19,35,36,37,38,48,49,50,50a-tetradecahidro-20,23:30,33dieteno-3,18:35,48-bis(iminometano)-1H,15H-4,8:10,14:25,28:43,47tetrameteno-34H-[1,14,6,22]dioxadiazaciclooctacosino[4,5-m][10,2,16]=
benzoxadiazaciclotetracosen-56-il]-2-[(10-metilundecanoil)amino]-2-desoxiβ-D-glucopiranurónico (componente principal)
p. 175
nalfurafinum
nalfurafine
replace the action and use by the following:
κ-opioid receptor agonist
nalfurafine
remplacer la propriété et l'indication par la suivante:
agoniste des récepteurs κ aux opiacés
nalfurafina
sustitúyase la acción y el uso por los siguientes:
agonista del receptor κ de opiáceos
p. 166
eglumegadum
eglumegad
églumégad
eglumegad
eglumetadum
eglumetad
églumétad
eglumetad
p. 58
p. 60
lurasidonum
lurasidone
mitratapid
mitratapid
mitratapid
replace the description by the following
(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione
mitratapide
mitratapide
mitratapida
p. 216
axomadolum
axomadol
axomadol
axomadol
insert the following CAS registry number
insérer le numéro dans le registre du CAS suivant
insértese el número de registro del CAS por
187219-95-0
71
p. 216
72
idusulfasum
idusulfase
idusulfase
idusulfasa
idursulfasum
idursulfase
idursulfase
idursulfasa
Annex 1
PROCEDURE FOR THE SELECTION OF RECOMMENDED INTERNATIONAL
NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES*
The following procedure shall be followed by the World Health Organization in the selection of recommended international
nonproprietary names for pharmaceutical substances, in accordance with the World Health Assembly resolution WHA3.11:
1. Proposals for recommended international nonproprietary names shall be submitted to the World Health Organization on
the form provided therefor.
2. Such proposals shall be submitted by the Director-General of the World Health Organization to the members of the
Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations designated for this purpose,
for consideration in accordance with the “General principles for guidance in devising International Nonproprietary 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 procedure.
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.1
5. A formal objection to a proposed name may be filed by any interested person within four months of the date of
publication, under article 3, of the name in the Chronicle of the World Health Organization.1
A. Such objection shall:
(i)
identify the person objecting;
__________________
Text adopted by the Executive Board of WHO in resolution EB15.R7 (Off. Rec. Wld Health Org., 1955, 60, 3) and amended by the Board in
resolution EB43.R9 (Off. Rec. Wld Hlth Org., 1969, 173, 10).
1 The title of this publication was changed to WHO Chronicle in January 1959. From 1987 onwards lists of INNs are published in WHO Drug
Information.
*
73
(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 DirectorGeneral of the World Health Organization shall give notice in accordance with subsection A of article 3 that the name has
been selected by the World Health Organization as a recommended international nonproprietary name.
8. In forwarding a recommended international nonproprietary name to Member States under article 7, the Director-General
of the World Health Organization shall:
A. request that it be recognized as the nonproprietary name for the substance; and
B. request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the name,
including prohibiting registration of the name as a trade-mark or trade-name.
Annex 2
GENERAL PRINCIPLES FOR GUIDANCE IN DEVISING INTERNATIONAL
NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES*
1. International Nonproprietary Names (INN) should be distinctive in sound and spelling. They should not be inconveniently
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
74
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.
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
-actidum
-adolum
-adol-astum
-astinum
-azepamum
-bactamum
bol
-buzonum
-cain-cainum
cef-cillinum
-conazolum
cort
-dipinum
-fibratum
gest
gliio-ium
-metacinum
-mycinum
-nidazolum
-ololum
-oxacinum
-pridum
-pril(at)um
-profenum
prost
-relinum
-terolum
-tidinum
-ac
-actide
-adol )
-adol- )
-ast
-astine
-azepam
-bactam
bol
-buzone
-cain-caine
cef-cillin
-conazole
cort
-dipine
-fibrate
gest
gliio-ium
-metacin
-mycin
-nidazole
-olol
-oxacin
-pride
pril(at)
-profen
prost
-relin
-terol
-tidine
-trexatum
-verinum
vin-vin-
-trexate
-verine
vin)
)
-vin-
anti-inflammatory agents of the ibufenac group
synthetic polypeptides with a corticotropin-like action
analgetics
antiasthmatic, antiallergic substances not acting primarily as antihistaminics
antihistaminics
diazepam derivatives
β-lactamase inhibitors
steroids, anabolic
anti-inflammatory analgesics, phenylbutazone derivatives
antifibrillant substances with local anaesthetic activity
local anaesthetics
antibiotics, cefalosporanic acid derivatives
antibiotics, derivatives of 6-aminopenicillanic acid
systemic antifungal agents, miconazole derivatives
corticosteroids, except prednisolone derivatives
calcium channel blockers, nifedipine derivatives
clofibrate derivatives
steroids, progestogens
sulfonamide hypoglycaemics
iodine-containing contrast media
quaternary ammonium compounds
anti-inflammatory substances, indometacin derivatives
antibiotics, produced by Streptomyces strains
antiprotozoal substances, metronidazole derivatives
β-adrenoreceptor antagonists
antibacterial agents, nalidixic acid derivatives
sulpiride derivatives
angiotensin-converting enzyme inhibitors
anti-inflammatory substances, ibuprofen derivatives
prostaglandins
hypophyseal hormone release-stimulating peptides
bronchodilators, phenethylamine derivatives
histamine H2-receptor antagonists
folic acid antagonists
spasmolytics with a papaverine-like action
vinca alkaloids
__________________
75
1 A more extensive listing of stems is contained in the working document WHO/EDM/QSM 99.6 which is regularly updated and can be
requested from the INN Programme, WHO, Geneva.
Annexe 1
PROCEDURE A SUIVRE EN VUE DU CHOIX DE
DENOMINATIONS COMMUNES INTERNATIONALES
RECOMMANDEES POUR LES SUBSTANCES PHARMACEUTIQUES*
L’Organisation mondiale de la Santé observe la procédure exposée ci-dessous pour l’attribution de dénominations
communes internationales recommandées pour les substances pharmaceutiques, conformément à la résolution WHA3.11
de l’Assemblée mondiale de la Santé:
1. Les propositions de dénominations communes internationales recommandées sont soumises à l’Organisation mondiale
de la Santé sur la formule prévue à cet effet.
2. Ces propositions sont soumises par le Directeur général de l’Organisation mondiale de la Santé aux experts désignés à
cette fin parmi les personnalités inscrites au Tableau d’experts de la Pharmacopée internationale et des Préparations
pharmaceutiques; elles sont examinées par les experts conformément aux “Directives générales pour la formation des
dénominations communes internationales”, reproduites ci-après. La dénomination acceptée est la dénomination employée
par la personne qui découvre ou qui, la première, fabrique et lance sur le marché une substance pharmaceutique, à moins
que des raisons majeures n’obligent à s’écarter de cette règle.
3. Après l’examen prévu à l’article 2, le Directeur général de l’Organisation mondiale de la Santé notifie qu’un projet de
dénomination commune internationale est à l’étude.
A. Cette notification est faite par une insertion dans la Chronique de l’Organisation mondiale de la Santé1 et par l’envoi
d’une lettre aux Etats Membres et aux commissions nationales de pharmacopée ou autres organismes désignés par les
Etats Membres.
(i) Notification peut également être faite à toute personne portant à la dénomination mise à l’étude un
intérêt notoire.
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;
(iii) définition de la substance dont la dénomination est mise à l’étude;
(iv) délai pendant lequel seront reçues les observations et les objections à l’égard de cette dénomination;
nom et adresse de la personne habilitée à recevoir ces observations et objections;
(v) mention des pouvoirs en vertu desquels agit l’Organisation mondiale de la Santé et référence au présent
règlement.
C. En envoyant cette notification, le Directeur général de l’Organisation mondiale de la Santé demande aux Etats
Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété sur la dénomination
proposée pendant la période au cours de laquelle cette dénomination est mise à l’étude par l’Organisation mondiale de
la Santé.
4. Des observations sur la dénomination proposée peuvent être adressées à l’Organisation mondiale de la Santé par toute
personne, dans les quatre mois qui suivent la date de publication de la dénomination dans la Chronique de l’Organisation
mondiale de la Santé1 (voir l’article 3).
76
* 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 résolution
EB43.R9 (Actes off. Org. mond. Santé, 1969, 173, 10).
1 Depuis janvier 1959, cette publication porte le titre de Chronique OMS. A partir de 1987, les listes des DCIs sont publiées dans les Informations pharmaceutiques OMS.
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 dispositions de la soussection A de l’article 3, en indiquant que la dénomination a été choisie par l’Organisation mondiale de la Santé en tant que
dénomination commune internationale recommandée.
8. En communiquant aux Etats Membres, conformément à l’article 7, une dénomination commune internationale
recommandée, le Directeur général de l’Organisation mondiale de la Santé:
A. demande que cette dénomination soit reconnue comme dénomination commune de la substance considérée, et
B. demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété
sur cette dénomination, notamment en interdisant le dépôt de cette dénomination comme marque ou appellation
commerciale.
Annexe 2
DIRECTIVES GENERALES POUR LA FORMATION DE DENOMINATIONS
COMMUNES INTERNATIONALES APPLICABLES AUX
SUBSTANCES PHARMACEUTIQUES*
1. Les dénominations communes internationales (DCI) devront se distinguer les unes des autres par leur consonance 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 Dénominations
communes pour les Substances pharmaceutiques a examiné les directives générales pour la formation des dénominations communes
internationales et la procédure 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 synthèse de la pratique normalement suivie pour désigner les
substances tirées ou dérivées de produits naturels. Cette pratique consiste à employer des syllabes communes ou groupes de syllabes
77
communes (segments clés) qui sont caractéristiques 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.
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
-acum
-actidum
-adolum
-adol-astum
-astinum
-azepamum
-bactamum
bol
-buzonum
-cain-cainum
cef-cillinum
-conazolum
cort
-dipinum
-fibratum
gest
gliio-ium
-metacinum
78
Français
-ac
-actide
-adol
)
-adol- )
-ast
-astine
-azépam
-bactame
bol
-buzone
-caïn-caïne
céf-cilline
-conazole
cort
-dipine
-fibrate
gest
gliio-ium
-métacine
substances anti-inflammatoires du groupe de l’ibufénac
polypeptides synthétiques agissant comme la corticotropine
analgésiques
antiasthmatiques, antiallergiques n’agissant pas principalement en tant
antihistaminiques
substances du groupe du diazépam
inhibiteurs de β-lactamases
stéroïdes anabolisants
analgésiques anti-inflammatoires du groupe de la phénylbutazone
substances antifibrillantes à action anesthésique locale
anesthésiques locaux
antibiotiques, dérivés de l’acide céphalosporanique
antibiotiques, dérivés de l’acide 6-aminopénicillanique
agents antifongiques systémiques du groupe du miconazole
corticostéroïdes, autres que les dérivés de la prednisolone
inhibiteurs du calcium du groupe de la nifédipine
substances du groupe du clofibrate
stéroïdes progestogènes
sulfamides hypoglycémiants
produits de contraste iodés
ammoniums quaternaires
substances anti-inflammatoires du groupe de l’indométacine
__________________
Une liste plus complète de segments clés est contenue dans le document de travail WHO/EDM/QSM 99.6 qui est régulièrement mis à jour
et qui peut être demandé auprès du Programme des DCI, OMS, Genève.
1
Latin
Français
-mycinum
-nidazolum
ololum
-oxacinum
-pridum
-profenum
-pril(at)um
prost
-relinum
-terolum
-tidinum
-mycine
-nidazole
-olol
-oxacine
-pride
-profène
-pril(ate)
prost
-réline
-térol
-tidine
antibiotiques produits par des souches de Streptomyces
substances antiprotozoaires du groupe du métronidazole
antagonistes des récepteurs β-adrénergiques
substances antibactériennes du groupe de l’acide nalidixique
substances du groupe du sulpiride
substances anti-inflammatoires du groupe de l’ibuprofène
inhibiteurs de l’enzyme de conversion de l’angiotensine
prostaglandines
peptides stimulant la libération d’hormones hypophysaires
bronchodilatateurs, dérivés de la phénéthylamine
antagonistes des récepteurs H2 de l’histamine
-trexatum
-verinum
vin-vin-
-trexate
-vérine
vin)
-vin- )
antagonistes de l’acide folique
spasmolytiques agissant comme la papavérine
alkaloïdes du type vinca
Anexo 1
PROCEDIMIENTO DE SELECCION DE DENOMINACIONES COMUNES INTERNACIONALES
RECOMENDADAS PARA LAS SUSTANCIAS FARMACEUTICAS*
La Organización Mundial de la Salud seguirá el procedimiento que se expone a continuación para la selección de
denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas, de conformidad con lo
dispuesto en la resolución WHA3.11 de la Asamblea Mundial de la Salud:
1. Las propuestas de denominaciones comunes internacionales recomendadas se presentarán a la Organización Mundial
de la Salud en los formularios que se proporcionen a estos efectos.
2. Estas propuestas serán sometidas por el Director General de la Organización Mundial de la Salud a los Miembros del
Cuadro de Expertos de la Farmacopea Internacional y las Preparaciones Farmacéuticas encargados de su estudio, para
que las 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).
*
79
1
Denominada Crónica de la OMS desde enero de 1959. A partir de 1987, las listas de DCI se publican en Información Farmacéutica OMS.
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 de 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
80
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.
Anexo 2
PRINCIPIOS GENERALES DE ORIENTACION PARA FORMAR DENOMINACIONES
COMUNES INTERNACIONALES PARA SUSTANCIAS FARMACEUTICAS*
1. Las Denominaciones Comunes Internacionales (DCI) deberán diferenciarse tanto fonética como ortográficamente. No
deberán ser incómodamente largas, ni dar lugar a confusión con denominaciones de uso común.
2. La DCI de una sustancia que pertenezca a un grupo de sustancias farmacológicamente emparentadas deberá mostrar
apropiadamente este parentesco. Deberán evitarse los nombres que puedan inducir fácilmente en el paciente sugestiones
anatómicas, fisiológicas, patológicas o terapéuticas.
Estos principios primarios deberán ser tenidos en cuenta al aplicar los siguientes principios secundarios:
3. Al idear la DCI de la primera sustancia de un nuevo grupo farmacológico, deberá tenerse en cuenta la posibilidad de
formar DCI convenientes para las sustancias emparentadas que vengan a incrementar el nuevo grupo.
4. Al idear DCI para ácidos, se preferirán las de una sola palabra; sus sales deberán denominarse sin modificar el nombre
de ácido; p. ej., “oxacilina” y “oxacilina sódica”, “ibufenaco” e “ibufenaco sódico”.
5. Las DCI para las sustancias que se usan en forma de sal, deberán en general aplicarse a la base activa o,
respectivamente, al ácido activo. Las denominaciones para diferentes sales o ésteres de la misma sustancia activa
solamente deberán diferir en el nombre de ácido o de la base inactivos.
En los compuestos de amonio cuaternario, el catión y el anión deberán denominarse adecuadamente por separado, como
componentes independientes de una sustancia cuaternaria y no como sales de una amina.
6. Deberá evitarse el empleo de una letra o un número aislados; también es indeseable el empleo de guiones.
7. Para facilitar la traducción y la pronunciación se emplearán de preferencia las letras “f” en lugar de “ph”, “t” en lugar de
“th”, “e” en lugar de “ae” u “oe” e “i” en lugar de “y”; se deberá evitar el empleo de las letras “h” y “k”.
8. Siempre que las denominaciones que se sugieran estén de acuerdo con estos principios, recibirán una consideración
preferente las denominaciones propuestas por la persona que haya descubierto la sustancia, o la que primeramente
fabrique o ponga a la venta la sustancia farmacéutica, así como las denominaciones oficialmente adoptadas en cualquier
país.
9. En las DCI, la relación de grupo o parentesco (véanse los Principios Generales de Orientación, apartado 2) se indicará
en lo posible utilizando una partícula común. En la lista siguiente se dan algunos ejemplos de estas partículas en relación
con diversos grupos de sustancias, en particular los de nuevo cuño. Hay otras muchas partículas comunes en uso.1
Cuando la partícula no lleva ningún guión, cabe utilizarla en cualquier parte de la denominación.
__________________
* En su 20o 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.
81
1 El documento de trabajo WHO/EDM/QSM 99.6, que se pone al día regularmente, contiene una lista más extensa de partículas comunes.
Las personas que deseen recibirlo deberán solicitar su envío al Programa DCI, OMS, Ginebra (Suiza).
Latin
Español
-acum
-actidum
-adolum
-adol-astum
-astinum
-azepamum
-bactamum
bol
-buzonum
-cain-cainum
cef-cillinum
-conazolum
cort
-dipinum
-fibratum
gest
gliio-ium
-metacinum
-mycinum
-nidazolum
-ololum
-oxacinum
-pridum
-pril(at)um
-profenum
prost
-relinum
-terolum
-tidinum
-aco
-actida
-adol }
-adol- }
-ast
-astina
-azepam
-bactam
bol
-buzona
-cain-caina
cef-cilina
-conazol
cort
-dipino
-fibrato
gest
gliio-io
-metacina
-micina
-nidazo
-olol
-oxacino
-prida
-pril(at)
-profeno
prost
-relina
-terol
-tidina
-trexatum
-verinum
vin-vin-
-trexato
-verina
vin}
-vin}
82
antiinflamatorios del grupo del ibufenaco
polipéptidos sintéticos de acción semejante a la corticotropina
analgésicos
antiasmáticos y antialérgicos que no actúan principalmente como antihistamínicos
antihistamínicos
sustancias del grupo del diazepam
inhibidores de β-lactamasas
esteroides anabólizantes
analgésicos antiinflamatorios del grupo de la fenilbutazona
antifibrilantes con actividad anestésica local
anestésicos locales
antibióticos derivados del ácido cefalosporánico
antibióticos derivados del ácido 6-aminopenicilánico
antifúngicos sistémicos del grupo del miconazol
corticosteroides, excepto los del grupo de la prednisolona
antagonistas del calcio del grupo del nifedipino
sustancias del grupo del clofibrato
esteroides progestágenos
sulfonamidas hipoglucemiantes
medios de contraste que contienen yodo
compuestos de amonio cuaternario
antiinflamatorios del grupo de la indometacina
antibióticos, producidos por cepas de Streptomyces
antiprotozoarios del grupo del metronidazol
bloqueadores β-adrenérgicos
antibacterianos del grupo del ácido nalidíxico
sustancias del grupo de la sulpirida
inhibidores de la enzima transformadora de la angiotensina
antiinflamatorios del grupo del ibuprofeno
prostaglandinas
péptidos estimulantes de la liberación de hormonas hipofisarias
broncodilatadores derivados de la fenetilamina
antagonistas del receptor H2 de la histamina
antagonistas del ácido fólico
espasmolíticos de acción semejante a la de la papaverina
alcaloides de la vinca
Recommended INN: List 51
Pharmaceutical Substances (INN)
RECOMMENDED International Nonproprietary Names:
List 51
Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended
International Nonproprietary Names for Pharmaceutical Substances O
[ ff. Rec. Wld Health Org., 1955, 60, 3 (Resolution
EB15.R7); 1969, 173, 10 (Resolution EB43.R9)], the following names are selected as Recommended International
Nonproprietary Names. The inclusion of a name in the lists of Recommended International Nonproprietary Names does not
imply any recommendation of the use of the substance in medicine or pharmacy.
Lists of Proposed (1–85) and Recommended (1–45) International Nonproprietary Names can be found in Cumulative List
No. 10, 2002 (available in CD- ROM only).
Dénominations communes internationales
des Substances pharmaceutiques (DCI)
Dénominations communes internationales RECOMMANDÉES:
Liste 51
Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de
Dénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org. mond.
Santé, 1955, 60, 3 (résolution EB15.R7); 1969, 173, 10 (résolution EB43.R9)] les dénominations ci-dessous sont choisies
par l’Organisation mondiale de la Santé en tant que dénominations communes internationales recommandées. L’inclusion
d’une dénomination dans les listes de DCI recommandées n’implique aucune recommandation en vue de l’utilisation de la
substance correspondante en médecine ou en pharmacie.
On trouvera d’autres listes de Dénominations communes internationales proposées (1–85) et recommandées (1–45) dans
la Liste récapitulative No. 10, 2002 (disponible sur CD-ROM seulement).
Denominaciones Comunes Internacionales
para las Sustancias Farmacéuticas (DCI)
Denominaciones Comunes Internacionales RECOMENDADAS:
Lista 51
De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones Comunes
Internacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (Resolución
EB15.R7); 1969, 173, 10 (Resolución EB43.R9)], se comunica por el presente anuncio que las denominaciones que a
continuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas. La
inclusión de una denominación en las listas de las Denominaciones Comunes Recomendadas no supone recomendación
alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia.
Las listas de Denominaciones Comunes Internacionales Propuestas (1–85) y Recomendadas (1–45) se encuentran
reunidas en Cumulative List No. 10, 2002 (disponible sólo en CD-ROM).
83
Latin, English, French, Spanish:
Recommended INN
Chemical name or description; Molecular formula; Graphic formula
DCI Recommandée
Nom chimique ou description; Formule brute; Formule développée
Nombre químico o descripción; Fórmula empírica; Fórmula desarrollada
DCI Recomendada
adargileukinum alfa
adargileukin alfa
[88-arginine]interleukin 2 (human clone pTIL2-21a) (partly
glycosylated)
adargileukine alfa
[88-arginine]interleukine 2 humaine (clone pTIL2-21a) (en partie
glycosylée)
adargileukina alfa
[88-arginina]interleukina 2 humana (clon pTIL2-21a) (parcialmente
glicosilada)
C695H1124N180O202S7 (peptide)
APTSSSTKKT
alamifovirum
alamifovir
QLQLEHLLLD
LQMILNGINN
YKNPKLTRML
TFKFYMPKKA
TELKHLQCLE
EELKPLEEVL
NLAQSKNFHL
RPRDLISRIN
VIVLELKGSE
TTFMCEYADE
TATIVEFLNR
WITFCQSIIS
TLT
bis(2,2,2-trifluoroethyl) [(2-{2-amino-6-[(4-methoxyphenyl)sulfanyl]9H-purin-9-yl}ethoxy)methyl]phosphonate
alamifovir
[[2-[2-amino-6-[(4-méthoxyphényl)sulfanyl]-9H-purin9-yl]éthoxy]méthyl]phosphonate de bis(2,2,2-trifluoroéthyle)
alamifovir
[(2-{2-amino-6-[(4-metoxifenil)sulfanil]-9H-purin9-il}etoxi)metil]fosfonato de bis(2,2,2-trifluoroetilo)
C19H20F6N5O5 PS
H3CO
CF 3
S
H2N
84
O
N
N
P
N
N
O
O
O
CF 3
aprinocarsenum
aprinocarsen
2'-deoxy-P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')P-thiothymidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')P-thiothymidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'- deoxyP-thioguanylyl-(3'→5')-2'- deoxy-P-thiocytidylyl-(3'→5')P-thiothymidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-2'- deoxyP-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxyP-thioguanylyl-(3'→5')-2'- deoxy-P-thioadenylyl-(3'→5')-2'-deoxyP-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')2'-deoxyadenosine
aprinocarsen
2'-désoxy-P-thioadénylyl- (5'→3')-2'- désoxy-P-thiocytidylyl-(5'→3')P-thiothymidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-P-thiothymidylyl(5'→3')-2'-désoxy-P-thioguanylyl-(5'→3')-2'- désoxy-P-thioadénylyl(5'→3')-2'-désoxy-P-thioguanylyl-(5'→3')-P-thiothymidylyl-(5'→3')2'-désoxy-P-thioguanylyl- (5'→3')-2'- désoxy-P-thioguanylyl-(5'→3')P-thiothymidylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')-2'-désoxyP-thioguanylyl-(5'→3')-2'- désoxy-P-thiocytidylyl-(5'→3')P-thiothymidylyl-(5'→3')-2'-désoxy-P-thiocytidylyl-(5'→3')P-thiothymidylyl-(5'→3')-P-thiothymidylyl-(5'→3')-2'désoxyguanosine
aprinocarseno
2'-desoxi-P-tioadenilil-(5'→3')-2'- desoxi-P-tiocitidilil-(5'→3')P-tiotimidilil-(5'→3')-P-tiotimidilil-(5'→3')-P-tiotimidilil-(5'→3')2'-desoxi-P-tioguanilil-(5'→3')-2'- desoxi-P-tioadenilil-(5'→3')2'-desoxi-P-tioguanilil-(5'→3')-P-tiotimidilil-(5'→3')-2'-desoxiP-tioguanilil-(5'→3')-2'- desoxi-P-tioguanilil-(5'→3')-P-tiotimidilil(5'→3')-2'-desoxi-P-tiocitidilil-(5'→3')-2'-desoxi-P-tioguanilil-(5'→3')2'-desoxi-P-tiocitidilil-(5'→3')-P-tiotimidilil-(5'→3')-2'- desoxiP-tiocitidilil-(5'→3')-P-tiotimidilil-(5'→3')-P-tiotimidilil-(5'→3')2'-desoxiguanosina
C196H249N68O105P19S19
belimumabum
belimumab
immunoglobulin G1, anti-(human cytokine BAFF) (human
monoclonal LymphoStat-B heavy chain), disulfide with human
monoclonal LymphoStat-B λ-chain, dimer
bélimumab
immunoglobuline G1, anti-(cytokine BAFF humaine) ; dimère du
disulfure entre la chaîne lourde et la chaîne λ de l'anticorps
monoclonal humain LymphoStat-B
belimumab
immunoglobulina G1, anti-(citoquina BAFF humana) ; dímero del
disulfuro entre la cadena pesada y la cadena λ del anticuerpo
monoclonal humano LymphoStat-B
85
cantuzumabum mertansinum
cantuzumab mertansine
immunoglobulin G1, anti-(mucin CanAg) (human-mouse
monoclonal C242 heavy chain), disulfide with human-mouse
monoclonal C242 light chain, dimer, conjugate at the 6-amino
groups of four lysine residues forming an amide bond with (4RS)4-[(3-{[(1S)-2-{[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5 ]hexacosa10,12,14(26),16,18-pentaen-6-yl]oxy}-1-methyl-2-oxoethyl]=
methylamino}-3-oxopropyl)disulfanyl]pentanoyl groups
cantuzumab mertansine
immunoglobuline G1, anti-(mucin CanAg) ; dimère du disulfure
entre la chaîne lourde et la chaîne légère de l'anticorps monoclonal
de souris C242 humanisé dont les groupes 6-amino de quatre
lysines sont amidifiés par l'acide (4RS)-4-[[3-[[(1S)2-[[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy12,20-diméthoxy-2,5,9,16-tétraméthyl-8,23-dioxo-4,24-dioxa9,22-diazatétracyclo[19.3.1.110,14.03,5]hexacosa10,12,14(26),16,18-pentaén-6-yl]oxy]-1-méthyl-2-oxoéthyl]=
méthylamino]-3-oxopropyl]disulfanyl]pentanoïque
cantuzumab mertansina
inmunoglobulina G1, anti-(mucina CanAg) ; dímero del disulfuro
entre la cadena pesada y la cadena ligera del anticuerpo
monoclonal humanizado de ratón C242 en el que los grupos
6-amino de cuatro lisinas están amidificados por ácido (4RS)4-[[3-[[(1S)-2-[[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-cloro21-hidroxi-2,5,9,16-tetrametil -12,20-dimetoxi-4,24-dioxa8,23-dioxo-9,22-diazatetraciclo[19.3.1.1 10,14.03,5 ]hexacosa10,12,14(26),16,18-pentaen-6-il]oxi]-1-metil-2-oxoetil]metilamino]3-oxopropil]disulfanil]pentanoico
O
Ig
N
H
O
S
S
CH3
O
N
H3C
H3C
CH3
O
H
O
H
H
O
O
H CH3
H
CH3
Cl
N
OCH3
O
OH
N
H
H OCH3
CH3
cantuzumab = Ig(NH2)4
cimicoxibum
cimicoxib
4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)-1H-imidazol1-yl]benzenesulfonamide
cimicoxib
4-[4-chloro-5-(3-fluoro-4-méthoxyphényl)-1H-imidazol1-yl]benzènesulfonamide
cimicoxib
4-[4-cloro-5-(3-fluoro-4-metoxifenil)-1H-imidazol1-il]bencenosulfonamida
86
4
C16H13ClFN3O3S
H 3CO
F
O O
S
NH 2
N
Cl
N
dabuzalgronum
dabuzalgron
N-{6-chloro-3-[(4,5-dihydro-1H-imidazol-2-yl)methoxy]2-methylphenyl}methanesulfonamide
dabuzalgron
N-[6-chloro-3-[(4,5-dihydro-1H-imidazol-2-yl)méthoxy]2-méthylphényl]méthanesulfonamide
dabuzalgrón
N-{6-cloro-3-[(4,5-dihidro-1H-imidazol-2-il)metoxi]2-metilfenil}metanosulfonamida
C12H16ClN3O3S
H
N
H3C
CH3
S
O O
Cl
dacinostatum
dacinostat
N
O
N
H
(2E)-N-hydroxy-3-[4-({(2-hydroxyethyl)[2-(1H-indol3-yl)ethyl]amino}methyl)phenyl]propenamide
dacinostat
(2E)-N-hydroxy-3-[4-[[(2-hydroxyéthyl)[2-(1H-indol3-yl)éthyl]amino]méthyl]phényl]prop-2-énamide
dacinostat
(2E)-N-hidroxi-3-[4-({(2-hidroxietil)[2-(1H-indol3-il)etil]amino}metil)fenil]propenamida
C22H25N3O3
HN
N
OH
H
N
OH
O
87
dalbavancinum
dalbavancin
5,31-dichloro-38-de(methoxycarbonyl)-7-demethyl-19-deoxy-56-O[2-deoxy-2-[(10-methylundecanoyl)amino]- ß- D -glucopyranuronosyl]38-[[3-(dimethylamino)propyl]carbamoyl]-42-O-a- D-mannopyranosyl15-Nmethyl(ristomycin A aglicone) (main component)
dalbavancine
acide 2-désoxy-1-O-[(3S,15R,18R,34R,35S,38S,48R,50aR)-5,31dichloro-38-[[3-(diméthylamino)propyl]carbamoyl]-6,11,34,40,44pentahydroxy-42-(a- D-mannopyranosyloxy)-15-(méthylamino)2,16,36,50,51,59-hexaoxo2,3,16,17,18,19,35,36,37,38,48,49,50,50a-tétradécahydro20,23:30,33-diéthéno-3,18:35,48-bis(iminométhano)1H,15H-4,8:10,14:25,28:43,47-tétraméthéno34H-[1,14,6,22]dioxadiazacyclooctacosino[4,5-m][10,2,16]=
benzoxadiazacyclotétracosén-56-yl]-2-[(10-méthylundécanoyl)=
amino]-ß- D -glucopyranuronique (composant majeur)
dalbavancina
ácido 1-O-[(3S,15R,18R,34R,35S,38S,48R,50aR)-5,31-dicloro-38[[3-(dimetilamino)propil]carbamoil]-6,11,34,40,44-pentahidroxi-42(a- D-manopiranosiloxi)-15-(metilamino)-2,16,36,50,51,59-hexaoxo2,3,16,17,18,19,35,36,37,38,48,49,50,50a-tetradecahidro20,23:30,33-dieteno-3,18:35,48-bis(iminometano) -1H,15H4,8:10,14:25,28:43,47-tetrameteno34H-[1,14,6,22]dioxadiazaciclooctacosino[4,5-m][10,2,16]=
benzoxadiazaciclotetracosen-56-il]-2-[(10-metilundecanoil)amino]2-desoxi-ß-D -glucopiranurónico (componente principal)
C88-H100-Cl2-N10-O28
HO
O
OH HO
HO
HO
O
OH
O
OH
O
HO
HN
HN
H3C
N
CH3
O
H
H H
N
O
HO
O
H
N
H
Cl
H H
N
H
O
N
H
O
H H
N
H
O
N
H
CH3
H
O
Cl
O
CO2H
O
O
OH
CH3
HO
HN
CH3
O
88
deligoparinum natricum
deligoparin sodium
sodium salt of depolymerised heparin obtained by a controlled
chemical process based on generation of free radicals by means of
metal ions and hydrogen peroxide. The heparin starting material is
obtained from porcine intestinal mucosa. The process results in
oligosaccharide fragments of heparin of varying lengths. The
average relative molecular mass is about 3200 Daltons, ranging from
2250 to 3850 Daltons. The degree of sulfation is approximately 2.5
sulfate residues per disaccharide unit.
déligoparine sodique
sel de sodium d'héparine de basse masse moléculaire obtenue par
par dépolymérisation à l'aide de radicaux libres (générés par des
ions métalliques et du peroxyde d'hydrogène) d'héparine de
muqueuse intestinale de porc. La majorité des composants
présentent une structure acide 2-O-sulfo-α-D -glucopyranosuronique
à l'extrémité non réductrice et une structure 2-désoxy-6-O-sulfo-2(sulfoamino)- D-glucopyranose à l'extrémité réductrice de leur
chaîne ; la masse moléculaire relative moyenne est voisine de
3200 (2250 à 3850) ; le degré de sulfatation est voisin de 2,5 par
unité disaccharide.
deligoparina sódica
sal sódica de una heparina de baja masa molecular que se obtiene
de la heparina de la mucosa intestinal porcina por
despolimerización por radicales libres, generados por iones
metálicos y peróxido de hidrógeno; la mayoría de los componentes
tienen una estructura de ácido 2- O -sulfo-α-D -glucopiranosurónico
en el extremo no-reductor de la cadena y una estructura 2-desoxy6-O-sulfo-2-(sulfoamino)-D -glucopiranosa en el reductor; la masa
molecular media oscila entre 2250 y 3850, con un valor
característico de unos 3200; el grado de sulfatación es alrededor
de 2,5 por unidad de disacárido.
desvenlafaxinum
desvenlafaxine
4-[(1RS)-2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol
dèsvenlafaxine
4-[(1RS)-2-(diméthylamino)-1-(1-hydroxycyclohexyl)éthyl]phénol
desvenlafaxina
4-[(1RS)-2-(dimetilamino)-1-(1-hidroxiciclohexil)etil]fenol
C16H25NO2
OH
H
CH3
N
and enantiomer
et énanti omère
CH 3 y enantiómero
HO
diboterminum alfa
dibotermin alfa
human recombinant bone morphogenic protein-2 (hrBMP-2)
dibotermine alfa
protéine-2 humaine recombinante morphogénique de l'os (PMOrh2)
dibotermina alfa
proteína-2 humana recombinante morfogénica de hueso (PMOrh-2)
89
[C571H886 N160O 164 S9]2
QAKHKQRKRL
KSSCKRHPLY
VDFSDVGWND
WIVAPPGYHA
FYCHGECPFP
LADHLNSTNH
AIVQTLVNSV
NSKIPKACCV
PTELSAISML
YLDENEKVVL
KNYQDMVVEG
CGCR
diquafosolum
diquafosol
P1,P4-bis(5'-uridyl) tetrahydrogen tetraphosphate
diquafosol
uridine(5')tétraphospho(5')uridine
dicuafosol
tetrahidrógenotetrafosfato de P1,P4-bis(5'-uridilo)
C18H26N4O23 P4
HO
O
O
P
O
O
OH
P O
O
HO H
OH
O P
O
N
O
HO
O
N
O
P
HO
disermolidum
disermolide
H
N
O
O
O
N
OH
O
OH
(3Z,5S,6S,7S,8R,9S,11Z,13S,14S,15S,16Z,18S)-8,14,18trihydroxy-19-[(2S,3R,4S,5R)-4-hydroxy-3,5-dimethyl6-oxotetrahydro-2H-pyran-2-yl]-5,7,9,11,13,15hexamethylnonadeca-1,3,11,16-tetraen-6-yl carbamate
disermolide
carbamate de (1S,2S,3R,4S,6Z,8S,9S,10S,11Z,13S)-3,9,13trihydroxy-14-[(2S,3R,4S,5R)-4-hydroxy-3,5-diméthyl6-oxotétrahydro-2H-pyran-2-yl]-2,4,6,8,10-pentaméthyl1-[(1S,2Z)-1-méthylpenta-2,4-diényl]tétradéca-6,11-diényle
disermolida
carbamato de (3Z,5S,6S,7S,8R,9S,11Z,13S,14S,15S,16Z,18S)8,14,18-trihidroxi-19-[(2S,3R,4S,5R)-4-hidroxi-3,5-dimetil6-oxotetrahidro-2H-piran-2-il]-5,7,9,11,13,15-hexametilnonadeca1,3,11,16-tetraen-6-ilo
C33H55NO8
H2C
CH3
H
CH3 CH3 CH3
H
H
H
H2N
O
O
90
H
OH
H
H
H
H3C
OH
H
OH
CH3
H
CH3
H
OH
H
O
O
H
CH3
edifoligidum
edifoligide
duplex of 2'-deoxy-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')2'-deoxy-P-thioadenylyl-(3'→5')-2'-deoxy-P-thioguanylyl- (3'→5')2'-deoxy-P-thioadenylyl-(3'→5')-P-thiothymidylyl-(3'→5')P-thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'- deoxyP-thiocytidylyl-(3'→5')-2'- deoxy-P-thiocytidylyl-(3'→5')-2'-deoxyP-thiocytidylyl-(3'→5')-2'- deoxy-P-thioguanylyl-(3'→5')-2'-deoxyP-thiocytidylyl-(3'→5')-2'- deoxyguanosine and 2'- deoxyP-thioguanylyl-(3'→5')-2'- deoxy-P-thioadenylyl-(3'→5')P-thiothymidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'- deoxyP-thiocytidylyl-(3'→5')-2'- deoxy-P-thioguanylyl-(3'→5')-2'-deoxyP-thiocytidylyl-(3'→5')-2'- deoxy-P-thioguanylyl-(3'→5')-2'-deoxyP-thioguanylyl-(3'→5')-2'- deoxy-P-thioguanylyl-(3'→5')-2'-deoxyP-thioadenylyl-(3'→5')-2'- deoxy-P-thioadenylyl-(3'→5')-2'-deoxyP-thioadenylyl-(3'→5') -thymidine
édifoligide
2'-désoxy-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-désoxyP-thioadénylyl-(3'→5')-2'- désoxy-P-thioguanylyl-(3'→5')-2'-désoxyP-thioadénylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl(3'→5')-P-thiothymidylyl-(3'→5')-2'-désoxy-P-thiocytidylyl-(3'→5')2'-désoxy-P-thiocytidylyl-(3'→5')-2'- désoxy-P-thiocytidylyl-(3'→5')2'-désoxy-P-thioguanylyl- (3'→5')-2'- désoxy-P-thiocytidylyl-(3'→5')2'-désoxyguanosine et P-thiothymidylyl-(5'→3')-2'- désoxyP-thioadénylyl-(5'→3')-2'- désoxy-P-thioadénylyl-(5'→3')-2'-désoxyP-thioadénylyl-(5'→3')-2'- désoxy-P-thioguanylyl-(5'→3')-2'-désoxyP-thioguanylyl-(5'→3')-2'- désoxy-P-thioguanylyl-(5'→3')-2'-désoxyP-thiocytidylyl-(5'→3')-2'- désoxy-P-thioguanylyl-(5'→3')-2'-désoxyP-thiocytidylyl-(5'→3')-2'- désoxy-P-thiocytidylyl-(5'→3')P-thiothymidylyl-(5'→3')-2'-désoxy-P-thioadénylyl-(5'→3')2'-désoxyguanosine partiellement complémentaires
edifoligida
2'-desoxi-P-tiocitidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'- desoxiP-tioadenilil-(3'→5')-2'- desoxi-P-tioguanilil-(3'→5')-2'- deoxiP-tioadenilil-(3'→5')-P-tiotimidilil-(3'→5')-P-tiotimidilil-(3'→5')P-tiotimidilil-(3'→5')-2'- desoxi-P-tiocitidilil-(3'→5')-2'- desoxi-Ptiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tioguanilil(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxiguanosina y
P-tiotimidilil-(5'→3')-2'- desoxi-P-tioadenilil-(5'→3')-2'-desoxiP-tioadenilil-(5'→3')-2'- desoxi-P-tioadenilil-(5'→3')-2'- desoxiP-tioguanilil-(5'→3')-2'- desoxi-P-tioguanill-(5'→3')-2'-disoxiP-tioguanilil-(5'→3')-2'- desoxi-P-tiocitidilil-(5'→3')-2'- desoxiP-tioguanilil-(5'→3')-2'- desoxi-P-tiocitidilil-(5'→3')-2'- desoxiP-tiocitidilil-(5'→3')-P-tiotimidilil-(5'→3')-2'- desoxi-P-tioadenilil(5'→3')-2'-desoxiguanosina parcialmente complementario
. . . T. C. C. C. G. C. G).
(3'-5')d(P-thio) (C T A G A T T
(5'-3')d(P-thio) (T
A A A G G G C G C C T A G)
91
edotecarinum
edotecarin
12-ß-D -glucopyranosyl-2,10-dihydroxy-6-[[2-hydroxy1-(hydroxymethyl)ethyl]amino]-12,13-dihydro6H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione
édotécarine
12-ß-D -glucopyranosyl-2,10-dihydroxy-6-[[2-hydroxy1-(hydroxyméthyl)éthyl]amino]-12,13-dihydro6H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione
edotecarina
12-ß-D -glucopiranosil-2,10-dihidroxi-6-[[2-hidroxi1-(hidroximetil)etil]amino]-12,13-dihidro-6H-indolo[2,3-a]pirrolo=
[3,4-c]carbazol-5,7-diona
C29 H2 8N4O1 1
HO
O
N
H
N
HN
HO
O
OH
OH
O N
OH
HO
OH
edratidum
edratide
OH
glycyl- L-tyrosyl- L-tyrosyl- L-tryptophyl- L-seryl- L-tryptophyl-L-isoleucylL-arginyl- L-glutaminyl- L-prolyl- L-prolylglycyl- L-lysylglycyl- L-glutamylL-glutamyl- L-tryptophyl- L-isoleucylglycine
édratide
glycyl- L-tyrosyl- L-tyrosyl- L-tryptophyl- L-séryl- L-tryptophyl-L-isoleucylL-arginyl- L-glutaminyl- L-prolyl- L-prolyl-glycyl- L-lysyl-glycylL-glutamyl- L-glutamyl- L-tryptophyl-L-isoleucyl-glycine
edratida
glicil- L-tirosil- L-tirosil- L-triptofil- L-seril- L-triptofil- L-isoleucil- L-arginilL-glutaminil- L-prolil- L-prolilglicil- L-lisilglicil- L-glutamil- L-glutamilL-triptofil- L-isoleucilglicina
C111H149N27O28
H Gly
Tyr
Tyr
Trp
Ser
Trp
Ile
Arg
Gln
Pro
10
Pro
Gly
Lys
Gly
Glu
Glu
Trp
Ile
Gly OH
19
92
elsilimomabum
elsilimomab
immunoglobulin G1, anti-(human interleukin 6) (mouse monoclonal
B-E8 heavy chain), disulfide with mouse monoclonal B-E8 κ-chain,
dimer
elsilimomab
immunoglobuline G1, anti-(interleukine 6 humaine) ; dimère du
disulfure entre la chaîne lourde et la chaîne κ de l'anticorps
monoclonal de souris B-E8
elsilimomab
inmunoglobulina G1, anti-(interleuquina 6 humana) ; dímero del
disulfuro entre la cadena pesada y la cadena κ del anticuerpo
monoclonal de ratón B-E8
elvucitabinum
elvucitabine
4-amino-5-fluoro-1-[(2S,5R)-5-(hydroxymethyl)-2,5-dihydro2-furyl]pyrimidin-2(1H)-one
elvucitabine
4-amino-5-fluoro-1-[(2S,5R)-5-(hydroxyméthyl)-2,5-dihydrofuran2-yl]pyrimidin-2(1H)-one
elvucitabina
4-amino-5-fluoro-1-[(2S,5R)-5-(hidroximetil)-2,5-dihidro2-furil]pirimidin-2(1H)-ona
C9H10FN3O3
NH 2
F
N
O
N
O
HO
epitumomabum cituxetanum
epitumomab cituxetan
H
H
Conjugate of 4-{(2RS)-2-[bis(carboxymethyl)amino]-3-({2[bis(carboxymethyl)amino]ethyl}(carboxymethyl)amino)propyl}phen
yl isothiocyanate forming a thiourea with the 6-amino of a lysine of
immunoglobulin G1, anti-(human episialin) (mouse monoclonal
HMFG-1 γ1-chain), disulfide with mouse monoclonal HMFG-1 light
chain, dimer
épitumomab cituxétan
dérivé de la thiourée produite par réaction de l'isothiocyanate de
4-[(2RS)-2-[bis(carboxyméthyl)amino]-3-[[2-[bis(carboxyméthyl)=
amino]éthyl](carboxyméthyl)amino]propyl]phényle avec le 6-amino
d'une lysine de l'immunoglobuline G1, anti-(human episialin) ;
dimère du disulfure entre la chaîne γ1 et la chaîne légère de
l'anticorps monoclonal de souris HMFG-1
epitumomab cituxetán
derivado de la tiourea producido por reacción del isotiocianato de
4-[(2RS)-2-[bis(carboximetil)amino]-3-[[2[bis(carboximetil)amino]etil](carboximetil)amino]propil]fenil con el
6-amino de una lisina de la inmunoglobulina G1, anti-(episialina
humana) ; dímero del disulfuro entre la cadena γ1 y la cadena
ligera del anticuerpo monoclonal de ratón HMFG-1
93
HO2C
HO 2C
CO2H
N *
H
S
Ig
eptoterminum alfa
eptotermin alfa
N
H
N
N
CO2H
CO 2H
N
H
and epimer at C*
et l'épimère en C*
y el epímero al C*
epitumomab = Ig-NH2
human recombinant bone morphogenetic protein 7 (hrBMP-7) or
osteogenic protein-1 (OP-1)
eptotermine alfa
protéine-7 humaine recombinante morphogénique de l'os (PMOrh7) ou protéine-1 osteogénique (PO-1)
eptotermina alfa
proteína-7 humana recombinante morfogénicas de hueso (PMOrh7) o proteína-1 osteogénica (PO-1)
[C683H1061N197O208S10]2
H
N
HN
N
H
exatecanum alideximerum
exatecan alideximer
exatecan linked via the tetrapeptide (glycylglycylL-phenylalanylglycyl) to poly[oxy(2-hydroxymethylethylene)oxy=
(hydroxymethylmethylene)] partly O-substituted with carboxymethyl
groups with some carboxy groups amide linked to the tetrapeptide.
exatécan alideximer
exatécan lié par une chaîne tétrapeptidique (glycylglycylL-phénylalanylglycyl) à des éthers carboxyméthyliques de
poly[oxy(2-hydroxyéthylidène)oxy[1-(hydroxyméthyl)éthylène]]
exatecán alidexímero
exatecán ligado por una cadena tetrapeptídica (glicilglicilL-fenilalanilglicil) a éteres carboximetílicos de poli[oxi(2-hidroxietilideno)oxi[1-(hidroximetil)etileno]]
O
O
O
O
R
R
R
=
n
-H
-CH2-CO2H
or / ou / or :
CH2
Gly Gly Phe Gly NH
O
N
N
H3C
F
94
O
H
O
HO
O
CH3
exenatidum
exenatide
L-histidylglycyl- L-glutamylglycyl-L-threonyl- L-phenylalanyl- L-threonylL-seryl- L-aspartyl- L-leucyl- L-seryl- L-lysyl- L-glutaminyl- L-methionylL-glutamyl- L-glutamyl- L-glutamyl- L-alanyl- L-valyl- L-arginyl- L-leucylL-phenylalanyl- L-isoleucyl- L-glutamyl- L-tryptophyl- L-leucyl- L-lysylL-asparaginylglycylglycyl- L-prolyl- L-seryl- L-serylglycyl- L-alanylL-prolyl- L-prolyl- L-prolyl- L-serinamide
exénatide
exendine 4 (Heloderma suspectum), synthétique
exenatida
L-histidilglicil- L-glutamilglicil- L-treonil- L-fenilalanil- L-treonil- L-serilL-aspartil- L-leucil- L-seril- L-lisil- L-glutaminil- L-metionil- L-glutamilL-glutamil- L-glutamil- L-alanil- L-valil- L-arginil- L-leucil- L-fenilalanilL-isoleucil- L-glutamil- L-triptofil- L-leucil- L-lisil- L-asparaginilglicilglicilL-prolil- L-seril- L-serilglicil- L-alanil- L-prolil- L-prolil- L-prolil- L-serinamida
C184H282N50O60S
H His Gly Glu Gly Th r Phe Th r Ser Asp Leu Ser Lys G ln Met
10
Glu Glu Gl u Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn
20
Gly G ly Pro Ser Ser Gly
30
firocoxibum
firocoxib
Ala Pro Pro Pr o Ser NH 2
39
3-(cyclopropylmethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)=
phenyl]furan-2(5H)-one
firocoxib
3-(cyclopropylméthoxy)-5,5-diméthyl-4-[4-(méthylsulfonyl)=
phényl]furan-2(5H)-one
firocoxib
3-(ciclopropilmetoxi)-5,5-dimetil-4-[4-(metilsulfonil)fenil]furan-2(5H)ona
C17H20O5S
O O
S
O
CH3
O
O
fispemifenum
fispemifene
CH3
CH3
2-(2-{4-[(1Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy}=
ethoxy)ethanol
fispémifène
2-[2-[4-[(1Z)-4-chloro-1,2-diphénylbut-1-ényl]phénoxy]=
éthoxy]éthanol
fispemifeno
2-(2-{4-[(1Z)-4-cloro-1,2-difenilbut-1-enil]fenoxi}etoxi)etanol
95
C26H27ClO3
O
OH
O
Cl
fluoresceinum lisicolum
fluorescein lisicol
N6-({3',6'-dihydroxy-3-oxospiro[isobenzofuran-1(3H),9'-xanthen]5-yl}thiocarbamoyl)-N2-(3α,7α,12α-trihydroxy-5β-cholan-24-oyl)L-lysine
fluorescéine lisicol
acide (2S)-6-[[(3',6'-dihydroxy-3-oxospiro[isobenzofurane1(3H),9'-[9H]xanthén]-5-yl)thiocarbamoyl]amino]-2-[(3α,7α,12αtrihydroxy-5β-cholan-24-oyl)amino]pentanoïque
fluoresceina lisicol
ácido 5-[({(5S)-5-carboxi-5-[(3α,7α,12α-trihidroxi-5β-colan24-oil)amino]pentil}tiocarbamoil)amino]-2-(6-hidroxi-3-oxo3H-xanten-9-il)benzoico
C51H63N3O11S
S
O
HO
H
H 3C
H
CH3
N
H
HN
H
NH
CO2H
H
CH3
O
H
HO
H
HO
H
H
H
H
OH
O
O
OH
freselestatum
freselestat
2-[5-amino-6-oxo-2-phenylpyrimidin-1(6H)-yl]-N-[(1RS)-1-(5-tertbutyl-1,3,4-oxadiazol-2-yl)-3-methyl-1-oxobutan-2-yl]acetamide
frésélestat
2-(5-amino-6-oxo-2-phénylpyrimidin-1(6H)-yl)-N-[(1RS)-1-[[5-(1,1diméthyléthyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-méthylpropyl]=
acétamide
freselestat
2-[5-amino-6-oxo-2-fenilpirimidin-1(6H)-il]-N-[(1RS)-1-(5-terc-butil1,3,4-oxadiazol-2-il)-3-metil-1-oxobutan-2-il]acetamida
96
C23H28N6O4
H3C
O
CH 3
O
H3C
H
N N
H 3C
H
N
and enantiomer
et énanti omère
N y enantiómero
N
O
CH3 O
NH 2
galiximabum
galiximab
immunoglobulin G1, anti-(human CD80 (antigen)) (human-Macaca
irus monoclonal IDEC-114 heavy chain), disulfide with humanMacaca irus monoclonal IDEC-114 λ chain, dimer
galiximab
immunoglobuline G1, anti-(antigène CD80 humain), dimère du
disulfure entre la chaîne λ et la chaîne lourde de l’anticorps
monoclonal chimérique homme- macaque (Macaca irus) IDEC-114
galiximab
inmunoglobulina G1, anti-(antígeno CD80 humano), dímero del
disulfuro entre la cadena λ y la cadena pesada del anticuerpo
monoclonal quimérico hombre-macaco (Macaca irus) IDEC-114
hemoglobinum raffimerum
hemoglobin raffimer
The polyaldehyde [(2R,4S,6R,8R,11S,13R)-1,14-dihydroxy4-hydroxymethyl-3,5,7,10,12-pentaoxatetradecane-2,4,6,8,11,13hexacarbaldehyde] derived from raffinose [β-D -fructofuranosyl
α- D-galactopyranosyl-(1→6)-α-D -glucopyranoside] by treatment
with sodium periodate is reacted with human hemoglobin A 0 at the
2,3-DPG binding pocket. Both intermolecular and intramolecular
crosslinking occurs. This product is reduced to generate covalent
amine bonds with >95% crosslinked hemoglobin of which about
55% is polymerised.
hémoglobine raffimer
hémoglobine stabilisée et partiellement polymérisée, obtenue par
réduction du produit de la réaction du (2R,4S,6R,8R,11S,13R)1,14-dihydroxy-4-(hydroxyméthyl)-3,5,7,10,12pentaoxatétradécane-2,4,6,8,11,13-hexacarbaldéhyde (obtenu par
oxydation periodique du rafinose) avec l'hémoglobine humaine
hemoglobina rafímero
hemoglobina estabilizada y parcialmente polimerizada, obtenida por
reducción del producto de la reacción del (2R,4S,6R,8R,11S,13R)1,14-dihidroxi-4-(hidroximetil)-3,5,7,10,12-pentaoxatetradecano2,4,6,8,11,13-hexacarbaldehído (obtenido por oxidación periodica
de la rafinosa) con la hemoglobina humana
OH
1
Val (βHb)
HO
HO
O
O
HN
O
O
N
O
82
Lys (βHb)
OH
N
82
Lys (β'Hb)
97
icofungipenum
icofungipen
(1R,2S)-2-amino-4-methylenecyclopentane-1-carboxylic acid
icofungipen
(-)-acide (1R,2S)-2-amino-4-méthylènecyclopentanecarboxylique
icofungipeno
(-)-ácido (1R,2S)-2-amino-4-metilenociclopentanocarboxílico
C7H11NO2
CH2
H2N
CO 2H
H H
icrocaptidum
icrocaptide
glycyl-N2-ethyl- L-lysyl- L-prolyl- L-arginine
icrocaptide
glycyl-(N2-éthyl- L-lysyl)- L-prolyl-L-arginine
icrocaptida
glicil-(N2-etil- L-lisil)- L-prolil- L-arginina
C21H40N8O5
H3C
O
H
N
CO2H
H
N
H2N
O
H
N
H
O
NH2
N
NH2
NH2
iferanserinum
iferanserin
(E)-2'- {2-[(2S)-1-methyl-2-piperidyl]ethyl}cinnamanilide
iféransérine
(-)-(2E)-N-[2-[2-[(2S)-1-méthylpipéridin-2-yl]éthyl]phényl]3-phénylprop-2-énamide
iferanserina
(-)-(2E)-N-(2-{2-[(2S)-1-metilpiperidin-2-il]etil}fenil)-3-fenilprop2-enamida
C23H28N2O
O
NH
H
N
CH3
98
istradefyllinum
istradefylline
8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl3,7-dihydro-1H-purin-2,6-dione
istradéfylline
8-[(E)-2-(3,4-diméthoxyphényl)éthényl]-1,3-diéthyl-7-méthyl3,7-dihydro-1H-purin-2,6-dione
istradefilina
8-[(E)-2-(3,4-dimetoxifenil)vinil]-1,3-dietil-7-metil-3,7-dihidro1H-purin-2,6-diona
C20H24N4O4
O
H3C
CH3
O
OCH3
N
N
N
N
OCH3
CH3
ixabepilonum
ixabepilone
(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16pentamethyl-3-[(1E)-1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione
ixabépilone
(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16pentaméthyl-3-[(1E)-1-méthyl-2-(2-méthylthiazol-4-yl)éthényl]17-oxa-4-azabicyclo[14.1.0]heptadécane-5,9-dione
ixabepilona
(1S,3S,7S,10R,11S,12S,16R)-7,11-dihidroxi-8,8,10,12,16pentametil-3-[(1E)-1-(2-metil-1,3-tiazol-4-il)prop-1-en-2-il]-17-oxa4-azabiciclo[14.1.0]heptadecano-5,9-diona
C27H42N2O5S
H3C
HO
H
H CH3
H
H
CH3
H3C
CH3
H3C
H
O
ladostigilum
ladostigil
O
OH
S
N
CH3
H
NH
O
(3R)-3-(prop-2-ynylamino)indan-5-yl ethyl(methyl)carbamate
ladostigil
éthylméthylcarbamate de (3R)-3-(prop-2-ynylamino)-2,3-dihydro1H-indén-5-yle
ladostigilo
etilmetilcarbamato de (3R)-3-(prop-2-inilamino)indan-5-ilo
C16H20N2O2
O
H3C
N
CH 3
O
H
N
H
CH
99
lapatinibum
lapatinib
N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-({[2-(methylsulfonyl)=
ethyl]amino}methyl)-2-furyl]quinazolin-4-amine
lapatinib
N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-6-[5-[[[2(methylsulfonyl)ethyl]amino]methyl]-2-furyl]quinazolin-4-amine
lapatinib
N-[3-cloro-4-(3-fluorobenciloxi)fenil]-6-[5-({[2-(metilsulfonil)=
etil]amino}metil)-2-furil]quinazolin-4-amina
C29H26ClFN4O4S
N
N
O
O
O
NH
HN
Cl
S
H3C
O
lomeguatribum
lomeguatrib
6-(4-bromothenyloxy)-7H-purin-2-amine
lomeguatrib
6-[(4-bromothiophen-2-yl)methoxy]-7H-purin-2-amine
lomeguatrib
6-(4-bromoteniloxi)-7H-purin-2-amina
F
C10H8BrN5OS
S
O
H
N
N
Br
H2N
N
N
odiparcilum
odiparcil
4-methyl-7-(5-thio-β-D -xylopyranosyloxy)-2H-chromen-2-one
odiparcil
4-méthyl-7-[(5-thio-β-D -xylopyranosyl)oxy]- 2H-1-benzopyran-2-one
odiparcilo
4-metil-7-(5-tio-β- D-xilopiranosiloxi)-2H-cromen-2-ona
C15H16O6S
S O
O
OH
CH3
OH
HO
100
O
omigananum
omiganan
L-isoleucyl- L-leucyl- L-arginyl- L-tryptophyl-L-prolyl- L-tryptophylL-tryptophyl- L-prolyl-L-tryptophyl- L-arginyl- L-arginyl-L-lysinamide
omiganan
L-isoleucyl- L-leucyl- L-arginyl- L-tryptophyl-L-prolyl- L-tryptophylL-tryptophyl- L-prolyl-L-tryptophyl- L-arginyl- L-arginyl-L-lysinamide
omiganán
L-isoleucil- L-leucil- L-arginil- L-triptofil- L-prolil- L-triptofil- L-triptofilL-prolil- L-triptofil- L-arginil- L-arginil- L-lisinamida
C90H127N27O12
H Ile
Leu
Arg Trp
Pro
Trp Tr p Pro Trp
Arg
Arg
Lys NH 2
10
pactimibum
pactimibe
[7-(2,2-dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl]acetic
acid
pactimibe
acide [7-[(2,2-diméthylpropanoyl)amino]-4,6-diméthyl-1-octyl2,3-dihydro-1H-indol-5-yl]acétique
pactimiba
ácido [7-(2,2-dimetilpropanamido)-4,6-dimetil-1-octilindolin-5-il]
acético
C25H40N2O3
CH3
CO2H
N
CH3
HN
H 3C
H3C
patupilonum
patupilone
O
CH3
CH3
(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16pentamethyl-3-[(1E)-1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione
patupilone
(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16pentaméthyl-3-[(1E)-1-méthyl-2-(2-méthylthiazol-4-yl)éthényl]4,17-dioxabicyclo[14.1.0]heptadécane-5,9-dione
patupilona
(1S,3S,7S,10R,11S,12S,16R)-7,11-dihidroxi-8,8,10,12,16pentametil-3-[(1E)-1-(2-metil-1,3-tiazol-4-il)prop-1-en-2-il]4,17-dioxabiciclo[14.1.0]heptadecano-5,9-diona
C27H41NO6S
H3C
HO
H
O
H CH3
H
H
CH3
CH3
H3C
CH3
H3C
O
H
S
OH
N
H
O
O
101
pertuzumabum
pertuzumab
immunoglobulin G1, anti-(human ν (receptor)) (human-mouse
monoclonal 2C4 heavy chain), disulfide with human-mouse
monoclonal 2C4 κ-chain, dimer
pertuzumab
immunoglobuline G1, anti-(récepteur ν humain), dimère du disulfure
entre la chaîne κ et la chaîne lourde de l’anticorps monoclonal de
souris humanisé 2C4
pertuzumab
inmunoglobulina G1, anti-(receptor ν humano), dímero del disulfuro
entre la cadena κ y la cadena pesada del anticuerpo monoclonal
humanizado de ratón 2C4
pixantronum
pixantrone
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
pixantrone
6,9-bis[(2-aminoéthyl)amino]benzo[g]isoquinoléine-5,10-dione
pixantrona
6,9-bis[(2-aminoetil)amino]benzo[g]isoquinolina-5,10-diona
C17H19N5O2
O
HN
O
HN
NH2
N
pritumumabum
pritumumab
NH2
immunoglobulin G, anti-(human vimentin) (human monoclonal CLN
G11 γ1-chain), disulfide with human monoclonal CLN G11 κ-chain,
dimer
pritumumab
immunoglobuline G, anti-(vimentine humaine) ; dimère du disulfure
entre la chaîne γ1 et la chaîne κ de l'anticorps monoclonal humain
CLN H11
pritumumab
inmunoglobulina G, anti-(vimentina humana); dímero del disulfuro
entre la cadena γ1 y la cadena κ del anticuerpo monoclonal humano
CLN H11
C6440H9968N1708O2016S42
ralfinamidum
ralfinamide
(2S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide
ralfinamide
(+)-(2S)-2-[[4-[(2-fluorobenzyl)oxy]benzyl]amino]propanamide
ralfinamida
(+)-(2S)-2-[4-(2-fluorobenciloxi)bencilamino]propanamide
102
C17H19FN2O2
H CH3
N
H
O
NH2
O
F
rebimastatum
rebimastat
N-[(2S)-2-sulfanyl-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin1-yl)butanoyl]-L-leucyl-N1,3-dimethyl- L-valinamide
rébimastat
(2S)-N-[(1S)-2,2-diméthyl-1-(méthylcarbamoyl)propyl]-4-méthyl2-[[(2S)-2-sulfanyl-4-(3,4,4-triméthyl-2,5-dioxoimidazolidin1-yl)butanoyl]amino]pentanamide
rebimastat
N-[(2S) -2-sulfanil-4-(3,4,4-trimetil-2,5-dioxoimidazolidin1-il)butanoil]- L-leucil-N1,3-dimetil- L-valinamida
C23H41N5O5S
H 3C
H3C
CH3
CH 3
N
H3C
O H
O
N
N
H SH H
O
H
N
O
H 3C
O
N
H H
CH 3
CH 3
CH 3
segesteronum
segesterone
17-hydroxy-16-methylene-19-norpregn-4-ene-3,20-dione
ségestérone
17-hydroxy-16-méthylène-19-norprégn-4-ène-3,20-dione
segesterona
17-hidroxi-16-metileno-19-norpregn-4-eno-3,20-diona
C21H28O3
O
CH3
H
OH
CH2
H
H
CH3
H
O
semapimodum
semapimod
N,N'-bis{3,5-bis[1-(carbamimidoylhydrazono)ethyl]phenyl}=
decanediamide
sémapimod
N,N'-bis[3,5-bis[N-(carbamimidoylamino)acétimidoyl]phényl]=
décanediamide
semapimod
N,N'-bis{3,5-bis[1-(carbamimidoilhidrazono)etil]fenil}=
decanodiamida
103
C34H52N18O2
H
N
H2 N
CH 3
N
N
NH
NH
sufugolixum
sufugolix
O
NH
N
N
CH3
NH 2
NH
HN
N
H
H
N
NH
O
H2 N
CH3
N
H
CH3
NH2
5-{[benzyl(methyl)amino]methyl}-1-(2,6-difluorobenzyl)-6-[4(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine2,4(1H,3H)-dione
sufugolix
1-[4-[5-[(benzylméthylamino)méthyl]-1-(2,6-difluorobenzyl)2,4-dioxo-3-phényl-1,2,3,4-tétrahydrothiéno[2,3-d]pyrimidin6-yl]phényl]-3-méthoxyurée
sufugolix
5-{[bencil(metil)amino]metil}-1-(2,6-difluorobencil)-6-[4(3-metoxiureido)fenil]-3-feniltieno[2,3-d]pirimidina-2,4(1H,3H)-diona
C36H31F2N5O4S
F
H3C
O
HN
O
F
S
N
HN
O
N
N
O
H3C
tacapenemum
tacapenem
(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5oxopyrrolidin-3-yl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene2-carboxylic acid
tacapénem
(+)-acide (4R,5S,6S)-6-[(1R)-1-hydroxyéthyl]-4-méthyl-7-oxo3-[[(3R)-5-oxopyrrolidin-3-yl]sulfanyl]-1-azabicyclo[3.2.0]hept-2-ène2-carboxylique
tacapenem
(+)-ácido (4R,5S,6S)-6-[(1R)-1-hidroxietil]-4-metil-7-oxo-3-[[(3R)-5oxopirrolidin-3-il]sulfanil]-1-azabiciclo[3.2.0]hept-2-eno-2-carboxílico
104
C14 H1 8N2O5 S
CO 2H
O
H3C
HO
tafluprostum
tafluprost
N
S
H
H H H
H CH3
O
N
H
isopropyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxybut1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoate
tafluprost
(5Z)-7-[(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phénoxybut-1-ényl]3,5-dihydroxycyclopentyl]hept-5-énoate de 1-méthyléthyle
tafluprost
(5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-fenoxibut-1-enil]3,5-dihidroxiciclopentil}hept-5-enoato de isopropilo
C25H34F2O5
H
HO
talizumabum
talizumab
OH
H
H
H
O
O
F
O
CH3
CH3
F
immunoglobulin G, anti-(human immunoglobulin E Fc region)
(human-mouse monoclonal Hu901 γ-chain), disulfide with humanmouse monoclonal Hu901 κ-chain, dimer
talizumab
immunoglobuline G, anti-(région Fc de l’immunoglobuline E
humaine), dimère du disulfure entre la chaîne κ et la chaîne γ de
l’anticorps monoclonal de souris humanisé Hu901
talizumab
inmunoglobulina G, anti-(región Fc de la inmunoglobulina E
humana), dímero del disulfuro entre la cadena κ y la cadena γ del
anticuerpo monoclonal humanizado de ratón Hu901
technetium (99mTc) nitridocadum
technetium (99mTc) nitridocade
(SPY-5-21)-bis[ethoxy(ethyl)dithiocarbamato-κS,κS']nitrido=
[99mTc]technetium
technétium (99mTc) nitridocade
(SPY-5-21)-bis(éthoxyéthyldithiocarbamato-κS,κS')nitrido=
[99mTc]technétium
tecnecio (99mTc) nitridocado
(SPY-5-21)-bis(etoxietilditiocarbamato-κS,κS')nitrido[99m Tc]tecnecio
105
C10H20N3O2S499mTc
H3C
Tc
H3C
S
CH3
S
99m
N
tesofensinum
tesofensine
N
S
O
O
N
S
CH3
(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl8-azabicyclo[3.2.1]octane
tésofensine
(1R,2R,3S,5S)-3-(3,4-dichlorophényl)-2-(éthoxyméthyl)-8-méthyl8-azabicyclo[3.2.1]octane
tesofensina
(1R,2R,3S,5S)-3-(3,4-diclorofenil)-2-(etoximetil)-8-metil8-azabiciclo[3.2.1]octano
C17H23Cl2 NO
H
H
N CH3
H
Cl
H
O
Cl
CH3
tifenazoxidum
tifenazoxide
6-chloro-N-(1-methylcyclopropyl)-1,1-dioxo-1,4-dihydro-1λ6thieno[3,2-e][1,2,4]thiadiazin-3-amine
tifénazoxide
1,1-dioxyde de 6-chloro-N-(1-méthylcyclopropyl)-4H-thiéno[3,2-e]1,2,4-thiadiazin-3-amine
tifenazóxido
1,1-dióxido de 6-cloro-N-(1-metilciclopropil)-4H-tieno[3,2-e]-1,2,4tiadiazin-3-amina
C9H10ClN3O2S2
S
Cl
O O
S
N
N
H
tisocalcitatum
tisocalcitate
N
H
CH3
isopropyl (1S,3R,5Z,7E,22E,24R)-1,3,24-trihydroxy9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylate
tisocalcitate
(5Z,7E,22E,24R)-1α,3β,24-trihydroxy-9,10-sécocholesta5,7,10(19),22-tétraène-25-carboxylate de 1-méthyléthyle
tisocalcitato
(1S,3R,5Z,7E,22E,24R)-1,3,24-trihidroxi-9,10-secocolesta5,7,10(19),22-tetraeno-25-carboxilato de isopropilo
106
C31H48O5
H3C H
H
OH
CH3
O
H
H3C
CH3
O
CH3
CH3
H
CH2
HO
OH
H
ulifloxacinum
ulifloxacin
H
(1RS)-6-fluoro-1-methyl-4-oxo-7-(piperazin-1-yl)4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid
ulifloxacin
acide (1RS)-6-fluoro-1-méthyl-4-oxo-7-(pipérazin-1-yl)4H-[1,3]thiazéto[3,2-a]quinoléine-3-carboxylique
ulifloxacino
ácido (1RS)-6-fluoro-1-metil-4-oxo-7-(piperazin-1-il)4H-[1,3]tiazeto[3,2-a]quinolina-3-carboxílico
C16H16FN3O3S
H CH3
HN
N
N
F
S
and enantiomer
et énantiomère
y enantiómero
CO 2H
O
vareniclinum
varenicline
7,8,9,10-tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline
varénicline
(6R,10S)-7,8,9,10-tétrahydro-6,10-méthano-6H-pyrazino[2,3h][3]benzazépine
vareniclina
7,8,9,10-tetrahidro-6H-6,10-metanoazepino[4,5-g]quinoxalina
C13H13N3
H
N
HN
N
H
107
AMENDMENTS TO PREVIOUS LISTS
MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES
MODIFICACIONES A LAS LISTAS ANTERIORES
Recommended International Nonproprietary Names (Rec. INN): List 04
Dénominations communes internationales recommandées (DCI Rec.): Liste 04
Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 04
(Crónica de la OMS, Vol. 16, N° 4, Abril de 1962)
p. 158
suprimase
metodilazina
insértese
metdilazina
Recommended International Nonproprietary Names (Rec. INN): List 06
(WHO Chronicle, Vol. 20, No. 11, 1967)
(Chronique OMS, Vol. 20, N° 11, 1967)
(Crónica de la OMS, Vol. 21, N° 11, 1967)
p. 427
lauromacrogolum 400
lauromacrogol 400
p. 474
lauromacrogol 400
α-dodécyl-ω-hydroxypoly(oxyéthylène), la masse moyenne de la partie macrogol
(# 44n+18) est indiquée entre parenthèses après la dénomination
p. 340
lauromacrogol 400
sustitúyase la descripción por la siguiente:
éter monododecílico del polietilen glicol, al nombre le sigue un número (400) que
corresponde aproximadamente a la masa molecular media de la fracción
polietilenglicol
polyethylene glycol monododecyl ether, the name is followed by a number (400)
corresponding approximately to the average molecular mass of the polyethylene
glycol portion
Recommended International Nonproprietary Names (Rec. INN): Lis t 40
p. 194
108
supprimer
pregabaline
insérer
prégabaline
Procedure and Guiding Principles / Procédure et Directives / Procedimientos y principios generales
The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceutical
Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharmaceutical
Substances will be reproduced in uneven numbers of proposed INN lists only.
Les textes de la Procédure à suivre en vue du choix de dénominations communes internationales recommandées pour les
substances pharmaceutiques et des Directives générales pour la formation de dénominations communes internationales
applicables aux substances pharmaceutiques seront publiés seulement dans les numéros impairs des listes des DCIs
proposées.
El texto de los Procedimientos de selección de denominaciones comunes internacionales recomendadas para las sustancias
farmacéuticas y de los Principios generales de orientación para formar denominaciones comunes internacionales para
sustancias farmacéuticas aparece solamente en los números impares de las listas de DCI propuestas.
109

International Nonproprietary Names for

Transcrição

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