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WHO Drug Information Vol. 15, No. 1, 2001
WHO has developed guidelines on good manufac- • Export company XYZ exports products bearing
turing practices (GMP) for both finished pharma- with its own labels, without reference to the origi-
ceutical dosage forms and starting materials (4), nal producer. Additionally, the company may
while other regulations and guidelines continue to source from several different producers at the
be issued. A Guideline on Good Manufacturing same time.
Practice for Active Pharmaceutical Ingredients has
also been approved by the International Confer- • A distributor repackages a product in smaller
ence on Harmonization (ICH) (5). Other bodies, containers under its own name, without traceabil-
such as the International Pharmaceutical Excipients ity to the original producer. Such practice is also
Council or the United States Pharmacopeia, have fairly common in some European companies
published recommendations (6–7). WHO Guide- which are not obliged to communicate the origin of
lines for the Manufacture of Pharmaceutical Excipi- the goods.
ents were published in 1999 (8) although no
equivalent ICH guideline yet exists. Although high • A technical product or a food-grade product is re-
quality production standards will guarantee a good analysed by the broker/distributor and found
quality product, they do not confirm that high quality compliant with a given pharmacopoeia, and
starting materials are indeed delivered to the phar- relabelled as being of pharmaceutical quality.
maceutical manufacturers.
The above practices, and many more, have a
Industry has engaged in a voluntary programme of
potential impact because these products are even-
responsible care and product stewardship, as set
tually administered to humans for sometimes quite
out on the following page. Such programmes
serious health conditions. In all the cases above,
should ensure that only safe products are used.
there is no way to guarantee that the product
However, the best programmes cannot defeat all
originates from a plant where appropriate GMP
fraudulent practices. Unscrupulous individuals
standards have been implemented. Absent clean-
concerned with making quick and easy money will
ing validations, the use of low quality water, the use
continue to seek out any loopholes in regulations
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WHO Drug Information Vol. 15, No. 1, 2001
PRODUCT STEWARDSHIP*
• Product stewardship is the responsible and ethical management of health, safety and environmental
aspects of a product throughout its total life cycle. Product Stewardship is Responsible Care© applied
to products.
• Product stewardship improves market confidence. By defining and pursuing common goals throughout
the supply chain, we can achieve benefits for all businesses involved.
• No company operates in isolation. Everyone involved in the production, handling, use and disposal of
chemicals has a shared responsibility to ensure their safe management and use.
• By adopting a programme of Product Stewardship, every company can play its part in protecting humans
and the environment from potential harm.
• Each of us is confronted with a multitude of safety, health, and environmental issues regarding our
products. These may be voiced by our customers, environmental groups, and regulatory authorities.
They may arise from special expectations and public concern or from the industry’s own internal
assessment.
• Implementing Product Stewardship helps us to manage these issues more effectively, taking into
account health, safety and environmental as well as technical and economic aspects to ensure best
customer value.
• Chemical products must be managed and used safely along the supply chain, through manufacture,
packaging, distribution, use and ultimate disposal.
of unacceptable solvents such as benzene, or standards. For example, at the end of the year
process changes which go unreported and 2000, acetylsalicylic acid was reported to have
unvalidated, can result in unsafe medicinal prod- been offered, with compliance stated against BP–
ucts. Recent FDA warning letters indicate that 80 although the British Phamacopoeia monograph
some facilities who claim GMP compliance have was changed in 1986 and again in 2000. The
never carried out the corrections they committed to monograph change concerned related substances,
make in writing. Are these exceptions to the rule, or suspected to be mutagenic and now limited at
are they the tip of the iceberg? 0.1%. The samples of the product offered had over
0.2 % of the principal impurity.
Furthermore, if there is lack of traceability, a vari-
able or unknown origin of the goods, all process These are not the only recurring fraudulent prac-
validation files of the medicinal producer are — by tices by far. Several constructions are known, often
definition — meaningless, and this includes all the related to the registration process or patent in-
stability data. Processing conditions may vary fringement. A lot of money can be made by commit-
depending on the source of the starting materials, ting fraud, and the risks taken are sometimes
which has a direct impact on bioavailability and significantly lower than those, for example, of
hence on the efficacy of the medicinal product. narcotics dealers for which capital punishment is
often the penalty. Yet fraud with medicinal products
Another frequent observation is that products are can be as devastating to the end user as narcot-
being offered against obsolete pharmacopoeial ics!
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WHO Drug Information Vol. 15, No. 1, 2001
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WHO Drug Information Vol. 15, No. 1, 2001
(14). In this document, specific guidance is given ucts made by different processes to those declared
for the distribution of excipients, food and cosmetic in regulatory filings, will continue to enter into the
ingredients. It can be used either by manufacturers European Union. This particularly concerns gener-
to assess their distribution partners, or by custom- ics and over-the-counter (OTC) products, for which
ers to find out what level of GMP/GDP distributors controls are minimal. OTC products are generally
of excipients have achieved. not even inspected, so similar concerns apply to
imports of these products.
Do these regulations suffice
to safeguard public health? Recently, market prices of pharmaceutical ingredi-
Maintaining quality standards and product safety ents for generics and OTC products have been
has a price, but negating the need for requirements forced to below economic levels. The inroad onto
with purely commercial arguments is unacceptable the market of products manufactured under inad-
when the implicit risks to human health are consid- equate — or even in the absence of — systems
ered. The need for global recommendations and that should secure their quality and safety seems to
control is crucial: if the expense of applying quality be one important causative factor for this develop-
and safety practices risks forcing the compliant ment. Omitting the use of such systems allows for
companies out of business because they charge lower manufacturing costs and therefore offers an
higher prices than their unscrupulous rivals, then important competitive edge. The implicit risks to
this is obviously a horrifying prospect! It is possible humans are evident: such products are often sold
that the current GMP practices dealing with active to very large populations. For example, it is esti-
pharmaceutical ingredients (API), excipient trading mated that annually about 70,000 tons of paraceta-
and distribution are not sufficient to guarantee mol (acetaminophen) are consumed worldwide,
product quality and safety. representing a total of 150 billion tablets. A sub-
standard product could have a more lethal impact
Several guidance documents require full traceability than an atom bomb in such cases!
back to the original producers. However, a repacker
or re-labeller is also often considered to be a manu- Similar requirements will certainly also be needed
facturer, so that traceability to the last “manufactur- with regard to trade in pharmaceutical ingredients
ing step” is clearly insufficient. Other guidelines worldwide. The first steps that have been taken in
require a reference to the original producer on the this direction by WHO will hopefully lead to in-
certificate of analysis. The traceability requirement creased safety of medicines on a global scale.
clearly needs to be bi-directional and is best re-
flected in section 17.60 of ICH Q7a which states: In conclusion, the API manufacturing industry looks
"Agents, brokers, distributors, re-packers, or re- forward to presentation of a final text for Amend-
labellers should transfer all quality or regulatory ment of 75/319/EC for approval by the European
information received from an active pharmaceutical Council and European Parliament. After all, it is the
ingredient (API) or intermediate manufacturer to the safety of patients which is at stake.
customer, and from the customer to the API or
intermediate manufacturer." References
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WHO Drug Information Vol. 15, No. 1, 2001
7. United States Pharmacopeia. Good Manufacturing 11. GMP Audit Guideline for Distributors of Bulk Pharma-
Practices for Bulk Pharmaceutical Excipients, USP ceutical Excipients; International Pharmaceutical Excipi-
XXIV24, General Chapter 1078: 2040–2049, 2000. ents Council, (2000).
Pharmeuropa, 9(2): 302–322 (1997).
12. The European Association of Chemical Distributors
8. World Health Organization. GMP: Supplementary (FECC). GMP Guide for Active Pharmaceutical Ingredi-
Guidelines For The Manufacture of Pharmaceutical ents in Distributive Trade (1998).
Excipients. WHO Technical Report Series, No. 885,
(1999). 13. The European Chemical Industry Council (CEFIC),
Propylene Oxide / Propylene Glycols sector group.
9. International Federation of Pharmaceutical Manufactur- Guidelines for Handling and Distribution of Propylene
ers Associations (IFPMA). Counterfeiting. Download file Glycol USP/EP, (1999)
on http://www.ifpma.org
14. The European Chemical Industry Council (CEFIC) and
10. World Health Organization/US Food and Drug Admin- The European Association of Chemical Distributors
istration/US Centers for Disease Control. Report of the (FECC). European Single Assessment Document for
Diethylene Glycol Contamination Prevention Workshop, Chemical Distributors (ESAD), January 1999.
Washington, D.C. (1997).
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WHO Drug Information Vol. 15, No. 1, 2001
Personal Perspectives
Risk assessment as an least minimized through implementation of effective
preventive measures. For the purposes of the
element of drug control present article, three types of risk may be distin-
guished.
Professor Witold Wieniawski, Chairman,
Polish Pharmacopoeia Commission 1. Risks related to the
Warsaw, Poland introduction of new medicines
Risks related to the introduction of new medicines
The responsibility of governments to establish
are linked to the possibility that an unknown harmful
systems which assure that all pharmaceutical
effect of a new substance will appear when the
products used in a given country are both safe and
product is used extensively in the general popula-
effective is now generally accepted, even if the
tion. Elaborate systems have now been developed
extent of such responsibility may differ between
for the prevention of such risks based on early
countries. The operation of such systems may be
detection of harmful effects in the course of pre-
supervised by a special department within the
clinical testing or during clinical studies. Separate
Ministry of Health or delegated to a drug regulatory
sets of requirements are established for new chemi-
authority. In either case, such activities are carried
cal entities and for new products obtained from
out in close collaboration with those parties in-
biotechnology where additional kinds of risks can
volved in drug manufacture and distribution, includ-
be expected. However, even highly elaborate
ing manufacturers, wholesalers, hospitals, retail
systems cannot be completely foolproof, as is
pharmacies and other drug distribution outlets.
evidenced from cases where rapid withdrawal from
the market of recently approved products was
The main purpose of a drug regulatory system is to
necessary (1).
prevent the occurrence of harmful drug related
events which may have the potential to attain
2. Risks related to drug production
catastrophic proportions. Because of the need to
Risks that are related to the production of drugs
maintain public confidence in pharmaceutical
include events resulting from improper manufactur-
products for the general health of the population, a
ing processes or cases of mix-ups and mislabelling
system of government-imposed regulations is often
during production. This type of hazard is not related
in operation, while responsible institutions and
to the intrinsic pharmacological property of the
enterprises endeavour to ensure that no harmful
active substance or excipient but to the manufactur-
negligence occurs during manufacture, distribution
ing process. Improper production includes the use
and use of medicinal products. Such additional
of inadequate (substandard) starting materials as
activities ensure that all precautions are faithfully
well as deficiencies in the technological processes
implemented by all those involved.
of drug formulation. Such deficiencies could result,
for example, in the manufacture of products of
Medicines have important consequences for health
inadequate bioavailability, or may lead to the ap-
and their regulation may involve decisions with
pearance of unexpected contaminants in the final
international implications. As such, the advice of
product.
WHO in relation to these issues is considered
highly relevant. Drug regulatory systems operate Risks related to the use of incorrect starting materi-
within the economic environment of the country as als may have serious adverse consequences, as in
a whole and the level of development differs enor- the well-known cases of ethylene glycol being used
mously between countries, with regard to the in place of glycerol or as an admixture to an excipi-
particularities of the restrictions encountered. ent (2). Similarly, the risk of contamination by
adventitious impurities has also to be considered in
Drug-related hazards the case of starting materials. Risks related to mix-
While harmful events and risks are inherent in the ups may also occur within the drug distribution
nature of drugs, many risks can be avoided or at chain if re-packaging or re-labelling of products is
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WHO Drug Information Vol. 15, No. 1, 2001
undertaken by traders, wholesalers or at retail level. systems for the establishment of drug quality re-
Fraudulent production of counterfeit or adulterated quirements. This will include activities of pharmaco-
drugs is a serious problem which should be consid- poeia commissions and well established surveil-
ered separately (3). This criminal activity is linked to lance systems on the manufacture and distribution
immense health risks. of pharmaceuticals such as pharmaceutical inspec-
tion and national drug control laboratories. All
3. Risks related to improper use of drugs institutions function effectively in order to reduce to
The improper use of drugs may lead to scenarios a minimum the risks related to drug production and
where harm is caused instead of expected relief. distribution.
This includes mistakes made by physicians in the
selection of drugs, irrational prescribing, over- Administrative regulations related to the introduc-
prescribing (leading to over-consumption, particu- tion of new medicines and control of drug produc-
larly of antibiotics) (4), mistakes by auxiliary staff tion can be properly implemented in high-income
when administering medicines, lack of patient countries because the pharmaceutical industry, to
compliance, or mistakes made when taking medica- which they are addressed, is well developed and
tion. Some of those situations may also be created drug distribution services are staffed by fully quali-
by unethical promotional practices which influence fied personnel. Full implementation of the rules of
prescribing and consumption decisions. Effective good manufacturing practices (GMP) is also much
drug information and education is essential to simpler in facilities with high manufacturing stand-
counter such practices. It is debatable to what ards and having at their disposal well-equipped and
extent drug regulatory authorities are able to take well-staffed analytical laboratories. The same can
remedial action, since rational prescribing is prima- be said of institutions providing information on drug
rily the responsibility of institutions which supervise use for health professionals and the general public.
medical practitioners.
2. Drug regulation at the intermediate level
Drug regulatory authorities The medicines control situation is less sure in
There have been few attempts to establish a classi- countries at the intermediate level. Countries in this
fication of drug regulatory authorities into specific group rely heavily on the evaluation of new drug
groups, although the notion of a small drug regula- entities carried out in countries with a sophisticated
tory authority has been introduced by the WHO level of regulatory activity, avoiding, to some extent,
document Guiding Principles for Small National the risks associated with unexpected harmful
Drug Regulatory Authorities (5). The three following effects of new medicines. However, as the main
levels of drug regulation were identified in a recent source of pharmaceutical products will normally be
report on global harmonization of regulatory re- the domestic manufacture of generic pharmaceuti-
quirements of pharmaceuticals (6). These catego- cals, the main risk encountered is that related to
ries often reflect the degree of economic develop- production processes.
ment of countries, which confirms that the impor-
tance of economic factors in the health area ex- Because of the country's economic situation, drug
tends also to drug regulation. regulatory authorities have only moderate financial
means at their disposal. Activities are mainly based
1. A sophisticated level of drug regulation on the use of national resources, not on outside aid,
Countries with sophisticated drug regulatory activi- even if a measure of external advice is usually
ties are generally well equipped to prevent most available. Local pharmaceutical manufacture in the
types of risks related to medicines. Appropriate majority of countries in this group, with a few nota-
drug regulatory institutions exist to confirm the ble exceptions, is based on the importation of raw
safety and efficacy of new drug entities. The major- materials, which gives rise to particular kinds of
ity of these activities are now carried out according risk. Furthermore, the technical equipment of local
to guidelines established by the International Con- pharmaceutical enterprises may be more rudimen-
ference on Harmonization of Technical Require- tary in comparison with pharmaceutical manufac-
ments for the Registration of Pharmaceuticals for ture in the high-income countries. Drug distributors
Human Use (ICH). A brief review of ICH activities may also be more moderately equipped. Some
was recently published in WHO Drug Information countries in this group are also victims of fraudulent
(6). production of adulterated drugs. There is, therefore,
High-income countries with sophisticated drug a whole range of combinations of risk areas within
regulatory activities have properly functioning drug regulation that exists in countries of this group.
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WHO Drug Information Vol. 15, No. 1, 2001
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WHO Drug Information Vol. 15, No. 1, 2001
Existing literature on quality assurance of pharma- cases raw materials are shipped in a number of
ceuticals, which includes numerous WHO docu- containers, not a single one. The risks that may
ments, describes in detail the activities related to occur here include those due to natural deteriora-
drug quality assurance in respect of each of these tion of the substance, to mix-ups caused by mis-
elements. The advice given in that literature is fully takes in labelling of containers or to contamination
appropriate in a sitution where adequate resources of the material by foreign substances. Such pres-
are available. What is usually missing, however, is ence of adventitious impurities may occur by acci-
a listing of priority risk areas to be considered in dent or may be intentional.
cases when insufficient economic resources do not
permit a full implementation of all recommenda- When assessing the level of risk of an individual
tions. substance, numerous factors have to be consid-
ered: the stability — intrinsic properties, or improve-
Alternative control strategies ments made by the use of stabilizers or adequate
An assessment of individual risks related to specific containers; price of materials — expensive sub-
products and raw materials, and recognition of stances are particularly the target of fraudulent
hazards at specific stages of production or distribu- activity; and any other possible dangers related to
tion would permit national regulatory authorities to use. The high-risk category also includes such
better plan a drug control strategy and render its deceptively innocuous substances as polyols (e.g.
activities more effective within available resources. glycerol), where mix-ups or inept use as excipients
The main element to be considered is the extent of have, as already mentioned, been the cause of
reliance on documentary evidence concerning the many tragedies (1).
quality of products against confirmation of their
quality (identity, purity and strength) through testing Requirements concerning production facilities and
of samples. This applies equally to preparations processes are the subject of recommendations
and to raw materials, either of domestic or foreign related to good manufacturing practices (GMP).
origin. The assessment of risk is also needed here to
indicate those elements of the production process
Documentary evidence is much cheaper to procure, where mistakes can have the most harmful conse-
but it confirms nothing more than the results ob- quences. For example, the risks related to mix-ups
tained by the manufacturer's analytical laboratory at are the highest during the labelling stage, while the
the time the product was released onto the market. risk of cross-contamination (but also of mix-ups) is
Obviously, it requires an additional assurance that it highest at weighing areas. Risk assessment should
indeed pertains to the product in question. A con- also take into account the type of products that are
firmatory testing of samples is much more expen- manufactured in a given production facility.
sive, as it requires the maintenance of a suitable
testing laboratory added to the costs of analysis. Situation of low-income countries
Such confirmatory testing is therefore only carried The existence of countries with insufficient drug
out on a random basis. None the less, testing of regulation is an unfortunate situation which has
actual samples taken from the market can confirm been deplored by many authors (6). In such coun-
whether regulatory authority action is adequate and tries, the prevention of risks cannot be achieved
it will remind the manufacturers and importers of through local efforts and appropriate strategies
the existence of control. A proper combination of have to be developed to draw on outside assist-
the two approaches should also take into account ance. This is especially valid in relation to imported
the specificity of risk situations, examples of which pharmaceuticals on which these countries are
are given below. usually heavily dependent. In the case of donated
products, the assurance of quality should be the
In many countries, local manufacture of pharma- responsibility of the donor organizations. The use of
ceutical preparations is based on imported raw certificates issued according to WHO Certification
materials, both for active materials and excipients. Scheme on the Quality of Pharmaceutical Products
Assurance of the identity and purity of these materi- Moving in International Commerce is a possible
als can be based either on certificates of analysis solution and special procedures exist also for
issued by the manufacturer or trader, or on the assessing the acceptability of vaccines for pur-
results of confirmatory testing done locally by the chase by United Nations agencies. Unfortunately,
manufacturer of the pharmaceutical preparation. low-income countries are also highly vulnerable to
When such confirmatory testing is done locally, the risks related to counterfeited products.
size of the consignment is of importance as in most
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WHO Drug Information Vol. 15, No. 1, 2001
Conclusions References
Recognition of the risks that may occur in the drug
1. Fung, M.C., Thornton, A., Mybeck, K. et al. Evaluation
area is fundamental for the establishment of effec- of the characteristics of safety withdrawal of prescription
tive preventive strategies. Although some risks are drugs from worldwide pharmaceutical markets –1960 to
inherent in the utilization of pharmaceutical prod- 1999. Drug Information Journal, 35: 293–317 (2001).
ucts, the majority of such risks are avoidable. Drug
regulatory authorities need to match control require- 2. Singh, J., Dutta, A.K., Khare, S. et al. Diethylene glycol
ments to the available resources. In high-income poisoning in Gurgaon, India, 1998. Bulletin of the World
countries, resources for drug control activities are Health Organization, 79: 88–94 (2001).
considerable, hence eventual risks can be effec-
3. World Health Organization. Observations and recom-
tively kept at a very low level. In other countries,
mendations on counterfeit drugs. Quality Assurance of
where more limited resources are at the disposal of Pharmaceuticals: A compendium of guidelines and related
regulatory authorities, the assessment of risks and materials, Volume 1. Geneva, 1997.
designation of high-risk products, areas and situa-
tions will be a priority in designating priorities for 4. Report of the International Narcotics Control Board for
control measures. WHO recommendations on drug 2000. United Nations, New York (2001).
regulatory and control activities should indicate, to
the extent possible, the level of risk linked to spe- 5. World Health Organization. Guiding principles for small
cific elements and stages of the production and national drug regulatory authorities. Quality Assurance of
Pharmaceuticals: A compendium of guidelines and related
distribution of pharmaceuticals as this could im-
materials, Volume 1. Geneva, 1997.
prove the modalities of their implementation in
practice. 6. Global Harmonization and ICH. WHO Drug Information,
14(3): 145–159 (2000).
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WHO Drug Information Vol. 15, No. 1, 2001
The following travel agent has been appointed to handle registration and arrange hotel
accommodation for participants. For further information please contact:
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WHO Drug Information Vol. 15, No. 1, 2001
Current Topics
ward” was prepared. This was the subject of dis-
The WHO Model List of Essential cussion at an informal consultation held by WHO in
Drugs: latest developments March 2001. The discussion paper highlighted
various perceived problems.
The WHO Model List of Essential Drugs has been
successful in establishing and promoting the con- The range of diseases for which essential drugs
cept of essential drugs. For more than twenty are selected is not clear
years, it has served as the gold standard for coun- Some drugs for very rare diseases are included on
tries wishing to develop their own lists and has the Model List, while some second-line drugs for
been adapted for use in more than 150 WHO more common diseases are not. For example,
Member States. From a public health perspective, should the Model List include essential drugs for
priorities for the pharmaceutical system can be cystic fibrosis?
identified through the use of an essential drugs list.
For example, national lists are often linked to The selection criteria are insufficiently clear
national standard treatment guidelines used for There is much confusion about the extent to which
training of health workers, and can serve as a guide cost, cost-effectiveness and affordability criteria are
for the procurement of needed drugs, for reim- being used during selection. For example, the
bursement purposes in health insurance schemes decision not to include antiretroviral drugs (ARVs)
and for encouraging local pharmaceutical produc- for HIV/AIDS has provoked global discussion. The
tion. Committee had decided not to include ARVs for the
treatment of HIV/AIDS because there was insuffi-
The WHO Model List has been updated every two cient evidence of their long-term effectiveness in
years since it was first published in 1977. The resource-poor settings. Others believed that exclu-
current Model List contains a little over 300 active sion was based on cost considerations, and have
ingredients and is divided into a main list and a argued that inclusion of ARVs on the Model List
complementary list. At the last meeting of the WHO would create the necessary pressure to bring prices
Expert Committee on the Use of Essential Drugs down.
held in November 1999, several recommendations
were made concerning the process of updating Selection has been based on experience
both the methodology for selecting drugs for inclu- rather than evidence
sion in the Model List and the List itself. These In the past, the Committee has taken a decision
recommendations included linking the selection of based on the material presented and on their own
drugs on the Model List to standard treatment professional experience. However, there is no
guidelines developed by WHO. It was also agreed standard format application and no systematic
that decisions on selection of essential drugs search for and review of evidence prior to submis-
should be based on properly-identified evidence. It sion before the Committee in support of decisions.
was recommended that the Model List should Furthermore, there is no external review of the
prioritize those conditions and drugs for which Committee’s draft recommendations.
equitable availability and affordability should be
ensured before resources are spent on other treat- There are discrepancies between the WHO
ments. A recommendation on the need for more Model List and WHO treatment guidelines
explicit criteria was also made. About 250 of the 306 active ingredients on the
current Model List are also recommended in vari-
Updating and disseminating the WHO ous treatment guidelines published by different
Model List of Essential Drugs WHO programmes and departments. There are a
As a result of these recommendations, a draft few therapeutic categories where no WHO treat-
discussion paper “Updating and disseminating the ment guidelines exist (e.g. cytotoxics, hormones,
WHO Model List of Essential Drugs: the way for- diagnostic agents and gastrointestinal drugs).
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WHO Drug Information Vol. 15, No. 1, 2001
However, 155 drugs recommended in the total body agreement by all members. In practice, the recom-
of WHO treatment guidelines are not on the WHO mendations of the Committee and the text of the
Model List of 1999. If WHO recommends that report are rarely changed after the meeting and are
national essential drugs lists should be based on accepted by the Director-General of WHO.
national treatment choices and guidelines, the
WHO Model List could be developed in a similar The official report of the Committee
way. is published late
Publication of each of the last three official reports
Drugs are included for which there is no in English in the WHO Technical Report Series has
pharmacopoeial standard, or no supplier taken over a year. As the Committee meets every
In 1997, there were several substances on the two years, the report of the previous meeting and
Model List for which there was no pharmacopoeial the new WHO Model List therefore came out just
standard. Examples are eflornithine hydrochloride, before the next meeting, which seriously under-
heparin sodium, methylene blue, permethrin and mines the usefulness of the report and even of the
primaquine.1 There are several drugs on the Model meeting itself. The French, Spanish and Russian
List for which there is only one supplier, or for which translations of the 1997 report came out even later.
the supply of quality products has always been
problematic. Examples of such “abandoned” essen- In recent years, this problem has partly been solved
tial drugs are oily chloramphenicol injection, by publishing the Model List (without notes, and
suramin injection, ether and eflornithine. only in English) in WHO Drug Information and on
the WHO Medicines Website.
The reasons underlying the decisions of the
committee are insufficiently recorded Recommendations from the
The reasons for the recommendations of the Com- informal consultation
mittee are summarized in footnotes to the report. A series of questions was presented during the
However, these extensive footnotes are not repro- informal consultation in March 2001 and the follow-
duced in WHO Drug Information or on the WHO ing recommendations were issued.
Medicines Website (http://www.who.int/medicines),
which implies that this information is only available 1. The definition of essential drugs is still adequate
to the public through the Technical Report Series and does not need to change: “Essential drugs are
which is published by WHO much later. In addition, those drugs that satisfy the health care needs of the
notes from earlier meetings are only available majority of the population. They should therefore be
through copies of old Committee reports and are in available at all times in adequate amounts and in
practice difficult to find. Recently, WHO has made a appropriate dosage forms, at a price the individual
data base of the recorded reasons for recent Com- and the community can afford (1).”
mittee decisions which is available on request.
However, for many earlier decisions no records are 2. The WHO Model List should continue to be
available. presented in two levels. The core list should indi-
cate the minimum drug needs for a basic health
The recommendations of the committee care system, listing the most cost-effective drugs
are final and not open for review for priority conditions; while the complementary list
According to the rules and procedures for WHO should consist of drugs for priority diseases which
expert committees, the report of the Committee is are cost-effective but not necessarily affordable, or
prepared and approved before the end of the which may need specialized health care facilities,
meeting. There are no provisions for internal and and should include essential drugs for less frequent
external review of the report or recommendations diseases. The section on reserve anti-infective
after the meeting. The Chair of the Committee may agents could thus be integrated into the comple-
decide to omit a statement from the report but may mentary list.
only change the wording on the basis of written
3. The process of updating the Model List should be
more systematic and transparent. A revised stand-
1
The full list quoted by WHO in 1997 was: asparaginase, ardized format for applications should be drawn up,
dasozin mesilate, eflornithine hydrochloride, heparin to include a systematic review of comparative
calcium and heparin sodium, methylene blue, permethrin,
efficacy, safety and cost-effectiveness. An external
polygeline, potassium ferric hexacyaniferrate, and pri-
maquine. review of these draft applications and systematic
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WHO Drug Information Vol. 15, No. 1, 2001
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WHO Drug Information Vol. 15, No. 1, 2001
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WHO Drug Information Vol. 15, No. 1, 2001
New formulation of DTP vaccine It is estimated that approximately 276 000 patients
have received bupropion in the United Kingdom in
United States of America —The Food and Drug the first six months of marketing. A total of 3457
Administration (FDA) has approved a new, pre- reports of suspected adverse reactions have been
servative-free formulation for a diphtheria and received. The most frequently reported reactions
tetanus toxoid and acellular pertussis (DTaP) include:
vaccine (Tripedia®). The reformulated product
contains less than 0.3 µg mercury per dose (as • CNS reactions (e.g. insomnia, dizziness, depres-
thiomersal), which is less than 5% of the amount of sion, tremor, anxiety, agitation); and
thiomersal in the original version that the FDA
approved in 1992. • skin and hypersensitivity reactions (urticaria, rash,
pruritus).
Although no harmful effects have been reported
from thiomersal in vaccines when used at the Other reported recognized reactions include
recommended dosages, Federal public health angioedema, chest pain, increased blood pressure,
agencies, the American Academy of Pediatrics, and erythema multiforme and Steven-Johnson syn-
vaccine manufacturers have agreed to reduce or drome.
eliminate its use in vaccines to protect children
against the potential cumulative health risks of It is important to note that the reactions are sus-
mercury. pected and may relate to other factors. Eighteen
reports have had a fatal outcome although the
Since 1999, the FDA has approved paediatric contribution of bupropion is unproven.
formulations of hepatitis B vaccines that contain no
thiomersal (Recombivax HB®) or only trace Bupropion is associated with a dose-related risk of
amounts of the ingredient (Engerix B®). Thiomer- seizure with an estimated incidence of approxi-
sal-containing Haemophilus influenzae type b mately 0.1% based on doses up to the recom-
conjugate vaccine (HibTITER®) has been replaced mended daily dose of 300 mg. There have been 74
by a thiomersal-free, single-dose formulation. With reports in the United Kingdom of seizures sus-
the reformulated DTaP vaccine, all routinely recom- pected as being associated with the use of
mended paediatric vaccines in distribution will soon bupropion.
be free of thiomersal or will contain it in only trace
amounts. Bupropion inhibits metabolism of cytochrome P450
2D6. Caution is therefore advised when other
References medicines predominantly metabolized by these
enzymes are co-administered. These include
1. FDA News, P01-07 (2001).
certain antidepressants, antipsychotics, beta-
2. http://www.cdc.gov/nip/vacsafe. blockers and type 1C antiarrythmics.
18
WHO Drug Information Vol. 15, No. 1, 2001
A recently published study (1) suggests an associa- Prescribers are reminded that leflunomide should
tion between long-term high-dose infusion used for only be prescribed by specialists experienced in the
sedation and cardiac failure in adult patients with treatment of rheumatoid diseases. The EMEA
head injuries. Seven patients are described who wishes to draw attention to the following informa-
developed metabolic acidosis, hyperkalaemia or tion.
rhabdomyolysis. Similar reports, including hyper-
lipaemia and hepatomegaly have previously been • Leflunomide is contraindicated in patients with
reported in children administered propofol infusion impaired liver function.
for sedation in intensive care units (2).
• Rare cases of severe liver injury, including cases
Doctors are reminded that the recommended dose with fatal outcome, have been reported during
range for sedation (up to 4 mg/kg/hour) should not treatment. Most cases occurred within 6 months of
be exceeded (3). initiation of treatment. Although confounding
factors were present in many cases a causal
References relationship with leflunomide cannot be excluded.
1. Cremer, O.L. Long-term propofol infusion and cardiac • Concomitant treatment with methotrexate and/or
failure in adult head-injured patients. Lancet , 357: 117– other hepatotoxic medications is associated with
118 (2001).
an increased risk of serious hepatic reactions.
2. Current Problems in Pharmacovigilance, Volume 18
(1992). The full revised product information is available on
the EMEA Website (2).
3. Current Problems in Pharmacovigilance, Volume 27
(2001). References
19
WHO Drug Information Vol. 15, No. 1, 2001
In addition, the approved indication for levacetyl- The GlucoWatch Biographer® extracts fluid through
methadol will be revised to indicate that the drug is the skin by sending out tiny electrical currents.
not for use as first line therapy. Levacetylmethadol Glucose levels are measured using this fluid every
should be reserved for treatment of opiate-addicted 20 minutes for 12 hours — even during sleep. The
patients who fail to show an acceptable response to device sounds an alarm if the patient's glucose
other adequate treatments for addiction. Levacetyl- reaches dangerous levels.
methadol can be given less often than methadone.
20
WHO Drug Information Vol. 15, No. 1, 2001
21
WHO Drug Information Vol. 15, No. 1, 2001
migraine was made, and she recovered. The head- ADRAC has also received reports of ergotism
ache then recurred after restarting minocycline. arising from the combination of ergotamine with
Papilloedema was observed and the diagnosis of ritonavir and verapamil and has noted published
benign intracranial hypertension (with hemiplegic reports of similar interactions with HIV protease
migraine) was made. Treatment included aceta- inhibitors, particularly ritonavir (1, 2). These reports
zolamide. The patient had not fully recovered at the suggest that the basis of the interaction is inhibition
time of reporting. of either cytochrome P4503A4 in the liver or gut
P-glycoprotein with subsequent increase in ergot-
Physicians should regularly enquire about head- amine concentrations. As most inhibitors of
ache in patients receiving tetracycline therapy in CYP3A4 also inhibit P-glycoprotein, the concomi-
view of the potential risk of benign intracranial tant use of erythromycin and other known inhibitors
hypertension (BIH). BIH has been reported in of CYP3A4 with ergotamine preparations should be
association with a variety of medications, particu- avoided.
larly the tetracyclines and minocycline is the agent
most frequently cited. The lipophilic properties of References:
minocycline may be an explanation for the higher
number of reported cases. 1. Phan, T.G., Agaliotis, D., White, G. et al. Ischaemic
peripheral neuritis secondary to ergotism associated with
ritonavir therapy. Medical Journal of Australia, 171: 502–
If drug-induced BIH is suspected, the implicated 503.(1999).
drug should be discontinued. Tetracyclines should
not be prescribed concomitantly with retinoids (e.g. 2. Blanche, P., Rigolet, A., Gombert, B. et al. Ergotism
isotretinoin), another drug class associated with related to a single dose of ergotamine tartrate in an AIDS
BIH. patient treated with ritonavir. Postgraduate Medical
Journal, 75: 546–547 (1999).
Reference: Kingston H. Tetracyclines and Benign Intrac-
ranial Hypertension – a headache rare but real. Prescriber 3. ADRAC Bulletin, Volume 19, No 4, December 2000.
Update No. 21, January 2001. http://www.medsafe.
govt.nz/profs.htm.
Celecoxib and warfarin interaction
Ergotamine and erythromycin Australia — Since the introduction of celecoxib
(Celebrex®) onto the market in October 1999, the
interaction Australian Adverse Drug Reactions Committee
Australia — Ergotism is manifested by symptoms (ADRAC) has received 2218 reports of suspected
and signs of peripheral ischaemia due to constric- adverse drug reactions. Of these, 21 cases de-
tion of vascular smooth muscle caused by direct scribe an increase in the INR of patients on treat-
action of an ergot derivative. Headache, intermit- ment with warfarin. In the 16 cases where the
tent claudication, muscle pain, numbness, coldness value of the INR was specified, it rose from a stable
and pallor of the extremities may occur, and gan- value of around 2.0 to a peak ranging from 4.2 to
grene has been reported. Ergotism is usually 12.2 (median: 5.3). In two other cases the INR was
associated with excessive dosing of ergot prepara- described as “high” and “very high”. While most of
tions but has also been reported with normal doses the reports did not describe complications, bleeding
of ergotamine preparations when there was was reported in 6 cases. These included severe
concommitant use of macrolides (particularly eryth- oral bleeding, intracranial haemorrhage, epistaxis
romycin). The mechanism of the interaction is not and gastrointestinal haemorrhage. In most cases,
established but may involve an inhibition of ergot- the problem occurred within two weeks of the
amine metabolism or an increased gut absorption addition of celecoxib. Of the patients in whom the
resulting in an increase in serum ergotamine con- outcome was known, all recovered after withdrawal
centration. of celecoxib and, in some cases, withholding or
reducing the dose of warfarin.
In recent years, the Australian Adverse Drug Reac-
tions Committee (ADRAC) has received two reports In addition to these 21 cases, there have been 11
describing severe ergotism in association with the cases of bleeding in patients taking concomitant
combined use of ergotamine and erythromycin. celecoxib and warfarin. These reports described
purpura (3 cases), gastrointestinal haemorrhage
22
WHO Drug Information Vol. 15, No. 1, 2001
(2), haematuria (1), haematemesis (1), melaena 2001, the Australian Adverse Drug Reactions
(1), subdural haematoma (1), unspecified haemor- Committee (ADRAC) had received a total of 95
rhage (1) and stroke (1). There was no reference reports associated with cerivastatin, of which 17
to the INR in these reports except for one in which (18%) have described rhabdomyolysis. This can be
the INR was reported as unchanged. It is not clear compared with the other statins for which the
in these cases whether the bleeding was the result percentages range from 0.3 to 1.2%.
of an interaction, an additive effect, an effect of
celecoxib alone, or unrelated to the use of The 17 cases of rhabdomyolysis associated with
celecoxib. cerivastatin occurred from just over a week to 18
months after the introduction of cerivastatin but
The product information for celecoxib states that in most occurred in the first month of therapy. Seven
postmarketing experience, bleeding events have of the 15 cases in which the dose was stated
been reported, predominantly in the elderly, in occurred with daily dosages of 400 micrograms or
association with increases in prothrombin time in greater and two cases occurred shortly after the
patients receiving celecoxib concurrently with dose was increased to 800 micrograms daily.
warfarin. In the cases of increased INR and bleed-
ing reported to ADRAC, 5 of the 26 patients in Of particular interest is the fact that 10 of the 17
whom the age was stated were less than 50 years patients were also taking gemfibrozil. The sponsor
old. has made the concomitant use of cerivastatin and
gemfibrozil a contraindication. ADRAC wishes to
The product information also describes a study in alert prescribers to the possibility of rhabdomyolysis
healthy volunteer subjects given 2 mg to 5 mg with all statins. Cerivastatin should not be used in
warfarin daily in whom celecoxib had no effect on combination with gemfibrozil.
the prothrombin time. However, since warfarin is
metabolised mainly by CYP2C9 and this enzyme Reference: ADRAC Bulletin, Volume 20, No 1, February
can be inhibited by celecoxib, it is possible that in 2001.
some individuals, inhibition of CYP2C9 may be
significant, producing higher blood concentrations
of warfarin. There have been two recent publica- SSRIs and increased ocular pressure
tions describing this interaction. (1, 2) Australia — From November 1972 to January
2001, the Australian Adverse Drug Reactions
References
Committee (ADRAC) had received 92 reports of
1. Mersfelder, T.L., Stewart, L.R. Warfarin and celecoxib raised ocular pressure. Since 1992, there have
interaction. Annals of Pharmacotherapy, 34: 325–327. been 11 reports implicating selective serotonin
reuptake inhibitors (SSRIs) involving sertraline (4
2. Hasse, K.K., Rojas-Fernandez, C.H., Lane, L et al. reports), fluoxetine (3), paroxetine (3) and
Potential interaction between warfarin and celecoxib. citalopram (1). Ages of patients ranged from 32 to
Annals of Pharmacotherapy, 34:666–667 (2000). 70 years. Onset generally occurred within 6 months
of commencing the SSRI but ranged from one week
3. ADRAC Bulletin, Volume 20, No 1, February 2001. to 5 years. In 2 cases, the SSRI may have aggra-
vated pre-existing glaucoma. In one case, the
Cerivastatin: rare effect intraocular pressures, which had previously been
stabilized with treatment, almost doubled. Presen-
of rhabdomyolysis tations consisted of asymptomatic increases in
intraocular pressure noted on routine testing (6
Australia — Cerivastatin (Lipobay®) is the fifth of cases), eye pain (2 cases), and blurred vision (3
the HMG-CoA reductase inhibitors (statins) to be cases). At the time of reporting, 5 patients had not
marketed in Australia. Rhabdomyolysis is a known recovered and the outcome remained unknown for
but rare effect of the statins and is more likely to the other 6.
occur when a fibrate is taken concomitantly. Its
occurrence in association with cerivastatin appears Reference: ADRAC Bulletin, Volume 20, No 1, February
greater than with other statins. Up to January 2001.
23
WHO Drug Information Vol. 15, No. 1, 2001
24
WHO Drug Information Vol. 15, No. 1, 2001
Prescribers are advised as follows: The contraindications have recently been extended
to include patients with haemorrhage due to gastric
• Existing patients currently receiving droperidol as or duodenal ulcer, or gastric erosion. The section
a therapy should be recalled for review by on other adverse reactions was also previously
their psychiatrist and switched to an alternative revised to include haemorrhagic gastritis and
treatment. haemorrhage due to gastric/duodenal ulcer.
• No patient should have droperidol stopped until a Recently, four cases of gastric ulcer have been
suitable alternative treatment plan has been reported in association with the use of mono-
identified. ethanolamine oleate for which a causal relationship
could not be excluded. The Ministry of Health,
• Droperidol therapy should be tapered off through Labour and Welfare has therefore directed the
a stepwise reduction over a period of one to two licence holder to include gastric ulcer in the section
weeks whilst replacement antipsychotic therapy is on serious adverse reactions.
initiated. Reference: Pharmaceuticals and Medical Devices Safety
Information No. 164, January 2001, Ministry of Health,
Reference: Medicines Control Agency, Important Safety Labour and Welfare.
Messages, 11 January 2001. http://www.open.gov.uk/mca
Rivastigmine: revised
Mofezolac: revised data sheet product information
Japan — Mofezolac (Disopain®) was approved in
July 1994 as a nonsteroidal anti-inflammatory United States of America — The manufacturer of
analgesic agent which inhibits prostaglandin syn- rivastigmine (Exelon®), indicated for Alzheimer
thesis. disease has informed health professionals of recent
changes to the prescribing information. These
The data sheet has now been revised to include changes provide guidelines for reinitiating therapy
gastrointestinal haemorrhage, abnormal hepatic in patients who have interrupted treatment with
function, jaundice and thrombocytopenia as serious rivastigmine in order to reduce the risk of severe
adverse reactions. In addition, the contraindications vomiting. (1)
have been extended to include patients with serious
hepatic disorders, and the precautions extended to There is limited experience related to restarting
cover patients with, or with a history of, hepatic rivastigmine after an interruption in therapy at
disorders. doses higher than the recommended starting dose.
However, to reduce the possibility of severe vomit-
Fifteen cases of gastrointestinal haemorrhage, five ing in patients who have interrupted therapy for
cases of abnormal hepatic function and five cases longer than several days, treatment should be
of thrombocytopenia have been reported to the reinitiated with the lowest daily dose. Patients
Ministry of Health, Labour and Welfare. A causal should then be titrated back to their maintenance
relationship between mofezolac and these reac- dose as described in the product information. There
tions could not be excluded. has been one post-marketing case of severe vomit-
ing with oesophageal rupture reported to have
Reference: Pharmaceuticals and Medical Devices Safety occurred after reinitiation of treatment at an inap-
Information No. 164, January 2001, Ministry of Health, propriate single dose of 4.5 mg following interrup-
Labour and Welfare. tion of treatment for eight weeks (2).
References
Monoethanolamine oleate: 1. Letter from Novartis to health care providers dated 26
revised data sheet January 2001 at http://www.fda.gov/medwatch/safety/
2001/exelon.htm.
Japan — Monoethanolamine oleate (Oldamin®
Injection) was approved in June 1996 for haemos- 2, Babic, T., Banfic, L., Papa, J. et al. Spontaneous
tasis in oesophageal varices, haemorrhage and rupture of oesophagus (Boerhaave syndrome) related
sclerosis in oesophageal varices. to rivastigmine. Age and Aging, 29(4):370–371 (2000).
25
WHO Drug Information Vol. 15, No. 1, 2001
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.
26
WHO Drug Information Vol. 15, No. 1, 2001
ATC/DDD Classification
Estonia re-established its independence after being
ATC/DDD methodology: part of the Soviet Union for 50 years. The require-
a country perspective ments and rules for medicinal products were con-
trolled during that period by the central government
Ly Rootslane, Department of Pharmacy, Tartu and were similar for all Soviet republics. Before
University, Estonia 1991, all pharmacies, wholesalers and manufactur-
Alar Irs, Department of Clinical Pharmacology, ers were 100% state owned and purchases and
Tartu University, Estonia distribution of medicines were centralized. During
this period, the assortment of medicinal products
An interest in drug utilization in both scientific and was limited and trade names mimicked the name of
governmental circles has developed as a result of the active substance. As the manufacturing licence
the rapid increase in drug consumption over the last of each medicinal product was owned by the State,
30 years. In order to measure drug use, it is impor- products of different manufacturers carried one
tant to have both a classification system and a unit trade name. There was no standardized classifica-
of measurement. Medicinal products can be classi- tion of medicinal products at that time. Products
fied using different methods, either in alphabetic were classified according to alphabetic order,
order, by manufacturer, or by diseases treated. therapeutic groups, chemical structure, or sale and
Different systems have been used at different times storage conditions.
and in different countries but the most important
contribution has come from the Drug Utilization During the early years of Estonia’s independence,
Research Group (DURG) which has carried out major reforms were carried out in the health care
international drug utilization research. sector. The decision was made for Estonia to
The first studies on drug consumption undertaken develop its own system for the regulation of medical
in the mid–1960s showed great differences be- products modelled on those developed and oper-
tween population groups. The most important result ated by other Nordic countries. The Estonian State
of these studies was consensus that an internation- Agency for Medicines (SAM) was established in
ally accepted classification system of medicinal 1991 and began with only six employees. The main
products was needed. By modifying and extending tasks of the Agency were to grant marketing au-
the existing classification system set up by the thorizations and import/export licences, and carry
European Pharmaceutical Market Research Asso- out inspection of wholesalers, pharmacies and
ciation (EPhMRA), the Norwegian Medicinal Depot manufacturers. As retail and wholesale enterprises
developed a system known as the Anatomical were privatized, the assortment of medicinal prod-
Therapeutic Chemical (ATC) classification. At the ucts broadened. A new system of classification was
same time, the defined daily dose (DDD) as a unit needed but financial and human resources were
of measurement in drug utilization studies was also scarce. The ATC classification was chosen as a
established. Today, the WHO Collaborating Centre solution since it was considered to be easy to
for Drug Statistics Methodology in Norway collabo- understand, to have a reasonable structure, and the
rates with the WHO International Working Group for only expense was the price of the codebook. Fur-
Drug Statistics Methodology in determining ATC/ thermore, it was widely used in neighbouring coun-
DDD classification. tries and was recommended by WHO.
The ATC/DDD system in Estonia To introduce the concept, ATC codes were inserted
The ATC/DDD system is implemented in Estonia into the marketing authorization application and, to
promote the use of the classification by wholesal-
and is used for different regulatory and scientific
purposes. ers, the codes were attached to the import/export
certificates. Lists of authorized products including
Estonia is situated in the North-eastern part of the ATC codes were published in the national
Europe and is the smallest of the three Baltic pharmaceutical literature. New regulations for the
countries with a population of 1.45 million. In 1991, Wholesale Trade of Medicinal Products included
27
WHO Drug Information Vol. 15, No. 1, 2001
28
WHO Drug Information Vol. 15, No. 1, 2001
in the Nordic Countries because of their high risk/ As the medicinal products market develops, the
benefit ratio. As shown in Figure 1, the consump- statistics available a year later are no longer up to
tion of antihypertensives in Estonia was compared date. As a result, a more timely system had to be
to the use of the same drugs in Finland and Swe- developed. In co-operation with wholesalers, it was
den. In 1994, the most used medicines for treat- decided that the SAM would create new software
ment of hypertension in Estonia were central adren- and wholesalers would present data both in mon-
ergic agents (mostly reserpine), which were no etary value and by volume units quarterly. The aim
longer actively used in other Nordic countries. The of the SAM in developing the new programme was
use of antihypertensive drugs in Estonia doubled to summarize, correct and analyse wholesaler’s
during the period 1995–1998, but was still lower data and create statistical reports in different for-
than in Finland and Sweden in 1998 although there mats.
are no data to indicate that the incidence of hyper-
tension is lower in Estonia than in other Nordic The new software was introduced at the beginning
countries. Beta-blockers, ACE-inhibitors and cal- of 1999 and the wholesale data of 1998 were
cium-channel blockers had already replaced the collected. The software is able to create a variety of
older antihypertensive agents. different reports quarterly and makes it possible to
compare drug consumption and expenses. Some of
Annual drug consumption data the reports are available on the SAM web-side at
Once the national drug use patterns are known, http://www.sam.ee.
utilization data should be monitored over time,
documenting the changes and evaluating the Thus, the possibilities of drug utilization studies
patterns by relevant comparisons. Estonian drug have been extended, and studies can be carried
consumption data have been published annually out in a more timely manner. Quarterly data of drug
since 1994. The complete data were made avail- consumption is available in ATC/DDD format and
able a year later. also in monetary values. The statistics based on
29
WHO Drug Information Vol. 15, No. 1, 2001
ATC/DDD can also provide data about the sale of The present drug reimbursement scheme based on
prescription-only medicinal products or over-the- obligatory patient co-payment was introduced in
counter (OTC) products, differentiation between Estonia in 1993. The drug consumption data of
retail pharmacies or hospital sales, consumption of 1994 and 1995 were able to show the impact of the
medicinal products with marketing authorizations new system, although it was very difficult to explain
and products used on a named-patient basis. why the use of prescription only medicines (covered
by at least 50% reimbursement) increased more
Regularly obtained drug consumption data can be slowly than the use of OTC products.
used for evaluating the influence of different health
policy decisions. For example, the importation of Drug utilization monitoring has been helpful in
medical products containing phenacetin was not follow-up of all changes in the list of reimbursement
allowed in Estonia as of 1997 because of the products, e.g. to evaluate the validity of the as-
adverse reaction profile. As a consequence, the sumptions made by the authorities before the
use of phenacetin decreased and the consumption change was introduced. Therefore, data from drug
of ibuprofen as an alternative OTC analgesic in- utilization studies can be used to measure the
creased very rapidly. effects of drugs on overall health care costs and
resource consumption. These data are fundamental
Since 1999, medicinal products containing metami- to pharmacoeconomic evaluation as they can
zole were added to the list of prescription-only provide real-life estimates of drug use prevalence,
medicines because of a high risk of serious adverse effectiveness, compliance and safety.
reactions. Enteral metamizole was widely used in
Estonia as an OTC drug and was one of the most Data on the use of drugs have been regularly
popular analgesics. The use of tablets containing considered when taking decisions on regulatory
metamizole has decreased in 2000 compared to matters, in reimbursement policy, in teaching and in
1999. the development of formularies. As an example, the
use of morphine and other opiates is relatively low
30
WHO Drug Information Vol. 15, No. 1, 2001
in Estonia, but has increased year by year. During • The ATC/DDD system provides the means to
the Soviet period, morphine was prescribed for create national statistics, which can be compared
cancer pain only for terminally ill patients and historically with other countries.
administered mainly by injection. There have been
a lot of different workshops and meetings for doc- References
tors explaining the need for narcotic analgesics to 1. WHO Collaborating Centre for Drug Statistics Method-
provide better control of cancer pain. As a result, ology. Guidelines for ATC classification and DDD assign-
the consumption of morphine has increased ap- ment, Oslo, 2000.
proximately five times and half of the morphine
used in 2000 was administrated enterally or rectally 2. Kiivet, R.A., Bergman, U., Rootslane, L., Rago, L,
(Figure 2). Correct statistics are vital in identifying Sjoqvist, F. Drug use in Estonia in 1994–1995: a follow-up
problem areas and following-up the impact of from 1989 and comparison with two Nordic countries.
interventions. European Journal of Clinical Pharmacology, 54(2): 199–
224 (1998).
Conclusion 3. Suomen Lääketilasto 1994 (Finnish Statistics on
Medicines). National Agency for Medicines and Social
• The ATC classification is essential to drug utiliza- Insurance Institution, Helsinki 1995.
tion studies and to support regulatory decisions ,
reimbursement policy, under- and postgraduate 4. Suomen Lääketilasto 1999 (Finnish Statistics on
teaching, and in the development of formularies. Medicines). National Agency for Medicines and Social
Insurance Institution, Helsinki 2000.
• The ATC classification of medicinal products is
5. Svensk Läkemedelsstatistiks 1994 (Swedish Statistics
simple to use.
on Medicines) Apoteksbolaget AB, Stockholm, 1995.
• Implementation of a classification system on a 6. Svensk Läkemedelsstatistiks 1999 (Swedish Statistics
national basis requires more time and dedication on Medicines) Apoteksbolaget AB, Stockholm, 2000.
than financial resources.
31