WHO DRUG

INFORMATION

VOLUME 12 • NUMBER 1 A • 1998

WORLD HEALTH ORGANIZATION • GENEVA Volume 12, Number 1, 1998 World Health Organization, Geneva

WHO Drug Information

Contents Scopolamine patch to prevent peri-operative nausea 15 Pemoline withdrawn 15 General Policy Issues Melatonin on prescription only 16 Dangers of purchasing medical products Chlormezanone withdrawn 16 through the Internet 1 Alcohol warning on over-the-counter pain medications 16 Nefazodone: adverse reaction reports 16 Personal Perspectives Daclizumab: first monoclonal antibody Fifty years of drug regulation: solid against transplant rejection 16 accomplishments and an important future 3 Reboxetine not for use in elderly 17 Counterfeit antimalarials detected 17 Reports on Individual Drugs Hormone replacement therapy and breast cancer 6 ATC/DDD Classification Mefloquine effectiveness impaired by high (final) 18 withdrawal rates 7 Zopiclone and zolpidem hypnotics and drug ATC/DDD Classification dependence 8 (temporary) 20

General Information Essential Drugs Cardiovascular disease and hormonal contraceptives: latest results 9 WHO Model List (revised in December 1997) 22 Current availability of vaccines for diarrhoeal diseases and typhoid 10 Recent Publications and Regulatory Matters Documents Extended release oral dosage forms: Troglitazone and liver injury 13 guidance for applicants 36 Phenolphthalein products withdrawn 13 United Nations Consolidated List 36 Serotonin re-uptake inhibitors and neonatal Manual on quality assurance 36 withdrawal symptoms 14 Medicinal claims and food products 37 Raloxifene for the prevention of osteoporosis 14 Paediatric prescribing information 37 Mibefradil: low heart rate and severe interactions reported 14 New anti-obesity drug approved 15 Recommended International Nonproprietary Names: List 39 39

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General Policy Issues

Dangers of purchasing medical sold outside the official channels could also be improperly manufactured, packaged or stored. Most products through the Internet importantly, there is no guarantee that the pur- chaser is, in fact, receiving the brand product and The value and uniqueness of the Internet as a not a fraudulent or adulterated copy and it is often worldwide communications system is evidenced by difficult to identify the true source and integrity of its popularity. Among its many attributes, the Inter- the information used in its promotion. net provides a valuable tool for retrieving informa- tion on medicine and health and accessing impor- This particular use of the Internet has drawn atten- tant knowledge bases, such as those housed within tion to the differences between Member States with universities. As an aid to scientific enquiry, it allows regard to legislation and regulations. While histori- rapid and easy exchange of information among cally these have addressed the promotion, advertis- professional groups such as researchers, scientists ing and sale of medical products nationally, it has and health care professionals. It also creates the now become an issue of concern to every country. potential for general public access to up-to-date Given the difficulty in locating the company that is medical information and news on developments in responsible for posting information on the Internet, therapeutic strategies. a further problem for enforcement agencies is to identify the responsible party. In many cases, a web The Internet also allows users to post or exchange site which has been closed down may rapidly be opinions, wares and information irrespective of reopened in another area or even another country. origin, status or global location and one of its many features is an international commercial directory for Given the urgency of the situation, WHO convened the cross-border advertising, promotion and sale of an ad hoc working group of experts to prepare a products. Despite the visible advantages offered by report and recommendations for discussion at the the Internet, however, concern is growing at the World Health Organization's Executive Board possible misuse of the system. It is apparent that meeting held in January 1998. It is hoped that these an increasing number of medical products are sold recommendations will guide health authorities and through the Internet. The consequence of cross- other interested parties in handling the issue of border commerce in medical products is that with- cross-border advertising, promotion and sale of out regulatory control the safety, efficacy and medical products through the Internet or similar quality of products cannot be assured. Inappropri- electronic information systems. ate claims are being made for products which, in increasing instances, are promoted for indications A full report of the meeting of the ad hoc working which do not correspond to the approved use. group is available from WHO1. The recommenda- Products with significant health risks — such as tions prepared for discussion by the WHO Execu- abortion and self-sterilization kits or home test kits tive Board are set out below . for HIV or hepatitis — have been advertised for sale. The problem is furthermore compounded by 1. Member States should: the diversity of the products offered. • review existing legislation, regulation and guide- Even when medical products purchased over the lines to ensure that they are adequate and appli- Internet are not considered dangerous, patients cable to cover issues concerning cross-border ad- could compromise their health by not seeking vertising, promotion and sale of medical products proper medical advice and individual treatment. using the Internet; When purchasing in this way, a consumer may also be wasting valuable resources on ineffective, improper or needless products and potent prescrip- 1 World Health Organization. Cross-border advertising, tion-only medicines may have the potential for promotion and sale of medical products through the serious side-effects. Medical products which are Internet. Report of the ad hoc Working Group. Unpublished document DMP/Internet/97.1.

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• develop, evaluate and implement strategies for 2. The pharmaceutical industry, health profession- monitoring, surveillance and enforcement activi- als and consumer organizations and other inter- ties regarding cross-border advertising, promotion ested parties should: and sale of medical products using the Internet. When appropriate, measures for enforcement • educate their members to use the Internet effec- should be taken and, except in exceptional cir- tively; cumstances, widely published; • encourage their members, where appropriate, to • collaborate with other Member States on the is- promote the formulation and use of good informa- sues raised by the Internet, and designate appro- tional practices; where applicable, consistent with priate contact points, and disseminate this infor- the principles embodied in WHO Ethical Criteria mation also through WHO to all Member States; for Medicinal Drug Promotion; and

• disseminate information on problem cases and • monitor and report problem cases and aspects aspects of cross-border advertising, promotion relating to the cross-border advertising, promotion and sale of medical products using the Internet to and sale of medical products using the Internet. WHO, other Member States, and the public, when appropriate; 3. WHO should:

• establish Web-sites, where feasible, for dissemi- • encourage the international community to formu- nation of information about medical products, and late self-regulatory guidelines for good informa- regulatory information; tional practices, consistent with the principles of the WHO Ethical Criteria for Medicinal Drug Pro- • maintain and/or establish mechanism(s) for re- motion; sponding to inquiries from the public; • inform the public that the Internet is a powerful • develop a model guide for Member States to edu- new medium for the provision of health informa- cate people using the Internet on how best to ob- tion, and educate health professionals and con- tain information on medical products through the sumers on using the Internet; such education Internet; should include the ability to assess, to the extent possible, the benefits and risks of the products in • collaborate with other relevant international or- order to prevent harm to people from false or mis- ganizations and institutions on Internet issues re- leading information about medical products; lating to medical products;

• in the case of information, promotion and advertis- • urge Member States to set up or strengthen ing of medical products on the Internet, Member mechanisms to monitor and survey, where appro- States should encourage the development and priate, cross-border advertising, promotion and implementation of a voluntary code of conduct ap- sale or medical products using the Internet, and plicable to all organizations posting information on provide technical assistance as required; the Internet; this includes, for example, identifica- tion of the information source and its status (e.g. • urge Member States to take regulatory action, advertisement, data sheet, patient information where appropriate, for violations of their national leaflet) and operate within the context of a self- laws regarding advertising, promotion and sale of regulatory system, if necessary, backed up by leg- medical products using the Internet; islation; adherence to the principles of the WHO Ethical Criteria for Medicinal Drug Promotion • encourage Member States and concerned non- should be encouraged; and governmental organizations to report to WHO problem cases and aspects of the cross-border • collaborate with other Member States in order to advertising, promotion and sale of medical prod- establish appropriate measures to prevent cross- ucts using the Internet; and border advertising, promotion or sale of medical products using the Internet to countries in which it • report problem cases and concerns, as appropri- is illegal; where possible, an organized system of ate, to Member States. licensing of all entities engaged in the sale of medical products should be developed.

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Personal Perspectives

Fifty years of drug regulation: ment for independent ethical review of each re- search proposal, as reflected in the Declaration of solid accomplishments and Helsinki. These two basic ethical requirements, as an important future adopted by governments worldwide, serve not only to protect patients participating in clinical studies J. Richard Crout, M.D. but to stimulate public trust in the enterprise of Bethesda, Maryland, medical research. Without these standards, the United States of America development of new drugs and devices could not have flourished during the past fifty years. This year, the World Heath Organization celebrates its fiftieth anniversary. Throughout this time, WHO Adequate and well controlled trials has been witness to an era of astonishing advance- The requirement for adequate and well controlled ment in therapeutics. Drugs, vaccines and medical trials, which was first adopted by US Congress in devices undreamed of a half century ago are now the Food, Drug and Cosmetic Act amendments of commonplace. Infectious diseases, whilst still a 1962, was written into law with little debate and threat, are no longer the scourge they once were. hardly any appreciation — at that time — of the Smallpox is gone and many terrible infections such profound impact that it would have on the future of as poliomyelitis and leprosy are on the way to medical research. But it has transformed the scien- elimination. tific culture of the pharmaceutical industry and researchers. Well-planned clinical trials, rather than The control of cardiovascular disease, the major anecdotal evidence and uncontrolled studies, cause of death in industrialized countries, is now became the norm, and from this change came possible thanks to healthier lifestyle and effective about the current system for designing, conducting drugs for the treatment of hypertension and lipid and evaluating clinical studies on new drugs. Slowly disorders. People with gastric ulcer, leukaemia, and inevitably, controlled clinical trials became the deafness, osteoporosis, schizophrenia, HIV infec- scientific standard for evaluating new drugs, new tion, or asthma have all been helped by new treat- devices, and biologicals and have now been ex- ments developed by physicians and scientists, tended to include medical practices and treatment many of whom are still involved in research today. strategies. No regulatory standard has done more to improve the quality of therapeutic products than This therapeutic revolution has been born of the life the requirement — adopted thirty-six years ago — sciences and the technological successes of scien- that approval should be based on the evaluation of tists and the pharmaceutical industry. It has been adequate and well-controlled clinical trials. stimulated by a continual demand for better health care. Notwithstanding these advances, this miracu- Development of spontaneous lous half century could not have taken place without adverse drug reaction reporting the establishment of sound regulatory standards to Assuring drug safety is the single, most important provide an infrastructure conducive to ethical drug responsibility of regulatory agencies throughout the development. world. In spite of the best efforts by manufacturers Worldwide adoption of ethical standards to evaluate the safety of each new drug prior to marketing, the fact remains that between one and for the conduct of clinical research three per cent of newly approved drugs are eventu- The requirement for voluntary consent was the first ally removed from the market because of unaccept- principle set out in the Nuremberg Code of 1947. able adverse reactions. Furthermore, many new This principle has since been universally applied by products will be subject to labelling changes and governments, and is codified in international law as possibly new warnings in the light of reports from Article 7 of the United Nations International Cov- post-marketing surveillance. This kind of safety enant on Civil and Political Rights. The second experience can only be obtained from population principle of ethical clinical research is the require- use. Many nations, each in different ways, have

3 Personal Perspectives WHO Drug Information Vol. 12, No. 1, 1998

pioneered to support adverse reaction reporting Regulatory authorities responded by providing and pharmacoepidemiology. Over the years, an guidelines to clarify regulatory requirements, and international network of reporting systems and data many began to offer assistance to manufacturers in bases has matured — many in collaboration with the planning of their drug development pro- the World Health Organization. These various grammes. Of particular importance at this time was systems represent a major achievement in assuring the establishment of open advisory committee the safety and accurate labelling of all marketed meetings by the US Food and Drug Administration drugs. Without the network of scientists and physi- (FDA). These meetings are primarily called to cians who diligently report individual adverse reac- advise the Agency on drug and device approval tions, there would be little information to warn the requests, but have become very useful to pharma- medical profession, the pharmaceutical industry or ceutical manufacturers as an educational forum. the public of possible, sometimes serious, adverse They are regularly attended by industry representa- reactions. tives, not only from the United States but also from Europe and Japan. Adoption of "good practices" Good manufacturing practice, or GMP, was a policy Slowly but surely throughout the past two decades, invention of the 1960s and the first WHO good the culture of drug development has evolved to- manufacturing practices text was published in 1968. wards a carefully distanced partnership between The key innovation in this regulatory approach was industry and regulators, with the mutual intention of the concept that pharmaceutical products should be bringing useful new drugs more rapidly into medical produced only by manufacturers who maintain practice. This trend has been stimulated by a shift independent quality control units and are regularly in the tenor of consumer activism from a once inspected by the authorities. The latest WHO GMP overriding concern with drug safety during the text additionally sets out general guidelines and 1970s, to a call for the rapid release of effective standards to be applied during the manufacture of new treatments for serious and life-threatening pharmaceutical products (1). illnesses such as AIDS. With such an environment in place, the advice of regulators can be of great Later, in the 1970s, a similar proposal concerning benefit during the development process of new good laboratory practices, GLP, became common drugs, and will work to facilitate access to those in practice to assure the quality of data in toxicology need. studies. More recently, the WHO good clinical practices (GCP) guidelines have been published International harmonization (2), and adherence will assure clinical trial data of regulatory requirements which is adequate for regulatory purposes. The Drug regulatory legislation tends to be country general approach of requiring companies to bring specific, and this means that drug development by independent internal auditing and quality control to multinational companies is a complex business. It the essential data in drug dossiers has vastly may also create a situation where regulatory au- improved the evaluation process and has estab- thorities can surprise each other with conflicting lished trust in the accuracy of information in these decisions. The World Health Organization takes dossiers. credit for beginning a broad harmonization process which began in the 1970s, when regulatory officials Constructive collaboration were invited to consult on matters related to drug In the 1960s and 1970s, the development of new development, the rational use of drugs, scheduling therapeutic agents was, in many ways, dominated of narcotic and psychotropic substances and rec- by an adversarial attitude between manufacturers ommendations on the safety, efficacy and quality of and regulatory authorities. In order to improve the pharmaceutical products. Regulators of many situation, both parties invested heavily in activities countries met and came to know one another at the designed to improve both the science and policies International Conferences of Drug Regulatory of drug development. As a consequence of the Authorities (ICDRA) which were initiated in 1980 in thalidomide tragedy, manufacturers were faced with Annapolis, USA. The ICDRA continues to be held a severe regulatory environment which led them to every two years and provides a forum to discuss adopt clinical development programmes of quality. issues of importance and to promote collaboration This move towards more disciplined research among drug regulatory authorities from both devel- slowly transformed the quality of applications. oped and developing countries.

4 WHO Drug Information Vol. 12, No. 1, 1998 Personal Perspectives

The beginnings of international regulatory harmoni- advancing technologies in gene therapy, materials zation are rooted in the creation of the European science, and even nanotechnology. How will these Union and the need by countries within Europe to interventions be categorized? What form will future standardize procedures. This process has spread therapeutic innovations take? How will regulators to include the United States and Japan in a consor- be called on to deal with control of these new tium known as the International Conference on methods? Harmonization (ICH), which is made up of a part- nership of regulators and industry representatives As diagnostic medicine advances, new methods of from these three regions. Members of the ICH have measuring efficacy endpoints will continue to ap- worked hard and effectively to bring about the pear. It is also likely that more patients will partici- harmonization and mutual recognition of many pate in large clinical studies of simple design which guidelines including those on the content and are set up by networks of investigators. As the new format of new drug dossiers, and the conduct and millennium unfolds, new information technology will analysis of clinical studies. Although we are not yet influence the sale and advertising of products, and one world in terms of requirements for drug devel- drug regulation will evolve in line with these new opment, we are far closer than we were only a brief demands. Although revolutionary computer technol- five years ago thanks to the ICH and the efforts of ogy will assist regulators in dealing with complex its members. applications, final decisions will remain those of dedicated and experienced people. The future The drug regulatory systems of many developed A major ongoing challenge to future regulators will nations are now mature from a policy viewpoint. be to protect the integrity of the drug regulatory Standards exist for the safety, efficacy, labelling, system. Regulation is a political target — which is advertising and manufacture of pharmaceutical as it should be in a free society. But the message products, and mechanisms are in place to assure must be reinforced that drug regulation provides a the quality and accuracy of the data contained in fundamental public health benefit. The drug regula- the new drug dossiers. Extensive scientific and tors of the industrialized world, in spite of some procedural guidance to the industry is available in occasional political criticism and a few celebrated the form of regulations, guidelines and fora. At last, errors and lapses, have a generally commendable it would seem that no major new requirements are and constantly improving record of evaluating of immediate necessity. important new therapies without undue delay. They also have an excellent record of dealing promptly The expanding drug markets of the near future will with safety problems that threaten public health. be in countries such as Brazil, Mexico, India, China, Republic of Korea and the newly independ- Public awareness of pharmaceutical development ent states, such as those of the former Soviet is at an all-time high as can be seen on many Union. Pharmaceutical manufacturing is already television news programmes and as evidenced by well established in these nations and clinical re- national expenditure on drugs. The pharmaceutical search is expanding. The innovation of new thera- industry is flourishing, both financially and scientifi- peutic agents cannot be far behind. The establish- cally. This situation has come about from a propi- ment of regional consortia of regulatory authorities tious meshing of scientific knowledge, technical to evaluate new drug applications submitted by innovation, medical need, commercial demand and member countries seems set to continue. Thus, high regulatory standards. The result is a therapeu- while preserving its own independence, each tic revolution beyond the imagination of anyone country may no longer need to invest in a separate practising medicine at the birth of the World Health detailed review process and evaluation of the Organization fifty years ago. complete dossier. Since drug application review is labour-intensive, there is a real desire for coopera- References: tion in this area. Regional grouping may also be helpful in assisting poorer countries within the 1. World Health Organization. Good manufacturing prac- region whose public health resources could then be tices for pharmaceutical products. Technical Report Se- spent on priority issues of prevention and treat- ries, No. 823, 1992, Annex 1. ment. 2. World Health Organization. Guidelines for good clinical The clearest immediate challenge to future regula- practice (GCP) for trials on pharmaceutical products. tors would seem, then, the need to keep abreast of Technical Report Series, No. 850, 1995, Annex 3.

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Reports on Individual Drugs

Hormone replacement therapy cases per 10 000 person-years; a rate not signifi- cantly greater than the 36 per 10 000 person years and breast cancer seen in women without a history of breast cancer who had never received HRT. It is now an accepted fact that women with a family history of breast cancer have a higher risk of devel- Although the study was quite extensive in terms of oping this condition during their lifetime. With the patient data, it had some limitations. No validation increased use of hormone replacement therapy was made of the history of breast cancer, and no (HRT), it has become important to advise such data were provided on the particular HRT formula- patients of the risks involved in taking perimeno- tion which was being used in terms of hormone pausal or postmenopausal hormone therapy. ingredient, or the reasons for taking HRT. It is also disputable whether a period of five years is long Documented evidence is available that hormone enough to demonstrate tendencies in the develop- replacement therapy relieves menopausal symp- ment of breast cancer. However, despite its limita- toms and its long-term use seems to prevent or tions, the study has provided some interesting delay osteoporosis. It may also protect against information on questions of benefit and safety. ischaemic heart disease and partially prevent or delay the onset of Alzheimer disease (1). General The study suggests that, for most women, HRT is risks of HRT show that there is a slightly increased not associated with a statistically significant in- risk of deep vein thrombosis and/or pulmonary creased risk of breast cancer. A woman with a embolism (2, 3, 4). However, concerning the risk for family history of breast cancer may constitute an breast cancer, there is a considerable body of exception, although the modest increased risk in literature which discusses the association, but this study was consistent with chance. The mortality supporting data are not consistent. Previously, two rate in women with a history of breast cancer meta-analyses have found a positive association, seemed to show a decreased risk, and evidence two others found no association, and additional also suggested an inverse association with the rate recent studies have failed to clarify the situation (5). of death from coronary heart disease, stroke and The Iowa Women's Health Study, has now been from cancers other than breast cancer. Further published which extensively examines the risk of studies with similar objectives and conducted in a postmenopausal breast cancer, case fatality, and representative sample of HRT users and non-users total mortality in women with and without a family will help to determine conclusions. history of breast cancer (5). References Participants in the study were selected from a random sample of women aged between 55 and 69 1. WHO Drug Information, 10: 178 (1996). years in 1986. In this prospective cohort of 41 837 women, data were collected on HRT use as well as 2. Daly, E. , Vessey, M.P., Hawkins, M.M. et al. Risk of on family history of breast cancer in first-line rela- venous thromboembolism in users of hormone replace- ment therapy. Lancet, 348: 977–980 (1996). tives, which was reported as 12.2%. The study showed that among women with a family history of 3. Jick, H., Derby, L.E., Myers, M.W. et al. Risk of hospital breast cancer, currently using HRT and who had admission for idiopathic venous thromboembolism among done so for at least 5 years previously, breast users of postmenopausal oestrogens. Lancet, 348: 981– cancer at an age-adjusted annual rate was 61 983 (1996). cases per 10 000 person-years (95% CI, 28 to 94 4. Grodstein, F., Stampfer, M.J., Goldhaber, S.Z. et al. cases). Statistically, this rate was not higher than Prospective study of exogenous hormones and risk of the rate of 46 cases per 10 000 person-years in pulmonary embolism in women. Lancet, 348: 983–987 women who had never used HRT. (1996). Among women without a family history of breast 5. Sellers, T., Mink, P.J., Cerhan, J.R. et al. The role of cancer, the rate in those who are currently receiving hormone replacement therapy in the risk for breast cancer HRT and had done so for at least 5 years was 41 and total mortality in women with a family history of breast cancer. Annals of Internal Medicine, 127: 973–980 (1997).

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Mefloquine effectiveness impaired high withdrawal rates. Withdrawal from, and non- compliance with, malaria prophylaxis are hazardous by high withdrawal rates because they leave travellers incompletely pro- tected. Studies suggest that women more com- Mefloquine for prophylaxis of malaria has now been monly report adverse effects from mefloquine (6, 8) prescribed to over 8 million travellers worldwide and one study has shown that adult women experi- since its introduction onto the market in 1985, ence twice the toxicity from mefloquine chemo- despite being relatively expensive (1). Tolerability of prophylaxis as do adult men (11). Male soldiers are weekly mefloquine prophylaxis in travellers was less likely than ordinary travellers to withdraw from originally based on two uncontrolled, observational mefloquine (12). studies (2, 3). However, this tolerability is now in doubt as more observational data become available Thus, based on available evidence, the usefulness showing an excess of neuropsychiatric or neu- of mefloquine in prophylaxis may be limited to ropsychological side-effects in travellers taking highly motivated occupational subgroups or indi- mefloquine compared with travellers taking other vidual travellers at high risk of infection in areas of standard antimalarial prophylaxis (4–8). In fact, chloroquine-resistant malaria. It may also be advis- evidence is accumulating that mefloquine is more able to prescribe mefloquine for travellers only toxic than was previously thought, although as early when the destination is one where reliable diagnos- as 1989 some drug regulatory authorities intro- tic and treatment facilities for malaria are not readily duced restrictions on prophylactic use based on available. In such circumstances, the traveller spontaneous reporting of adverse drug reactions should be informed of the potential neurological or (9–10). Drug regulators in other countries — Aus- neuropsychiatric adverse reactions. Because they tralia, Ireland, Malaysia, the Netherlands, and the are rare, observation by a co-traveller or someone United Kingdom — introduced similar restrictions close may be advisable to detect these symptoms between 1994 and 1997. This controversy has now at an early stage (12). Recommendations for travel- prompted public debate in the United Kingdom, lers, including the advisability of initiating Canada and the Netherlands (12). mefloquine prophylaxis 2–3 weeks before travel, are issued by WHO (13). A systematic review has been conducted (12) to assess evidence from randomized controlled trials In light of this situation, it would seem preferable of the efficacy, tolerability and overall effectiveness not to approve candidate drugs for routine unre- of mefloquine prophylaxis in preventing malaria stricted use until large randomized controlled infection in non-immune adult travellers. Information clinical trials have documented the efficacy, safety has been obtained from clinical trial consulting and tolerability of a product in the anticipated target registers, data bases, indexes, pharmaceutical population. industry sources and key scientists and has re- sulted in 37 trials being identified as eligible, with References 10 meeting the inclusion criteria. These 10 trials provide information on a total of 2750 non-immune 1. Handschin, J., Crevoisier, C., Sturchler, D. Mefloquine in malaria prophylaxis: low efficacy or low compliance? adults randomized to mefloquine or to a control Lancet, 346:1294 (1995). group. One placebo-controlled trial examined malaria incidence directly and showed mefloquine 2. Steffen, R., Fuchs, E., Schildknecht, J. et al. Mefloquine to be highly effective as prophylaxis for malaria in a compared with other malaria chemoprophylactic regimens drug-resistant area. However, four placebo-control- in tourists visiting East Africa. Lancet, 341: 1299 (1993). led trials showed that mefloquine was not well tolerated, as demonstrated by withdrawal of the 3. Lobel, H. O., Miani, M., Eng, T. et al. Long-term malaria drug, which was consistently higher than with prophylaxis with weekly mefloquine. Lancet, 341: 848–851 placebo. Five studies covered field trials comparing (1993). mefloquine with other chemoprophylaxis, and 4. WHO Drug Information, 10: 58–61 (1996). mefloquine was shown to be as well tolerated as other chemoprophylaxis, although there was a 5. WHO Drug Information, 10: 177 (1996). trend towards higher withdrawals in the mefloquine group. 6. Barret P.J., Emmins, P.J., Clarke, P.D. Comparison of adverse events associated with use of mefloquine and This review generates clear uncertainty with regard combination of chloroquine and proguanil as antimalarial to the tolerability and effectiveness of mefloquine in prophylaxis: postal and telephone survey of travellers. conventional malaria prophylaxis because of the British Medical Journal, 313: 525–528 (1996).

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7. Corbett, E.L., Doherty, J.F., Behrens, R.H. Adverse In 1987, a study involving 10 normal healthy volun- events associated with mefloquine. Study in returned teers was carried out to test whether zopiclone was travellers confirms author's findings. British Medical likely to produce rebound after short-term use (5). A Journal, 313: 1552 (1996). comparison was made with placebo and a standard 8. Van Riemsdijk, M.M., van der Klauw, M.M. et al. benzodiazepine hypnotic, temazepam. The study Neuropsychiatric effects of antimalarials. European also tested whether tapering the dosage lessened Journal of Clinical Pharmacology, 52: 1–6 (1997). any potential rebound symptoms. Zopiclone tended to be associated with some dysphoric effects such 9. Mefloquin: Ergänzungen in der Packungsbeilage zur den Abschnitten Nebenwirkungen und Kontraindica- as feelings of being troubled, tense, antagonistic or kionen. Bundesgesundheitsblatt, 10: 469–470 (1989). bored whereas temazepam produced drowsiness, clumsiness, dreaminess and sadness. An increase 10. Idänpään-Heikkilä, J. Kyrönseppä, H., Lääkeinfo – in these symptoms was noted after stopping Finnish Medical Journal, 45: 1960–1961 (1990). temazepam, but this effect was lessened when the 11. ter Kuile, F.O., Nosten, F., Thieren, M. et al. High- dose was tapered. Zopiclone was associated only dose mefloquine in the treatment of multi-drug resistance with minimal effects. However, in a recent report of falciparum malaria. Journal of Infectious Diseases, 166: four cases (3), situations were described where 1393–1400 (1992). patients — because they had increased their intake 12. Croft, A., Garner, P. Mefloquine to prevent malaria: a of zopiclone above the dose prescribed — suffered systematic review of trials. British Medical Journal, 315: symptoms on withdrawal which included craving, 1412–1416 (1997). anxiety and insomnia. For reasons not explained in the report, three of the patients took the hypnotic 13. International Travel and Health. Vaccination require- even in daytime, and one patient had a previous ments and health advice. World Health Organization, history of benzodiazepine dependence. Geneva, 1998. ISBN 92 4 158023 2. The dependence liability of zopiclone and zolpidem remains somewhat unclear based on the available Zopiclone and zolpidem hypnotics studies and data. It would seem that, with the and drug dependence products currently available, any effective treatment of insomnia is bound to cause some kind of de- Benzodiazepines were first introduced as anxioly- pendence during treatment for chronic sleep prob- tics and hypnotics more than 30 years ago. It soon lems and is more likely to occur in certain types of become evident, however, that they cause depend- personality or in patients dealing with difficult life ence and that discontinuation can lead to with- crises and will depend on whether the patient is or drawal symptoms which often mimic the very same has been drug or alcohol dependent. Caution illness for which the treatment was initiated. For should therefore be exercised when prescribing these reasons, most benzodiazepines are sched- hypnotics, and this should be limited to short-term uled under the international Convention on Psycho- treatment only. tropic Substances, and some physicians are reluc- tant to prescribe them for insomnia or anxiety. References 1. Bianchi, M., Musch, B. Zopiclone discontinuation: Given this situation, alternative treatment and new review of 25 studies assessing withdrawal and rebound innovative drugs were sought and the hypnotics, phenomena. International Clinical Psychopharmacology, 5 zopiclone and zolpidem, were introduced ten years (suppl.2): 139-145 (1990). ago. Although they are unrelated chemically to benzodiazepines, they act via the benzodiazepine/ 2. Monti, J.M., Effect of zolpidem on sleep in insomniac gamma aminobutyric acid receptor complex. They patients. European Journal of Clinical Pharmacology, 36: have been marketed in many countries for the 461 (1989). short-term treatment of insomnia and early clinical 3. Jones, I.R., Sullivan, G. Physical dependence on zopi- trials showed that zopiclone and zolpidem do not clone: case reports. British Medical Journal, 316: 117 cause a rebound effect, dependence, or withdrawal (1998). phenomena and that they are a safe option for treating insomnia (1–3). Some drug regulatory 4. Committee on Safety of Medicines. Current Problems, Number 30, 1990. agencies have received reports on neuropsychiatric reactions similar to those observed during benzo- 5. Lader M., Frcka, G. Subjective effects during adminis- diazepine use, but symptoms rapidly disappeared tration and on discontinuation of zopiclone and temaze- on discontinuation of the drug (4). pam in normal subjects. Pharmacopsychiatry, 20: 67–71 (1987).

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General Information

Cardiovascular disease and The Scientific Group was composed of experts from different regions of the world, including researchers hormonal contraceptives: involved in recent large-scale studies on cardiovas- latest results cular disease and hormonal contraception. During its discussions, the Group relied, to a large extent, Steroid hormone contraceptives have been avail- on published literature — although it was also able since the 1960s and are estimated to be used provided with unpublished information from several by more than 100 million women throughout the new studies. In view of the major changes that have world, of which 93 million are users of the combined taken place over time in the hormonal content of oral contraceptive pills. Over the years, there have combined oral contraceptives and in prescribing been successive changes in the composition and patterns, the Group paid particular attention to use of these preparations, most notably with regard studies using data collected after 1980. General to the combined products. These have had their comments concerning cardiovascular disease and hormone content reduced, multiphasic formulations hormonal contraception were also presented. have been developed, and different progestogens introduced. Additionally, women using this contra- The Scientific Group was also able to draw on the ceptive method are now likely to be selected and expertise provided by the principal investigators of monitored more carefully than in the past and they several recent studies, on researchers working on also tend to be younger. Oral and injectable pro- new data, and representatives of the United Na- gestogen-only preparations are used less fre- tions Population Fund (UNFPA) and the Interna- quently, and mostly by women for whom combined tional Planned Parenthood Federation (IPPF). oral contraceptives are contraindicated. Members of the drug regulatory authorities of Germany, the United Kingdom, the United States of Reports linking combined oral contraceptives with America, and the European Union, as well as venous and arterial thrombotic events began to representatives of the major pharmaceutical com- appear soon after their introduction. Since then, a panies marketing steroid contraceptives, were also large number of epidemiological studies have invited. investigated whether users of combined oral contra- ceptives are at increased risk of cardiovascular The Group concluded that the incidence and mor- disease. Information is now available from several tality rates of all cardiovascular diseases in women large, recent studies, including the WHO Collabora- of reproductive age, including stroke, myocardial tive Study of Cardiovascular Disease and Steroid infarction, and venous thromboembolism, are very Hormone Contraception, on the effects of the more low. Any additional cardiovascular disease inci- recently introduced combined oral contraceptives. dence or mortality attributable to oral contraceptives Current scientific data on use of steroid hormone is very small if the users do not smoke and do not contraception as it relates to risk of myocardial have other cardiovascular risk factors. In women infarction, ischaemic and haemorrhagic stroke, and who do not smoke, who have their blood pressure venous thromboembolic disease was recently checked regularly, and who do not have hyperten- reviewed at a meeting of a WHO Scientific Group in sion or diabetes, the relative risk of myocardial Geneva arranged by the UNDP/UNFPA/WHO/ infarction in users of combined oral contraceptives World Bank Special Programme of Research, is not increased regardless of age. Neither is there Development and Research Training in Human an increase in the risk of myocardial infarction in Development. The Scientific Group also studied the past users of combined oral contraceptives. These incidence of cardiovascular disease among women conclusions seem to apply equally in developed of reproductive age in general. The combined effect and developing countries. On the other hand, the of risk factors for cardiovascular disease and use of available data do not allow a conclusion to be made hormonal contraceptives, and whether different that the risk of myocardial infarction in users of low- compositions of combined oral contraceptives have dose combined oral contraceptives is related to different cardiovascular risk profiles, were also progestogen type. The suggestion that gestodene discussed.

9 General Information WHO Drug Information Vol. 12, No. 1, 1998

or desogestrel-containing low-dose combined oral Combined oral contraceptive preparations contain- contraceptives may carry a lower risk of myocardial ing desogestrel and gestodene probably carry a infarction compared with low-dose formulations small risk of venous thromboembolism beyond that containing levonorgestrel remains to be substanti- attributable to combined oral contraceptives con- ated. taining levonorgestrel. There are insufficient data to draw conclusions with regard to combined oral In women who do not smoke, have their blood contraceptives containing norgestimate. pressure checked, and do not have hypertension, the relative risk of ischaemic stroke is increased by Although the Scientific Group conclusions focused about 1.5 fold in current users of combined oral on the cardiovascular effects of steroid hormone contraceptives in comparison with past users. contraceptives, other considerations also influence There is no increase in the relative risk of ischaemic women and couples when they make their choice of stroke with increasing duration of use of combined contraceptive method. These factors include real oral contraceptives. Neither is there an increase in and perceived risks and benefits associated with the relative risk of ischaemic stroke in women who each method of contraception. Social, economic, have ceased use of oral contraceptives. These psychological and cultural factors are also impor- conclusions seem to apply equally in developed tant. The conclusions and recommendations of the and developing countries. There are, however, Scientific Group should not, therefore, be taken in insufficient data to allow a conclusion to be made isolation. Instead, they should form part of the about whether the risk of ischaemic stroke is re- detailed information needed when making informed lated to progestogen type in combined oral contra- choices in this important area of family planning ceptives. and preventive health care. In women under 35 years of age who do not smoke and who do not have hypertension, the relative risk Reference; World Health Organization. WHO Scientific of haemorrhagic stroke associated with oral contra- Group Meeting on Cardiovascular Disease and Steroid ceptive use is not increased. There is no increase Hormone Contraceptives: Summary of Conclusions. in the risk of haemorrhagic stroke with increasing Weekly Epidemiological Record, 72: 361–363 (1997). The complete report of the Scientific Group will be published duration of use and there is no increase in the as WHO Technical Report Series, No. 877, 1998. relative risk of haemorrhagic stroke in women who have previously used oral contraceptives. The incidence of haemorrhagic stroke increases with Current availability of vaccines for age, and current use of combined oral contracep- tives appears to magnify this effect of ageing. diarrhoeal diseases and typhoid These conclusions seem to apply equally in devel- Dr B. Ivanoff & Dr P.H. Lambert, oped and developing countries. Vaccine Research and Development, The Scientific Group noted that the already el- Global Programme on Vaccines, evated risks of myocardial infarction and stroke World Health Organization, Geneva among women who smoke or who have high blood pressure, are further increased if such women use The control of diarrhoeal diseases and typhoid combined oral contraceptives. fever is still an important public health challenge for many developing countries. It is estimated that Recently, there has been much publicity about the these diseases are responsible for the death of 2.5 risk of venous thromboembolic disease associated million children each year and one virus — rotavirus with use of oral contraceptives, and in particular — and four bacteria — Salmonella typhi, shigella, about a possible excess risk associated with use of Escherichia coli ETEC, and Vibrio cholerae — are the more recently introduced pills containing new held responsible. Preventive measures based on progestogens (desogestrel, gestodene, or sound hygiene, such as purifying water supplies, norgestimate). In this respect, the Scientific Group improving water delivery, and providing sanitary concluded that current users of combined oral installations and sewage systems (1), are efficient contraceptives have a low absolute risk of venous long-term means of control of bacteria. However, thromboembolism which is none the less three- to the high incidence of rotavirus infection in children sixfold higher than that in non-users. The risk is from developed countries with high standards of probably highest in the first year of use and de- hygiene suggests that the incidence of rotavirus clines thereafter, but persists until discontinuation. infection needs to be addressed by other means.

10 WHO Drug Information Vol. 12, No. 1, 1998 General Information

Although it is crucial to introduce and sustain pre- is produced from a pathogenic strain in which a ventive measures, it is also recognized that imple- deletion mutation has been introduced leading to a mentation is difficult in some developing countries loss of capacity to produce pathogenic A subunit of or in particularly difficult situations such as following the cholera toxin (8). Given in one oral dose, it natural disasters or in refugee camps. Efforts to provided excellent protection (96%) in volunteers develop effective treatment and vaccines against after challenge with a pathogenic cholera strain (9). the pathogens responsible for diarrhoeal diseases This vaccine is produced in Switzerland and is and typhoid have consequently been identified as licensed in Argentina, Canada, Finland, Peru, urgent. Improved vaccines are currently available Philippines and Switzerland. It is also expected to for cholera and typhoid, and a vaccine against be licensed in the USA and other European coun- rotavirus has recently been developed and submit- tries in the near future. ted for licensing. Development of vaccines is also continually hampered by the problem of emergence Typhoid vaccine of antibiotic-resistant bacterial strains (2). The parenteral, killed whole-cell vaccine is used less and less and is being phased out because of Cholera vaccines its side effects. Two new, safe and effective vac- New oral cholera vaccines have rendered the cines are currently licensed which are based either previous parenteral killed vaccine outdated. The on defined subunit antigens or on whole-cell live new vaccines are more effective, and able to confer attenuated bacteria. One is composed of Vi capsu- higher and longer-lasting protection. Until 1992, lar polysaccharide of Salmonella typhi given in one V. cholerae serogroup O1 was the only organism single dose parenterally, and elicits protection implicated in epidemics. However, a further sero- seven days after injection (10, 11). The protective group, labelled O139, was later identified during efficacy provided is still more than 50% five years outbreaks in India and Bangladesh (3–5). The after a single dose and ten years after immuniza- currently available vaccine is based on O1 sero- tion, 58% of vaccinees are still carrying more than 1 group, and a vaccine for the O139 serogroup is mg/ml of IgG antibodies in their blood (12). This awaiting licensing review. vaccine is licensed in more than 63 countries throughout the world. The other vaccine is com- Of the two oral vaccines now on the market, the posed of a live attenuated mutant Salmonella typhi first is composed of B subunit cholera toxin added Ty21a given by oral route in three doses two days to V. cholerae strains (classical and El Tor) killed by apart (13). The protective efficacy, evaluated seven formalin or heat. This vaccine elicits antibodies years after the last dose, was 67% in endemic against B subunit, avoiding fixation of the toxin on areas (14) GM1 ganglioside receptors and against LPS (lipo- polysaccharide). It is given in low oral doses one Rotavirus vaccine week apart and provides protection seven days It is important to underscore that rotavirus is not after the second dose. Evaluated in endemic areas, transmitted by food or water and that the incidence it provided 86% protection during six months after of rotavirus infections in developing countries is vaccination in all age groups (6, 7). After three similar to developed countries (15). This means that years of follow up, vaccinees over 5 years of age the recommendations for the control of bacterial were still protected at a level of 72%. However, in diarrhoeal disease do not apply to rotavirus. children less than five years of age, the level of protection had decreased six months after the A live oral vaccine has recently been produced and second dose. This vaccine is produced in Sweden submitted for licensing (16). This is a tetravalent and is licensed in Argentina, El Salvador, Guate- reassortant (animal strain with human strain) vac- mala, Honduras, Nicaragua, Norway, Peru and cine (17) given in three doses one month apart in a Sweden. Because of a similarity between B subunit small volume (2.5 ml). It provided 85% protection structure and the heat labile toxin (LT) of E. coli, against severe diarrhoea due to rotavirus — it is this vaccine confers protection for three months this kind which causes death in infants — and 56% against diarrhoea due to E. coli ETEC at a level of protection against less severe diarrhoea due to 67%. rotavirus (18, 19). The WHO Vaccine Research and Development Unit placed rotavirus vaccine The second cholera vaccine is a live oral attenu- high in its priorities. During a recent meeting in ated vaccine administered in one dose. Protective Geneva, recommendations on rotavirus vaccine efficacy is obtained seven days later. This vaccine use in developing countries were adopted (15).

11 General Information WHO Drug Information Vol. 12, No. 1, 1998

Conclusion 9. Levine, M.M., Kaper, J.B., Herrington, D. et al. Safety, Given the considerable progress made in the immunogenicity and efficacy of recombinant live oral development of vaccines against diarrhoeal dis- cholera vaccine CVD103 and CVD103-HgR. Lancet, 2: 467–470 (1988). eases and typhoid fever, the future prevention of these diseases may be possible. Vaccines could be 10. Acharya, V.I., Lowe, C.U., Thapa, R. et al. Prevention used as a complementary action for such time as it of typhoid fever in Nepal with the Vi capsular poly- takes countries to implement adequate food- saccharide of Salmonella typhi. A preliminary report. New handling and water sanitation measures. Because England Journal of Medicine, 317: 1101–1104 (1987). multiple enteric infections often occur simultane- ously, it would seem logical that future strategies 11. Klugman, K., Gilbertson, I.T., Kornhoff, H.J. et al. will be directed to the development of comprehen- Protective activity of Vi polysaccharide vaccine against sive combined vaccination against the major infec- typhoid fever. Lancet, 2: 1165–1169 (1987). tions – rotavirus, shigella, salmonella, ETEC and 12. Klugman, K., Keddy, K., Bouveret Le Cam, N. et al. cholera. Long-term serological response to Vi vaccine and References protective immunity. 3rd Asia-Pacific Symposium on Typhoid Fever and Other Salmonellosis. Bali, Indonesia, 1. The management and prevention of diarrhoea: practical 9 December 1997. guidelines, Third edition. World Health Organization, Geneva, 1993. 13. Germanier, R., Furer, E. Isolation and characterization of galE mutant Ty21a, of Salmonella typhi: a candidate 2. Ivanoff, B. Levine, M.M. Typhoid fever: continuing strain for a live oral typhoid vaccine. Journal of Infectious challenges from a resilient foe. Bulletin de l'Institut Disease, 141: 553–558 (1975). Pasteur, 95: 129–142 (1997). 14. Ivanoff, B., Levine, M.M. Lambert, P.H. Vaccination 3. Alber, J., Siddique, A.K., Islam, M.S. et al. Large against typhoid fever: recent status. Bulletin of the World outbreak of clinical cholera due to Vibrio cholerae non-O1 Health Organization, 72: 957–971 (1994). in Bangladesh. Lancet, 341: 704 (1993). 15. World Health Organization. Rotavirus vaccines for 4. Ivanoff, B., Clemens, J. Caractéristiques epidémiolo- developing countries. Weekly Epidemiological Record, 72: giques, cliniques, et microbiologiques de la nouvelle 33–40 (1997). souche de Vibrio cholerae O139. Médécine Tropicale, 54: 75–77 (1994). 16. Glass, R., Gentsch, J.R., Ivanoff, B. New lessons for rotavirus vaccines. Science, 272: 46–48 (1996). 5. Berche, P. Ivanoff, B. Vers la huitième pandémie de choléra? La Presse Médicale, 23: 872–873 (1994). 17. Kapikian, A.Z., Flores, J., Hoshino, Y. et al. Rotavirus: 6. Black, R.E., Levine, B., Clements, M.L. et al. Protective the major etiologic agent of severe infantile diarrhoea may efficacy in humans of killed whole vibrio oral cholera be controllable by a Jennerian approach to vaccination. vaccine with and without the B subunit of cholera toxin. Journal of Infectious Diseases, 153: 815–822 (1996). Infection and Immunity, 55: 1116–1120 (1987). 18. Kapikian, A.Z., Hoshino, Y., Chanock, R.M. et al. 7. Sanchez, J.L., Vasquez, B., Begue, R.E. et al. Efficacy of a quadrivalent rhesus rotavirus-based human Protective efficacy of oral whole cell/recombinant-B- rotavirus vaccine aimed at preventing severe rotavirus subunit cholera vaccine in Peruvian military recruits. diarrhoea in infants and young children. Journal of Lancet, 344, 1273–1275 (1994). Infectious Diseases, 174: 65–72 (1996). 8. Kotloff, K.I., Wasserman, S.S., O'Donnell, S. et al. 19. Perez-Schael, et al. Efficacy of the rhesus rotavirus Safety and immunogenicity in North Americans of a single based quadrivalent vaccine in infants and young children dose of live ora cholera vaccine CVD103HgR. Results of in Venezuela. New England Journal of Medicine, 337: a randomized, placebo-controlled, double-blind crossover 1181–1187 (1997). trial. Infection and Immunity, 60: 4430–4432 (1992).

12 WHO Drug Information Vol. 12, No. 1, 1998

Regulatory Matters

Troglitazone and liver injury outweigh the risks if patients are appropriately selected and monitored. United States of America — In November 1997, References the Food and Drug Administration (FDA) informed physicians of a warning introduced by the manufac- 1. FDA Talk Paper, T97–55, November 1997. turers of troglitazone. The product had been ap- 2. FDA Talk Paper, T 97–61, December 1997 proved several months earlier, in January 1997, for the treatment of adult-onset (type II) diabetes United Kingdom — Based on reports received mellitus in patients whose blood glucose levels are from the United States of America and Japan not adequately controlled by other therapies, for concerning serious hepatic reactions, the Medicines use in combination with insulin or sulfonylurea. Control Agency (MCA) has decided that the risks By October 1997, some 500 000 patients in the associated with use of troglitazone, an oral anti- United States had used the drug and, of these, diabetic agent, outweigh the potential benefits and some 85 000 had taken it for a period of six months troglitazone has been voluntarily withdrawn as of 1 or more. During that time, 35 reports of liver injury December 1997. of varying degrees had been received ranging from Troglitazone was marketed in the United Kingdom mildly elevated liver transaminase levels to liver in October 1997 and has been prescribed to 5000 failure resulting in one case of liver transplantation patients. One report of liver dysfunction has been and one death. The Agency estimates that as many received during this period. as 2% of users may have to stop using the drug because of elevated liver transaminase levels, Reference: Current Problems, December 1997. although it is doubtful whether this would lead to permanent liver damage. The FDA consequently recommended routine liver Phenolphthalein products function tests to be carried out during the first two withdrawn months, and thereafter every three months during the first year of use. Tests were also recommended Germany — The Federal Institute for Drugs and for any patient taking troglitazone who developed Medical Devices has recommended marketing symptoms of liver dysfunction such as vomiting, authorization holders of phenolphthalein laxative abdominal pain, fatigue, loss of appetite, or dark products to withdraw their products from the market urine. In the event of jaundice or liver injury, treat- because of potential toxicological risks (1). ment should be discontinued immediately. As reported in the previous issue of this journal, the Within one month of issuing this warning, an addi- United States Food and Drug Administration has tional 125 reports of liver injury, including three of proposed to ban over-the-counter sale of products death from liver failure from Japan, were received. containing phenolphthalein. (2). Stronger recommendations were immediately issued in December 1997 indicating the need for References more frequent monitoring of liver enzymes. These 1. Communication from the Federal Institute for Drugs included testing at initiation of therapy, monthly for and Medical Devices (BfarM), dated 15 October 1997. the first six months, every two months for the next six months and periodically thereafter. 2. WHO Drug Information, 11: 251 (1997).

It is estimated that 18 million Americans suffer from Italy — The Ministry of Health has suspended the this life-threatening form of diabetes which can lead marketing authorization for laxatives containing to coronary heart disease, blindness, kidney failure phenolphthalein with immediate effect. This will and limb amputation, and despite the serious involve 13 products marketed in Italy. reactions which have been reported, the FDA still considers that the benefits of this treatment can Reference: Marketletter, 12 January 1998.

13 Regulatory Matters WHO Drug Information Vol. 12, No. 1, 1998

European Union — In December 1997, the Com- Raloxifene for the prevention mittee for Proprietary Medicinal Products (CPMP) issued a position paper on the genotoxic and of osteoporosis carcinogenic potential of phenolphthalein. The paper is aimed to provide Member countries with United States of America — The Food and Drug information when considering whether national Administration has approved raloxifene for the restrictions on the availability of phenolphthalein- prevention of osteoporosis in postmenopausal containing medicinal products should be taken. The women. It is estimated that 19 million Americans CPMP has concluded that "carcinogenicity and are at risk of osteoporosis. repeat dose genotoxicity studies of phenolphthalein in mice have identified a hazard with respect to Raloxifene is a new class of drugs called selective carcinogenic and genotoxic activity". However, "it is estrogen receptor modulators (SERMs) that are not possible to establish whether the hazard identi- being studied for their ability to mimic the effects of fied in experimental animals is relevant to humans, estrogen in some tissues but not in others. Clinical and if so the extent of the risk." data indicate that raloxifene acts like estrogen, though to a lesser degree, thereby increasing bone Reference: European Agency for the Evaluation of density and lowering blood lipids, without increasing Medicinal Products. Committee for Proprietary Medicinal HDL levels. During clinical trials it was shown not to Products (CPMP) position paper on the genotoxic and adversely affect breast and uterine tissue. How- carcinogenic potential of phenolphthalein. CPMP/818/97. ever, the effect on actual bone fracture risk is not December 1997. yet known and is being evaluated in ongoing trials.

Japan — The Pharmaceutical and Medical Safety The most serious side-effect documented to date is Bureau of the Ministry of Health and Welfare has an increased risk of venous thromboembolic events issued a statement that laxative products containing (VTEs). This was similar to the risk of VTE in phenolphthalein have been voluntarily withdrawn by women taking hormone replacement therapy. Other the manufacturers. side-effects were hot flashes and leg cramps.

Reference: Communication from the Pharmaceutical and Women with a history of blood clots or VTE should Medical Safety Bureau to WHO dated 27 January 1998. not use raloxifene, nor should women who are pregnant or may become pregnant, because of the Serotonin re-uptake inhibitors and potential danger to the fetus. neonatal withdrawal symptoms Reference: FDA Talk Paper, T97–62, December 1997. Australia — The selective serotonin re-uptake inhibitors (SSRIs), such as fluoxetine, fluvoxamine, Mibefradil: low heart rate and paroxetine and sertraline, are the most widely used severe interactions reported class of antidepressants in Australia. To date, over 2900 reports of adverse drug reactions have been United States of America — The Food and Drug received by health authorities, and these include Administration has advised physicians of new reactions in infants born to mothers taking this kind warnings to the product information of mibefradil, a of drug. new selective calcium antagonist which was first marketed in the United States in June 1997 and Reactions typically occur 2 to 3 days after birth and subsequently in 28 other countries throughout the involve withdrawal symptoms such as tachypnoea, world. By December 1997, some 80 000 patients irritability, jitteriness, fever, anorexia, cyanosis, fits had been treated for the drug, which is indicated for and lethargy. There have also been 4 cases in hypertension and chronic angina. breast-fed babies whose mothers were taking SSRIs. According to reports, the babies became Both the Food and Drug Administration and the agitated, unsettled or somnolent. Conditions im- manufacturer have received reports of dangerously proved immediately when the mother discontinued lowered heart rate in over 20 patients. These taking the drug. reports affected patients who had relatively low heart rates before initiating treatment, pre-existing Reference: Australian Adverse Drug Reactions Bulletin, heart disease with sinus node problems, or were Number 4, 1997. elderly healthy women. More than half of these

14 WHO Drug Information Vol. 12, No. 1, 1998 Regulatory Matters

patients were also taking another heart-rate lower- uptake of the neurotransmitters norepinephrine and ing drug such as a beta blocker. serotonin. The anti-obesity drug dexfenfluramine also inhibits re-uptake of serotonin, but additionally In addition, the warning states that there may be causes an increase in the release of serotonin from severe interactions if mibefradil is taken together the nerve cell. with some lipid-lowering drugs which may result in possibly life-threatening muscle injury. Seven The most common side-effects of sibutramine reports have been received so far associated with include dry mouth, headache, constipation and co-administration of mibefradil and simvastatin, insomnia. The drug causes a small increase in which appear more frequently than the incidence of average blood pressure and in some patients this muscle injury reported during treatment with simv- can be higher. The FDA consequently recommends astatin alone. Muscle injury may cause weakness, that patients have blood pressure monitored regu- tenderness and pain in muscles and may result in larly. Patients with uncontrolled high blood pressure rhabdomyolysis which can cause temporary or should not take sibutramine. During clinical trials, permanent damage to the kidneys. In severe cases no cases of primary pulmonary hypertension have the heart may be affected. The original labelling been reported and echocardiograms of patients also contraindicates mibefradil with astemizole, taking sibutramine did not show a higher incidence cisapride or terfenadine. This is because mibefradil of valvular disease than those on placebo. suppresses CYP3A4, a liver enzyme, and this Reference: FDA Talk Paper, T97–57, November 1997. causes drugs to accumulate in the body. It is apparent that mibefradil interferes in some way with the metabolism of lipid-lowering drugs, which Scopolamine patch to prevent are known to very rarely induce muscle injury. peri-operative nausea However, not all lipid-lowering drugs are metabo- lized in the same way and the risk of interaction United States of America — A scopolamine patch with mibefradil may be slight. Mibefradil has also has been reintroduced into the United States mar- been shown to increase blood levels of the ket. Originally approved for nausea and vomiting immunosuppressants ciclosporin and tacrolimus, associated with motion sickness, scopolamine is which also interfere with the elimination of statins. now additionally indicated for nausea and vomiting This combination should therefore be avoided. as a result of anaesthesia and pain relief medica- tion used during or after surgery. The patch is for Marketing experience so far indicates that mibe- single use only and should not be worn for more fradil seems to be particularly complicated in terms than three days. It is not indicated for children. of its interactions with other commonly prescribed cardiovascular drugs. A careful risk/benefit evalua- The most common side-effects are dryness of tion of the drug may be needed to compare it with mouth, drowsiness, and temporary blurring of use of current chemically unrelated calcium channel vision. blockers. Reference: FDA Talk Paper, T97–59, November 1997. Reference: FDA Talk Paper, T97–65, December 1997. Pemoline withdrawn New anti-obesity drug approved United Kingdom — The Committee on Safety of United States of America — The Food and Drug Medicines has withdrawn pemoline, used for the Administration has approved sibutramine for the treatment of hyperkinetic disorder, based on reports management of obesity, a widespread chronic received from the USA that there is a significant risk condition that contributes, with other risk factors, to of serious hepatic toxicity. The Committee notes the death of an estimated 300 000 Americans each that evidence of efficacy is limited and considers year. Marketing is pending subject to review by the that the risks of treatment outweigh the benefits. Drug Enforcement Administration. Reference: Current Problems in Pharmacovigilance, Sibutramine is indicated for weight loss when used Volume 23, 1997. together with a reduced calorie diet. It works to suppress the appetite primarily by inhibiting the re-

15 Regulatory Matters WHO Drug Information Vol. 12, No. 1, 1998

Melatonin on prescription only liver damage in persons who drink more than three alcoholic beverages a day. New Zealand — The Ministry of Health has classi- fied melatonin-containing products as prescription- For products containing salicylic acid, choline only medicines as there is insufficient documenta- salicylates, ibuprofen, ketoprofen, magnesium tion available on efficacy, safety and quality. A salicylate, naproxen and sodium salicylate, three number of products containing melatonin claim to or more alcoholic beverages will increase the risk cure insomnia, overcome jet-lag, delay ageing, of stomach bleeding. For products containing prolong sexual vitality, and benefit sufferers from combinations of paracetamol with other analgesic chronic diseases such as cancer (1). or antipyretic drugs, the warning calls attention to the risk of liver damage and stomach bleeding. Many other countries have regulated melatonin as a prescription-only drug (2). Although these warnings require a 90-day comment period in which the public and manufacturers can References: respond to the proposal, the FDA has requested manufacturers to voluntarily include the alcohol 1. Prescriber Update, Number 15, 1997. warning in their labelling. Pain relievers previously 2. WHO Drug Information, 10: 189 (1996). marketed as prescription drugs and now available over-the-counter have already complied with this requirement. Chlormezanone withdrawn Reference: HHS News, P97–37, November 1997. Germany — The Federal Institute for Drugs and Medical Devices has withdrawn the marketing authorization for all products containing chlorme- Nefazodone: adverse zanone, a mild tranquillizer with muscle-relaxant reaction reports properties (1). This action has been taken following information from a multicountry case-control study Sweden — The Medical Products Agency has on the risk of severe cutaneous reactions associ- analysed reports of adverse reactions to the anti- ated with this drug (2). depressant, nefazodone, which is a serotonin reuptake inhibitor. Between 1995 and 1997 almost References 2 million defined daily doses had been sold, which represented some 64 000 treatment months. 1. Pharmazeutische Zeitung, 142: 3908 (1997). 2. WHO Drug Information, 10: 137 (1996). Of the 53 adverse reactions reported, 26 were of nausea, headache, paraesthesia, myoclonia, convulsions, tics and neuropathy; 18 were gastro- Alcohol warning on over-the- intestinal reactiions; and 12 were psychic reactions. counter pain medications The Agency stated that new adverse reactions included hepatitis, dyspnoea and skin reactions. United States of America — The Food and Drug Administration has announced its intention to Reference: Information från Läkemedelsverket, Number require an alcohol warning on all over-the-counter 7, 1997. (OTC) pain medications which contain acetyl- salicylic acid, salicylates, paracetamol, ibuprofen, Daclizumab: first monoclonal ketoprofen or naproxen. antibody against transplant This follows a review by the FDA on the effect of rejection alcohol consumption in users of various OTC analgesics. The proposed warnings are aimed at United States of America — The Food and Drug alerting consumers to the specific risks incurred Administration has approved the first monoclonal from heavy alcohol consumption and its interaction antibody to help prevent acute kidney transplant with analgesics. For products containing paraceta- rejection. The product, daclizumab, was approved mol, the warning indicates that use of paracetamol for use in conjunction with a standard course of and other pain relievers may increase the risk of immunosuppressive therapy.

16 WHO Drug Information Vol. 12, No. 1, 1998 Regulatory Matters

It is estimated that, in 1996, over 11 000 people Counterfeit antimalarials detected received kidney transplants and up to 40% required additional intervention, another transplant, or dialy- Kenya — The National Quality Control Laboratory sis. Organ transplant patients must take has analysed a counterfeit antimalarial product immunosuppressants for the rest of their lives, and which contains paracetamol but does not contain risk negative side-effects from these products. In the active ingredients described on the package. addition, transplant patients are at increased risk of The packaging of the counterfeit describes the developing infections and lymphomas. It is hoped product to be Metakelfin® which normally contains that the new product will be beneficial to such pyrimethamine and sulfalene, and is marketed for patients. the treatment of malaria. The manufacturer of Metakelfin®, Pharmacia & Upjohn, has published Reference: World Drug List communicated to WHO on warning notices in the press including information 16 December 1997. that generic equivalents Betakelfin®, Malfin®, Malakelfin® and Befin® have also been detected Reboxetine not for use in elderly which are not genuine. United Kingdom — The manufacturer of the new Reference: Communication from the National Quality Control Laboratory, Nairobi, dated 11 August 1997. antidepressant, reboxetine, has removed the rec- ommended dosage for the elderly from the product information. As yet, placebo-controlled clinical trials in the elderly have not been carried out. The Euro- pean Medicines Evaluation Agency has indicated that the lack of information from placebo-controlled studies does not allow them to assess safety and efficacy for this class of patients. Reference: The Pharmaceutical Journal, 259: 796 (1997).

17 WHO Drug Information Vol. 12, No. 1, 1998

ATC/DDD Classification (final)

The following final classifications were agreed at a meeting of the WHO International Drug Utilization Working Group which took place from 29 to 30 April 1997 in Geneva. They came into force on 1 January 1998. All requests for classification should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology, P.O. Box 100, Veivet, 0518, Oslo, Norway (telephone: 00 47 22 16 9811, fax: 0047 22 16 9818, e-mail: [email protected]). The inclusion of a substance in the lists does not imply any recommendation of use in medicine or pharmacy.

ATC Level INN/common name ATC code

New ATC level codes (other than 5th level): Peripherally acting antiobesity products A08A B Drugs used in erectile dysfunction G04B E Drugs used in benign prostatic hypertrophy G04C Alpha-adrenoreceptor antagonists G04C A Testosterone-5-alpha reductase inhibitors G04C B Other drugs used in benign prostatic hypertrophy G04C X Medical gases V03A N

New ATC 5th level codes: atorvastatin C10A A05 capsaicin N01B X04 dolasetron A04A A04 donepezil N07A A05 ferric acetyl transferrin B03A B08 fexofenadine R06A X26 fluoride, combinations A12C D51 gamolenic acid, combinations D11A X52 hydroxocobalamin V03A B33 lactobacillus fermentum G01A X14 lysine B05X B03 mepartricin G04C X03 montelukast R03D C03 nelfinavir J05A E04 orlistat A08A B01 perflenapent V08D A03 *(was dodekafluroopentane) phospholipids, microspheres of V08D A04 proguanil, combinations P01B B51 rimexolone S01B A13 saruplase B01A D08 technetium (99mTc) votumumab V09I A04 temozolomide L01A X03 zolmitriptan N02C C03

* additional information

18 WHO Drug Information Vol. 12, No. 1, 1998 ATC/DDD Classification

ATC Level INN/common name ATC code

Change of name: previous: (air-filled microspheres of human albumin) new: albumin, human, microspheres of V08D A01

ATC code changes: previous new

alfuzosin G04B X02 G04C A01 alprostadil G04B X05 G04B E01 dacarbazine L01X X13 L01A X04 finasteride G04B X04 G04C B01 papaverine A03A D01 G04B E02 * (concerns formulations for intracavernous use) papaverine, comb. A03A D51 G04B E52 pygeum africanum G04B X07 G04C X01 serenoa repens G04B X09 G04C X02 tamsulosin G04B X08 G04C A02 yohimbine V03A X01 G04B E04

New DDDs:

INN/common name DDD Unit Route of ATC code administration

diclofenac combinations (* correspond 0.1 g O M01A B55 to the DDD for diclofenac) dirithromycin 0.5 g O J01F A13 fexofenadine 120 mg O R06A X26 ibutilide 1 mg P C01B D05 letrozole 2.5 mg O L02B G04 miglitol 0.3 g O A10B F02 nicotine 60 mg Inhal N07B A01 olanzapine 10 mg O N05A H03 ropinirole 6 mg O N04B C04 sertindole 16 mg O N05A E03 sumatriptan 25 mg R N02C C01 valsartan 80 mg O C09C A03

* additional information

19 WHO Drug Information Vol. 12, No. 1, 1998

ATC/DDD Classification (temporary)

The following temporary classifications were agreed at a meeting of the WHO International Drug Utilization Working Group which took place on 27 and 28 October 1997 in Oslo. Comments on, or objections to, the classification should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology, P.O. Box 100, Veivet, 0518, Oslo, Norway (telephone: 00 47 22 16 9811, fax: 0047 22 16 9818, e-mail: [email protected]) before 15 March 1998. Provided there have been no objections, the classification will come into force on 30 April 1998. A final list of classifications will be published subsequently in this journal. The inclusion of a substance in the lists does not imply any recommendation of use in medicine or pharmacy.

ATC Level INN/common name ATC code

New ATC level codes (other than 5th level): Colony stimulating factors L03A A Interferons L03A B Interleukins L03A C Nucleoside reverse transcriptase inhibitors J05A F Non-nucleoside reverse transcriptase inhibitors J05A G

New ATC 5th level codes: alteplase S01X A13 ancestim L03A A12 betamethasone S02B A07 capecitabine L01B C06 cerivastatin C10A A06 copper usnate G01A X15 daclizumab L04A A08 desogestrel G03A C09 entacapone N04B X02 etonogestrel G03A C08 fibrinogen, human B02B C10 glatiramer acetate L04A A07 grepafloxacin J01M A11 haemoglobin crosfumaril B05A A08 heparinoid, combinations C05B A51 magnesium pyridoxal 5-phosphate glutamate C10A X07 nucleoside reverse transcriptase inhibitors, combinations J05A F30 phentolamine G04B E05 rituximab L01X X20 sodium phenylbutyrate A16A X03 tasosartan C09C A05 technetium (99mTc) apcitide V09G A07 tolterodine G04B D07 vorozole L02B G05

Change of name: previous: (cytokines) new: colony stimulating factor L03A A

20 WHO Drug Information Vol. 12, No. 1, 1998 ATC/DDD Classification

ATC Level INN/common name ATC code ATC code changes: previous new apomorphine V03A B07 N04B C07 didanosine J05A B07 J05A F02 interferon alfa L03A A04 L03A B01 interferon beta L03A A11 L03A B02 interferon gamma L03A A08 L03A B03 interleukin-2 L03A A01 L03A C01 lamivudine J05A B10 J05A F05 milnacipran N06A A24 N06A X17 nevirapine J05A X03 J05A G01 poly I:C L03A A05 L03A X07 poly ICLC L03A A06 L03A X08 stavudine J05A X04 J05A F04 terazosin C02C A05 G04C A03 thymopentin L03A A07 L03A X09 trimetazidine C01D X17 C01E B14 venlafaxine N06A A22 N06A X16 zalcitabine J05A B08 J05A F03 zidovudine J05A B05 J05A F01

New DDDs: INN/common name DDD Unit Route of ATC code administration atorvastatin 10 mg O C10A A05 azathioprine 150 mg O, P L04A X01 cerivastatin 0.2 mg O C10A A06 ciclosporin 250 mg O, P L04A A01 dolasetron 200 mg O, P A04A A04 donepezil 7.5 mg O N07A A05 estradiol 1 mg TD gel G03C A03 etonogestrel 67 µg SC impl. G03A C08 ginkgo biloba 120 mg O N06B X19 indinavir 2.4 g O J05A E02 lercanidipine 10 mg O C08C A13 mibefradil 75 mg O C08C X01 mizolastine 10 mg O R06A X25 muromonab-CD3 5 mg P L04A A02 mycophenolic acid 2 g O L04A A06 naratriptan 2.5 mg O N02C C02 ritonavir 1.2 g O J05A E03 stavudine 80 mg O J05A F04* tacrolimus 5 mg O, P L04A A05 tiagabine 30 mg O N03A G06 Change of DDD: etidronic acid (based on 400 mg O M05B A01 treatment of osteoporosis) risperidone 5 mg O N05A X08 topiramate (based on combination therapy) 300 mg O N03A X11 zidovudine 0.6 g O, P J05A F01° ° temporary ATC code

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