WHO DRUG

INFORMATION

VOLUME 9 • NUMBER 1 • 1995

WORLD HEALTH ORGANIZATION • GENEVA WHO DRUG INFORMATION

WHO Drug Information provides an overview of topics relating to drug development and regulation that are of current relevance and importance, and includes the lists of proposed and recommended International Nonproprietary Names for Pharmaceutical Substances (INN). Its contents reflect, but do not present, WHO policies and activities and they embrace socioeconomic as well as technical matters.

The objective is to bring issues that are of primary concern to drug regulators and pharmaceutical manufacturers to the attention of a wide audience of health professionals and policy-makers concerned with the rational use of drugs. In effect, the journal seeks to relate regulatory activity to therapeutic practice. It also aims to provide an open forum for debate. Invited contributions will portray a variety of viewpoints on matters of general policy with the aim of stimulating discussion not only in these columns but wherever relevant decisions on this subject have to be taken.

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© World Health Organization 1995

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ISSN 1010-9609 Volume 9, Number 1, 1995 World Health Organization, Geneva

WHO Drug Information

Contents

General Policy Topics Hydroxyurea and sickle-cell disease: encouraging response in a multicentre study 26 Socially-responsive development of medicines Progress in managing beta-thalassaemia: iron II. Antibiotics in eclipse 1 chelation and beyond 28 Personal Perspectives Regulatory Matters OTC advertising: in whose interest? 10 Cyproterone acetate and hepatic reactions 30 High-potency pancreatins and bowel strictures 30 Reports on Individual Drugs Metformin gains approval in USA 30 Commensal enterobacteria and prevention of New requirements for paediatric labelling 32 rotavirus diarrhoea 14 Pimozide and cardiac arrhythmias 32 Saccharomyces boulardii: a valuable adjunct HIV test using oral fluid samples 33 in recurrent Clostridium difficile disease? 15 Naltrexone approved as an adjunct in the ACE inhibitors and non-diabetic chronic renal treatment of alcoholism 33 failure 16 Use of quinacrine for female sterilization Oral contraceptives and breast cancer: more arouses concern 33 insight into a complex association 18 Clozapine and myocarditis 34 DMPA and breast cancer: a largely reassuring analysis 20 Essential Drugs An antistreptococcal vaccine to prevent Rheumatoid arthritis 35 rheumatic fever? 22 Acetylsalicylic acid 36 Fluconazole and cryptococcal meningitis 23 Ibuprofen 37 Corrigendum 24 Indometacin 38 Chloroquine 39 General Information Penicillamine 40 Acinetobacter. a paradigm for hospital- Sulfasalazine 40 acquired infection 25 Methotrexate 41 Prednisolone 42

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WHO Drug Information Vol. 9, No. 1, 1995

General Policy Topics

Socially-responsive development of medicines

Never has it been more important, during the evolution of modern medicine, to take stock of the challenges ahead. In two short decades, confidence that infections and transmissible disease could be effectively contained has been replaced by apprehension about the emergence of new infections and of multidrug-resistant organisms.

The antibiotic era may be in irreversible decline. Defensive strategies that embrace both public and private sector interests need to be developed as a matter of urgency.

The following commentary is part II of a series on different aspects of the underlying situation.

John Dunne, Editor WHO Drug Information

the single most significant public health achieve­ II. Antibiotics in eclipse ment of the past century (1). Bacterial resistance in Within the developed world, there is already a whole generation of clinicians for whom acute bac­ the hospital environment terial disease has posed little, if any, therapeutic The basis of concern challenge. With the advent of the first generation of antibiotic preparations in the 1940s, many infec­ Throughout the early decades of this century, infec­ tions — previously potentially lethal — became tious bacterial disease was the principal cause of curable with an immediacy that invited compla­ death in every country. Hospitals were populated cency (2). It was inevitable that the impressive with patients, young and old, many of whom were efficacy and safety of antibiotics should come to be to die from acute bacterial infections including taken for granted. The consequences of this diphtheria, pneumonia, meningitis, typhoid fever, septicaemia, endocarditis and miliary tuberculosis. attitude are manifest. Antibiotics have become Others were admitted with tertiary syphilis, widely and often inappropriately used in community rheumatic heart disease and other delayed, practice to treat minor intercurrent infections (3). terminal complications of bacterial infections. They are intensively used in hospitals both to treat and protect patients against nosocomial infections. Outside the sphere of human medicine, they are All of this changed as living standards improved, used in enormous quantities to support intensive public health services developed and, most stock rearing in farms and fisheries (4, 5). reassuringly, as these infections became im­ mediately responsive to antibiotics. UN statistics By 1983, the total world market in antibiotics was indicate that, over the past half century, public estimated to approach US$ 9 billion annually (6), health and socioeconomic development has and the projection that these costs will rise some resulted in an unprecedented increase in life fivefold by the turn of the century may already have expectancy. In Europe, this has risen from 65 to been exceeded (7). Within the United Kingdom, for 74 years, in South America from 51 to 65 years, in example, the total cost of antibiotics prescribed Asia from 41 to 65 years, and in Africa from 38 to within the national health service rose fourfold to 52 years. Much of this improvement has been the equivalent of some US$ 600 million between attributed to reduction of deaths from infectious 1980 and 1991 (8). Much of this rise reflects disease — a success that has been described as increasing use of recently-developed, highly-

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expensive antibiotics. This trend, in turn, has been bacteria by disrupting the integrity of the outer cell driven by recognition that widespread and inten­ wall. Most other widely-used antibiotics prevent sive use of first-line antibiotic agents has favoured bacterial growth by inhibiting one or more vital the emergence of resistance to these less-costly steps in protein synthesis. products. Inherent, genetically-determined resistance to anti­ For too long the assumption has been commonly biotics is common among bacterial species. By held by clinicians — and often fostered by manu­ definition, a narrow-spectrum antibiotic is lethal to facturers — that resistance might be countered relatively few pathogenic species. The remainder indefinitely by the development of new generations are inherently resistant for a variety of reasons (16). of antibiotic substances. This complacent view no They may lack receptor configurations to which the longer holds any vestige of legitimacy. Over the antibiotic can attach; they may be relatively im­ past few years, strains of many highly pathogenic permeable to the antibiotic or actively extrude it; species resistant to all widely-available antibiotics they may inactivate it by producing a detoxifying have emerged and proliferated at rates that were enzyme; or they may lack a metabolic pathway that never envisaged (9-13). is the prime target of the antibiotic.

Bacteria have evolved with a diversity that has The emergence of secured their success in virtually every environment capable of supporting life. It seems prudent, given newly-resistant strains this capability, to accept the worst case hypothesis The facility with which many initially susceptible — that natural selection of resistant strains is an bacteria can acquire one or more mechanisms of inevitable corollary to sustained antimicrobial resistance to a widely-used antibiotic is now all too pressure — and to plan accordingly. It is still not evident. Indeed, it seems probable that all bacteria generally appreciated, even within the scientific possess an inherent flexibility that enables them, community, that organisms commonly responsible sooner or later, to evolve genes rendering them for respiratory infections, diarrhoea, urinary resistant to any antibiotic (13). The emergence of infections and sepsis are now often resistant to all resistant strains results from the operation of widely-available first-line antibiotics. Meanwhile, "selection pressure" — or the preferential survival of newly developed alternative products remain resistant variants within the population of bacteria prohibitively expensive for public sector use in exposed to the antibiotic. The time frame of such many countries. In the United States alone, the cost events varies considerably but, once formed, such of treating hospital-acquired drug-resistant strains tend to spread rapidly within the species. infections is now estimated to add as much as US$ 4.5 billion annually to the cost of health care Within a few years of the introduction of penicillin in (14, 15). the 1940s, resistant isolates of Staphylococcus aureus and Neisseria gonorrhoeae had become widespread (17, 18). In contrast, penicillin Mechanisms of bacterial resistance resistance was not described in Haemophilus Antibiotics are essentially substances produced and influenzae or Streptococcus pneumoniae until three extruded by bacteria that inhibit the growth of to four decades later (19-21). As yet, group A beta¬ microbes competing in their natural habitat. By haemolytic streptococci remain fully sensitive to common usage, however, the definition has been penicillin. However, recently reported erythromycin- extended to include systemically-administered resistant strains have created a recognition that synthetic antimicrobial substances, including the penicillin resistance could emerge in these sulfonamides, quinolones, trimethoprim, and potentially highly dangerous species at any time several anti-tuberculosis drugs. (22).

The unifying characteristic of all medicinal anti­ Initially, it was assumed that resistant strains biotics is that, whereas they disrupt specific emerge simply as a result of chromosomal mutation metabolic processes vital to the growth of bacteria, or inductive expression of a latent chromosomal they are largely innocuous to higher forms of life. At gene. However, mutational change could not ac­ the same time, they are highly diverse in the count for the sudden and simultaneous acquisition mechanisms by which they inactivate susceptible of resistance to several different antibiotics, which bacteria. Penicillins, cefalosporins and the glyco¬ has been observed repeatedly over the past peptide antibiotics (vancomycin and teicoplanin) kill decade in many bacterial species. The ominous

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explanation is that genes determining resistance to USA, such organisms are claimed to be responsible one or several antibiotics can be transferred from for 60 000 to 70 000 deaths each year (31, 32). organism to organism — and sometimes from Initially, they were found only in larger regional and species to species — packaged in teaching hospitals. They are now widespread in extrachromosomal structures known as plasmids smaller units and nursing homes (33) where meti¬ (23, 24) or in loops of DNA called transposons that cillin-resistant strains of Staphylococcus aureus are move reversibly between plasmids and chromo­ proving particularly difficult to eradicate (34, 35). somes (25). Staphylococcal disease Although assumptions were initially made that Drug-resistant strains of S. aureus are now among plasmid-mediated resistance would be unstable, the most life-threatening organisms in the hospital experience now suggests otherwise. Indeed, environment. They are a foremost cause of skin multidrug-resistant strains of pneumococci have and wound infections, and of bacteraemias; they been shown to remain stable in vitro over hundreds are responsible for many lower respiratory tract of generations (26). Nor is there persuasive infections, for infections arising around indwelling evidence to support the view that the genetic load catheters and prosthetic devices, and for cases of implicit in the acquisition of multiple resistance menstrual toxic shock. genes attenuates pathogenic virulence (11). Susceptible and resistant strains of staphylococci, When antibiotics first became widely available in for example, have been reported to be fully capable the early 1950s, staphylococci were fully sus­ of producing toxin and of causing disease (27). ceptible to penicillin, tetracycline and erythromycin. Within a decade, however, strains resistant to each The practical implications of this knowledge have of these substances were widespread. First to been succinctly summarized in the following way emerge were beta-lactamase-producing isolates of (13): "Once a resistant strain emerges, there are Staphylococcus aureus. The enzymes produced by mechanisms by which such an advantageous these organisms inactivated the beta-lactam change may be passed on to subsequent genera­ nucleus of naturally-occurring penicillins and the tions and to unrelated bacteria. Indeed, when a new early broad-spectrum derivatives (16). The situation type of drug resistance is noticed through a patient was temporarily assuaged during the 1970s as a failing to respond to drug treatment, it is unlikely result of the introduction of meticillin and other that the resistance will have evolved in that patient. semi-synthetic penicillins containing a modified The initial mutation may well have occurred beta-lactam nucleus which was not a substrate for elsewhere, often in a different type of bacterium, beta-lactamases (36). Within a decade, however, and the new gene may have become quite strains resistant to meticillin, resulting from the widespread throughout the bacterial world by the expression of cell-wall binding proteins with a low time it is detected" (28). affinity for penicillin, became widespread both in Europe and North America (37-39). Prevalence of resistant strains in hospitals Several distinct strains of Staphylococcus aureus Because it is in hospitals that antibiotics are most have developed this mechanism of resistance, intensively used, it is here that resistance is most which is of considerable importance because it is highly prevalent. Estimates applicable to the United operative against all beta-lactam antibiotics States (29) and the United Kingdom (30) indicate including penicillins, cefalosporins, carbapenems that 5-10% of patients acquire an infection during and penems (40). In some of the strains now an admission to hospital. During 1992, some two epidemic, the responsible gene is chromosomal million such infections were recorded in the United rather than plasmid-borne, and these are presumed States alone (31). Most of these infections are to be highly stable. Moreover, other resistance caused by widely-distributed commensal genes frequently carried on the same chromosome organisms, notably staphylococci, enterococci, extend this spectrum of resistance to other anti­ enterobacteria, streptococci, and Klebsiella biotics including erythromycin, tetracyclines, species. minocycline, streptomycin, spectinomycin, sulfon­ amides and fusidic acid (16). In the United Kingdom, it is estimated that some two-thirds of Increasingly, these hospital-acquired (or noso­ S. aureus outbreaks in hospitals now involve multi- comial) infections are caused by drug-resistant resistant strains of this nature (41). strains of bacteria that are difficult to control. In the

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The only agents now reliably effective against these Enterobacteria organisms are the two glycopeptide antibiotics, Among the aerobic Gram-negative enterobacteria, vancomycin and teicoplanin, which block the syn­ Escherichia coli remains the most prevalent single thesis of bacterial cell walls by binding to the cause of urinary tract infections, pyelonephritis, and terminus of peptide stems (42). In the United hospital-acquired bacteraemia. More recently, States, many large hospitals now spend 10-15% of Klebsiella, Serratia, Proteus and Enterobacter have their total pharmaceutical budget on vancomycin emerged as important causes of hospital-acquired alone (11, 15). If vancomycin-resistant strains were infections, and many strains are now resistant to to emerge and spread — a highly tangible risk that multiple antibiotics (38). is ever present — some of the most prevalent noso­ comial infections would become virtually unbeat­ Strains of E. coli clinically resistant to ampicillin and able. It is ominous that widespread use of this vital cefalosporins commonly contain a gene which antibiotic has already resulted in the emergence of strongly promotes expression of beta-lactamase. vancomycin-resistance in enterococci (43-45) — Although this gene is chromosomal in its location, particularly since vancomycin resistance in Entero¬ its structure suggests that it may initially have been coccus faecium, which is plasmid-mediated, has transmitted from Shigella (49). Some of these been transferred by conjugation in the laboratory to strains are resistant to ampicillin, even in the Gram-positive cocci (46). Vancomycin resistance presence of one of the specific beta-lactamase could thus well spread by this mechanism not only inhibitors, clavulanate or sulbactam (16). Moreover, to S. aureus, but to other major pathogens including they have become so widely distributed in develop­ group A and B streptococci and Streptococcus ed and developing countries that first-line antibiotics pneumoniae (13). are now seldom useful in urinary tract and other infections attributed to E. coli (16). Enterococci Enterococci were once recognized simply as The beta-lactamases generated by other Gram- commensals prominent in the gut flora. In recent negative organisms are usually plasmid-mediated years they have become — after S. aureus and (50). The most prevalent of these enzymes confers Escherichia coli— the third most prevalent cause resistance to penicillins and second generation of hospital-acquired infections in the United States cefalosporins, but not to the broad-spectrum cefalo­ (11, 47). Enterococcus faecalis — and to a lesser sporins, cefamycins, monobactams and carba¬ extent E. faecium — account for many cases of penems. However, a more recently identified and endocarditis and of urinary tract, wound, abdominal widely dispersed variant commonly associated with and pelvic infections. Because enterococci have nosocomial isolates of Klebsiella pneumoniae pronounced inherent resistance to many antibiotics, (51-54) inactivates a wider spectrum of antibiotics, these infections have always been difficult to treat. including broad-spectrum cefalosporins and The standard regimen has been a synergistic monobactams. combination of a penicillin and an aminoglycoside: penicillin increases the permeability of the bac­ As yet, these isolates remain susceptible to the terium to the aminoglycoside, which can then cefamycins, cefoxitin and cefotetan. However, accumulate in lethal amounts within the periplasmic given the frequency with which similar mutant space (16). enzymes have been selected by exposure to broad- spectrum cefalosporins under laboratory conditions Increasingly, however, hospital isolates have be­ (55-57), the clinical introduction of new cefalo­ come resistant to beta-lactam antibiotics, tetracyc­ sporins and other beta-lactam antibiotics seems line, chloramphenicol, aminoglycosides and fluoro­ destined inevitably to favour selection of beta- quinolones. Vancomycin, held in reserve to treat lactamases with ever wider spectra of activity (58). these resistant strains, remained reliably effective It is portentous that one well-characterized enzyme until the 1980s. Within the past decade, infections not only extends the spectrum of activity to resulting from strains resistant not only to penicillin embrace the cefamycins; it is also resistant to the and aminoglycosides but also to vancomycin have lactamase inhibitors, clavulanic acid and sulbactam been reported which are essentially untreatable (59). (48). Thus far, these multidrug-resistant strains are uncommon, but death rates exceeding 30% have Consequential efforts have been made to develop been reported in outbreaks of bacteraemic antibiotics with specific activity against beta- infections in which they have been implicated (11). lactamase-producing organisms. These have

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resulted in the introduction of imipenem and other sive to penicillins, but beta-lactamase-producing carbapenems, a class of broad-spectrum beta- strains are now reported to be widespread (16). lactam antibiotics resistant to known clinically- Potent beta-lactamase activity is also evident in relevant beta-lactamases. However, this success strains of B. fragilis, the major anaerobe in the large has been tempered by the discovery of an enzyme bowel, while strains of a closely-related species, B. capable of hydrolysing these antibiotics which is thetaiotaomicron hydrolyse highly beta-lactamase expressed by chromosomal genes in strains of stable compounds, including cefoxitin and even several Enterobacteriaceae species — including E. imipenem and other carbapenems (60). The cloacae, Bacteroides fragilis, Serratia marcescens, disturbing possibility exists that the responsible and virtually all isolates of Xanthomonas maltophilia gene may eventually be transferred to E. coli and (60-62). other potentially pathogenic enterobacteria (16). Some organisms, notably Pseudomonas aeru­ ginosa, have developed resistance to beta-lactams The outlook through other genetically-determined mechanisms. For as long as present trends prevail — and there These have resulted in expression of binding are no means immediately in prospect of creating proteins with reduced affinity for penicillin (63-64) radical change — strains of pathogenic bacteria and in loss of an outer membrane protein which resistant to all available therapy are at risk of provides a channel for the entry of beta-lactam emerging within the hospital environment under the antibiotics into the periplasmic space (65). Some pressure of antibiotic use. The very real possibility strains of P. aeruginosa and P. cepacia are now of vancomycin resistance emerging in a meticillin- additionally resistant to the carbapenems. Not only resistant strain of S. aureus, or of resistance to do these strains produce substantial amounts of carbapenems spreading more widely among the beta-lactamase, they are also essentially aerobic, Gram-negative enterobacteria would have impermeable to beta-lactam antibiotics. particularly serious implications for the safety of patients in hospitals. Analogous depletion of specific binding sites has resulted in many strains of P. aeruginosa and But precisely which patients are at risk? In the P. cepacia becoming comparably resistant to Nordic countries, it seems, "mainly immune- fluoroquinolone antimicrobials (66, 67) and to compromised people are involved, especially those aminoglycosides (68, 69). This resistance even who have a long history of treatment with anti- extends to amikacin, a semi-synthetic derivative of bacterials" (74). This implies that multidrug-resistant kanamycin designed to provide a poor substrate for hospital bacteria are essentially opportunistic the various enzymes that mediate resistance to pathogens dangerous only to the most vulnerable aminoglycosides in staphylococci (70) and of patients. However, to return to the example of enterococci (71). staphylococci, this has not been the experience in the United States (27, 75, 76), or even in the United Increasingly, unbeatable Pseudomonas infections Kingdom (78-80). In these countries meticillin are causing deaths within intensive care units (16) resistance is not considered to be a correlate for and in patients with cystic fibrosis or other either virulence or spread in staphylococci: some, conditions that render them vulnerable to infection but by no means all such strains of staphylococci, (72). A closely related organism, Xanthomonas possess each of the acknowledged virulence maltophilia — formerly known as Pseudomonas factors, have epidemic potential, and may cause maltophilia — has similarly been implicated in such severe infections (36). outbreaks in units where imipenem has been extensively used. Such deaths have also been Within the United Kingdom, the cost of treating attributed to Acinetobacter, a common skin com­ infections caused by these strains and of con­ mensal, only recently identified as an important taining endemic outbreaks in the worst affected cause of nosocomial disease (73). (See p. 25). hospitals is already recognized to be an onerous charge on the public health budget (36). Similarly, Anaerobic bacteria within the United States, it has been estimated that Bacteroides species and other anaerobic bacteria in some intensive-care units, patients now have a that reside in the mouth are a frequent cause of 25-70% risk of acquiring a nosocomial infection, aspiration pneumonia in vulnerable patients. and that most of these are caused by multidrug- Initially, these infections were consistently respon­ resistant organisms (11, 29, 32).

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To what extent drug-resistant organisms are needed that can be obtained only through prevalent within hospitals in developing countries is increased investment in basic research (11, 58). unclear. It is commonly assumed that "infections Yet economic circumstances are eroding such caused by multiple resistant strains are rife through­ investment, both in the public and the private out the developing world" (13, 80). It is evident that sectors (11). emergence of resistance is favoured wherever chronic shortage of antibiotics results in under­ There is a case also to be made for a basic re­ dosing, where lack of microbiological laboratories orientation of antibiotic prescribing strategy within results in blind prescribing, and where lack of hospitals. The emphasis over the past decade — reserve agents augments the risk of therapeutic during which the current crisis has developed — failure. It would be illogical to contend, however — has been to favour the use of products with a broad within the context of hospital-acquired infections — antibacterial spectrum. These provide a certain that less-developed countries serve as a reservoir margin of security for patients seriously ill with an of multidrug-resistant hospital pathogens. These undiagnosed infection. By the same token, when strains are likely to emerge only in institutions they are extensively used, they also exert signifi­ where expensive reserve antibiotics are used on cant selection pressure on an increasing number such a scale as to generate the necessary selection and variety of potential pathogens. This, it is pressure. argued, points to a need for new types of anti­ microbials, each with a narrow spectrum of activity, Developing countries desperately need hospital which are intended to be held in reserve as microbiological laboratories, reliable supplies of strategic tools to contain specific drug-resistant first-line and reserve antibiotics, and effective organisms (10, 11). Breakthroughs, it has been clinical and laboratory surveillance systems. This suggested, might be possible not only with new need, however, is generated by their concern to antibiotic substances but also with synthetic agents, serve their own populations and to overcome high conceptually similar to the beta-lactamase levels of resistance to first-generation antibiotics, inhibitors, clavulanic acid and sulbactam, designed and not because they pose an illusory threat as a to block specific receptor mechanisms (82). source of newly-emerging resistant strains to other countries. The challenge is formidable. If technological pro­ gress is to be made within a time frame that reflects The containment of hospital-acquired infections is the urgency of the situation, a political climate must based everywhere upon the application of a well- be fostered immediately that will encourage an validated set of general principles which, in some alliance among the major interest groups, including countries, has long been codified (3). These stress governments, academia and research-based two complementary needs (81): pharmaceutical companies (83). An environment must be created in which valid concerns about the • the importance of developing, within every need for cost containment in the provision of hospital, a simple and flexible antibiotic- medical services are balanced by the recognition prescribing policy on a disease-specific basis, that continued investment in innovative research is relying whenever possible on knowledge of required simply to conserve the hard-won gains of prevailing antibiotic sensitivity patterns and the past. controlled use of reserve antibiotics; and References • the institution of rigorous standards of hygiene, 1. US Department of Health and Human Services. Healthy barrier nursing and, whenever appropriate, bed people 2000: national health promotion and disease isolation. prevention objectives. DHSS Publication No. (PHS) 91- 50213, US Government Printing Office, 1990. In the longer term, such measures are manifestly no more than palliative. Meanwhile, fears are being 2. Lederberg, J. Medical science, infectious disease, and realized of a crisis in the management of acute the unity of humankind. Journal of the American Medical infections. Innovative approaches need to be Association, 260: 684-685 (1988). explored. Experience with the beta-lactam anti­ 3. Marr, J., Moffet, H., Kunin, C. Guidelines for improving biotics and the aminoglycosides indicates that the use of antimicrobial agents in hospitals: a statement much more is needed than the introduction of by the Infectious Diseases Society of America. Journal of variants of antibiotics already compromised by the Infectious Diseases, 157: 869-876 (1988). emergence of resistant strains. New insights are

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4. DuPont, H., Steele, J. Estimating worldwide current 18. Dougherty, T. Genetic analysis and penicillin-binding antibiotic usage: report of Task Force I. Reviews of protein alterations in Neisseria gonorrhoeae with chromo¬ Infectious Diseases, 9 (suppl 3): 232-243 (1987). somally-mediated resistance. Antimicrobial Agents and Chemotherapy, 30: 649-652 (1986). 5. National Academy of Science/Institute of Medicine. Committee on Human Health Risk Assessment of Using 19. Mendelman, P., Chaffin, D., Kalaitzoglu, G. Penicillin- Subtherapeutic Antibiotics in Animal Feed. Human health binding proteins and ampicillin resistance in Haemophilus risks with the subtherapeutic use of penicillin or tetra­ influenzae. Journal of Antimicrobial Chemotherapy, 25: cycline in animal feed. National Academy Press, 525-534 (1990). Washington, D.C. 1989. 20. Needham, C. Haemophilus influenzae: antibiotic 6. Liss, R., Batchelor, F. Economic evaluations of anti­ susceptibility. Clinical Microbiological Reviews, 1: 218-227 biotic use and resistance — a perspective. Reviews of (1988). Infectious Diseases, 9 (suppl 3): 297-312 (1987). 21. Klugman, K. Pneumococcal resistance to antibiotics. 7. Col, N., O'Connor, R. Estimating worldwide current Clinical and Microbiological Reviews, 3: 171-196 (1990). antibiotic usage: report of Task Force I. Reviews of Infectious Diseases, 9: 447-460 (1987). 22. Seppälä, H., Nissenen, A., Jävenen, H. et al. Resistance to erythromycin in group A streptococci. New 8. British Society for Antimicrobial Chemotherapy, General England Journal of Medicine, 326: 292-297 (1992). Practice Working Group. Community antibiotic usage in England and Scotland from 1980 to 1993. As quoted in: 23. Jacoby, G., Swartz, M. Plasmids: microbiologic and Diseases fighting back: the growing resistance of TB and clinical importance. Seminars on Infectious Diseases, 3: other bacterial diseases to treatment. Parliamentary Office 1-37 (1980). of Science and Technology, London, 1994. 24. Foster, T. Plasmid-determined resistance to anti­ 9. Lederberg, J., Shope, R., Oaks, S. eds. Emerging microbial drugs and toxic metal ions in bacteria. Micro­ infections: microbial threats to health in the United States. biological Reviews, 47: 361-409 (1983). National Academy Press, Washington, D.C. 1992. 25. Shapiro, J. ed. Mobile genetic elements. Academic 10. Cohen, M. Epidemiology of drug resistance: implica­ Press, New York, 1983. tions for a post-antimicrobial era. Science, 257: 1050- 1055 (1992). 26. Jabes, D., Nachman, S., Tomasz, A. Penicillin-binding protein families: evidence for the clonal nature of penicillin 11. Tomasz, A. Multiple-antibiotic-resistant pathogenic resistance in clinical isolates of pneumococci. Journal of bacteria: a report on the Rockefeller University Workshop. Infectious Diseases, 159: 16-25 (1989). New England Journal of Medicine, 330: 1247-1251 (1994). 27. Muder, R., Brennen, C, Wagener, M. et al. Methicillin- resistant staphylococcal colonization and infection in a 12. Tonks, A. Drug resistance is a worldwide threat. long-term care facility. Annals of Internal Medicine, 114: British Medical Journal, 309: 1109 (1994). 107-112 (1991).

13. Diseases fighting back— the growing resistance of 28. O'Brien, T. Global surveillance of antibiotic resistance. TB and other diseases to treatment. Parliamentary Office New England Journal of Medicine, 326: 339-340 (1992). of Science and Technology, London, 1994. 29. Wenzel, R. The mortality of hospital-acquired 14. Public Health Focus: surveillance, prevention, and bloodstream infections: need for a new vital statistic? control of nosocomial infections. Morbidity and Mortality International Journal of Epidemiology, 17: 225-227 (1988). Weekly Report, 41: 783-787 (1992). 30. Hospital Infection Society. Second National 15. McGowan, J. Antibiotic resistance in hospital bacteria: Prevalence Survey of Infections in Hospitals. Third current patterns, modes for appearance or spread, and International Conference of the Hospital Infection Society. economic impact. Reviews of Medical Microbiology, 2: Press Release, 8 September 1994. 161-169 (1991). 31. Centers for Disease Control. Public Health Focus: 16. Neu, H. The crisis in antibiotic resistance. Science, surveillance, prevention and control of nosocomial 257:1064-1073 (1992). infections. Morbidity and Mortality Weekly Report, 41: 873-877 (1992). 17. Lyon, B., Skurray, R. Antimicrobial resistance of Staphylococcus aureus: genetic basis. Microbiological 32. Leu, H-S., Kaiser, D., Mori, M. et al. Hospital-acquired Reviews, 51: 88-134 (1987). pneumonia: attributable mortality and morbidity. American Journal of Epidemiology, 129: 1258-1267 (1989).

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33. Emori, T., Gaynes, R. An overview of nosocomial 47. Handwerger, S., Raucher, B., Altarac, D. et al. infections, including the role of the microbiological Nosocomial outbreak due to Enterococcus faecium highly laboratory. Clinical Microbiological Reviews, 6: 428-442 resistant to vancomycin, penicillin, and gentamicin. (1993). Clinical Infectious Diseases, 16: 750-755 (1993). 34. Johnson, A., Woodford, N. Bacterial antibiotic 48. Woodford, N. Antimicrobial resistance amongst resistance. Current Opinion in Infectious Diseases, 6: enterococci isolated in the UK: a reference laboratory 515-519 (1993). perspective. Journal of Antimicrobial Chemotherapy, 32: 344-346 (1993). 35. Duckworth, G. Diagnosis and management of methicillin-resistant Staphylococcus aureus infection. 49. Olsson, O., Bergström. S., Lindberg, F., Normark, S. British Medical Journal, 307: 1049-1052 (1993). ampC beta-lactamase hyperproduction in Escherichia coli: natural ampicillin resistance generated by horizontal 36. McDougal, K., Thornsberry, C. The role of beta- chromosomal DNA transfer from Shigella. Proceedings of lactamase in staphylococcal resistance to penicillinase- the National Academy of Sciences, USA. 80: 7556-7560 resistant penicillins and cephalosporins. Journal of Clinical (1983). Microbiology, 23: 832-839 (1986). 50. Medeiros, A. Plasmid-determined beta-lactamases. 37. Borowski, J., Kamienska, K., Ruteka, I. Methicillin- In: Bryan, L. ed. Microbial resistance to drugs. Handbook resistant staphylococci, British Medical Journal, 1: 983 of Experimental Pharmacology. Volume 91, pp 101-127. (1964). Springer-Verlag, Berlin. 1989. 38. Tenover, F. Novel and emerging mechanisms of anti­ 51. Knothe, H., Shah, P., Kreméry, V. et al. Transferable microbial resistance in nosocomial pathogens. American resistance to cefotaxime, cefoxitin, cefamandole and Journal of Medicine, 91 (suppl. 3B): 76-81 (1991). cefuroxime in clinical isolates of Klebsiella pneumoniae and Serratia marcescens. Infection, 11: 315-317 (1983). 39. Wenzel, R., Nettleman, M., Jones, R., Pfaller, M. Methicillin-resistant Staphylococcus aureus: implications 52. Kliebe, C, Nies, B., Meyer, J. et al. Evolution of for the 1990s and effective control measures. American plasmid-coded resistance to broad-spectrum cephalo­ Journal of Medicine, 91 (suppl. 3B): 221-227 (1991). sporins. Antimicrobial Agents and Chemotherapy, 28: 302-307 (1985). 40. Pierre, J., Williamson, R., Bornet, M., Gutmann, L. 53. Philippon, A., Labia, R., Jacoby, G. Extended- Presence of an additional penicillin-binding protein in spectrum beta-lactamases. Antimicrobial Agents and methicillin-resistant Staphylococcus epidermis, Staphylo­ Chemotherapy, 33: 1131-1136 (1989). coccus haemolyticus, Staphylococcus hominis and Staphylococcus simulans with a low affinity for methicillin, 54. Philippon, A., Ben Redjeb, S., Fournier, G., Ben cephalothin, and cefamandole. Antimicrobial Agents and Hassan, A. Epidemiology of extended spectrum beta- Chemotherapy, 34: 1691-1694 (1990). lactamases. Infection, 17: 347-354 (1989).

41. Marples, R., Reith, S. Methicillin-resistant S. aureus in 55. Kliebe, C, Nies, B., Meyer, J. et al. Evolution of England and Wales, CDR Review, 2: R25-R29 (1992). plasmid-coded resistance to broad-spectrum cephalo­ sporins. Antimicrobial Agents and Chemotherapy, 28: 42. Reynolds, P. Structure, biochemistry and mechanism 302-307 (1985). of action of glycopeptide antibiotics. European Journal of 56. Gutmann, L, Kitzis, M., Billot-Klein, D. et al. Plasmid- Clinical Microbiology and Infectious Diseases, 8: 943-950 mediated beta-lactamase (TEM-7) involved in resistance (1990). to ceftazidime and aztreonam. Reviews of Infectious 43. LeClerq, R., Derlot, E., Duval, J., Courvalin, P. Plas¬ Diseases, 10: 860-866 (1988). mid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. New England Journal of Medicine, 57. Sougakoff, W., Goussard, S., Gerbaud, G., Courvalin, 319: 157-161 (1988). P. Plasmid-mediated resistance to third-generation cephalosporins caused by point mutations in TEM-type 44. Uttley, A., Collins, C, Naidoo, J., George, R. Vanco¬ penicillinase genes. Reviews of Infectious Diseases, 10: mycin-resistant enterococci. Lancet, 1: 57-58 (1988). 879-884 (1988). 45. Sahm, D., Kissinger, J., Gilmore, M. et al. In vitro 58. Jacoby, G., Archer, G. New mechanisms of bacterial susceptibility studies of vancomycin-resistant Enterococ­ resistance to antimicrobial agents. New England Journal cus faecalis. Antimicrobial Agents and Chemotherapy, 33: of Medicine, 324: 601-612 (1991). 1588-1591 (1989). 59. Papanicolaou, G., Medeiros, A., Jacoby, G. Novel 46. Noble, W., Virani, Z., Cre, R. Co-transfer of vanco­ plasma-mediated beta-lactamase (MIR-1) conferring mycin and other resistance genes from Enterococcus resistance to oxyimino- and alfa-methoxy beta-lactams in faecalis NCTC 12201 to Staphylococcus aureus. FEMS clinical isolates of Klebsiella pneumoniae. Antimicrobial Microbiology Letter, 72: 195-198 (1992). Agents and Chemotherapy, 34: 2200-2209 (1990).

8 WHO Drug Information Vol. 9, No. 1, 1995 General Policy Topics

60. Jacoby, G., Medeiros, A. More extended-spectrum 71. Patterson, J., Zervos, M. High-level gentamicin beta-lactamases. Antimicrobial Agents and Chemo­ resistance in Enterococcus: microbiology, genetic basis, therapy, 35: 1697-1704 (1991). and epidemiology. Reviews of Infectious Diseases, 12: 644-652 (1990). 61. Cuchural, G., Malarny, M., Tally, F. Beta-lactamase- mediated imipenem resistance. In: Bacteroides fragilis. 72. Proceedings of the Third Decennial International Antimicrobial Agents and Chemotherapy, 30: 645-648 Conference on Nosocomial Infections. American Journal (1986). of Medicine, 91 (suppl 3B) (1991).

62. Dufresne, J., Vésina, G., Levesque, R. Cloning and 73. Urban, C., Go, E., Mariano, N. et al. Effect of expression of the imipenem-hydrolysing beta-lactamase salbactam on infections caused by imipenem-resistant operon from Pseudomonas maltophilia in Escherichia coli. Acinetobacter calcoaceticus biotype anitratus. Journal of Antimicrobial Agents and Chemotherapy, 32: 819-826 Infectious Diseases, 167: 448-451 (1993). (1988). 74. Nordic Council on Medicines. General anti-infectives 63. Bellido, F., Veuthey, C., Blaser, J. et al. Novel for systemic use. Developments in the Nordic Countries resistance to imipenem associated with an altered PBP-4 1990-93. Newsletter, No. 4, 1994. in a Pseudomonas aeruginosa clinical isolate. Journal of Antimicrobial Chemotherapy, 25: 57-68 (1990). 75. Coleman, D. Methicillin-resistant Staphylococcus aureus: molecular epidemiology and expression of 64. Pierre, J., Boisivon, A., Gutmann, L. Alteration of PBP- virulence determinants. In: Cafferky, M. ed. Methicillin- 3 entails resistance to imipenem in Listeria monocyto­ resistant Staphylococcus aureus: clinical management genes. Antimicrobial Agents and Chemotherapy, 34: and laboratory aspects. Marcel Decker, New York, 1992, 1695-1698 (1990). pp. 37-56.

65. Trias, J., Nikaido, H. Outer membrane protein D2 76. Hershow, R., Khayr, W., Smith, N. A comparison of catalyses facilitated diffusion of carbapenems and clinical virulence of nosocomially acquired methicillin- penems through the outer membrane of Pseudomonas resistant and methicillin-sensitive Staphylococcus aureus aeruginosa. Antimicrobial Agents and Chemotherapy, 34: infections in a university hospital. Infection Control and 52-57 (1990). Hospital Epidemiology, 13: 587-593 (1992).

66. Daikos, G., Lolans, V., Jackson, G. Alterations in outer 77. Townsend, D., Ashdown, N., Bradley, J. et al. membrane proteins of Pseudomonas aeruginosa "Australian" methicillin-resistant Staphylococcus aureus in associated with selective resistance to quinolones. a London hospital? Medical Journal of Australia, 2: 339- Antimicrobial Agents and Chemotherapy, 32: 785-787 340 (1984). (1988). 78. Bradley, J., Noone, P., Townsend, D., Grubb, W. 67. Kresken, M., Wiedemann, B. Development of Methicillin-resistant Staphylococcus aureus in a London resistance to nalidixic acid and the fluoroquinolones after hospital. Lancet, 1:1493-1495 (1985). the introduction of norfloxacin and ofloxacin. Antimicrobial Agents and Chemotherapy, 32: 1285-1288 (1988). 79. Duckworth, G., Lothian, J., Williams, J. Methicillin- resistant Staphylococcus aureus: report of an outbreak in 68. Maloney, J., Rimland, D., Stephens, D. et al. Analysis a London teaching hospital. Journal of Hospital Infection, of amikacin-resistant Pseudomonas aeruginosa 11: 1-15 (1988). developing in patients receiving amikacin. Archives of Internal Medicine, 149: 630-634 (1989). 80. Gibbons, A. Exploring new strategies to fight drug- resistant microbes. Science, 257: 1036-1038 (1992). 69. Bryan, L, O'Hara, K., Wong, S. Lipopolysaccharide changes in impermeability type aminoglycoside resistance 81. Geddes, A. Antibiotic therapy; a resume. Lancet, 1: in Pseudomonas aeruginosa. Antimicrobial Agents and 286-289 (1988). Chemotherapy, 26: 250-255 (1984). 82. Gootz, T. Discovery and development of new 70. Thomas, W., Archer, G. Mobility of gentamicin antimicrobial agents. Clinical Microbiological Reviews, 3: resistance genes from staphylococci isolated in the United 13-31 (1990). States: identification of Tn4031, a gentamicin resistance transposon from Staphylococcus epidermidis. 83. Kunin, C. Resistance to antimicrobial drugs: a Antimicrobial Agents and Chemotherapy, 33: 1335-1341 worldwide calamity. Annals of Internal Medicine, 118: 557- (1989). 561 (1993).

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Personal Perspectives

OTC advertising: Perhaps we should turn this argument on its head and question the need for OTC advertising in the in whose interest? first place. The yardstick should be, as the WHO Ethical Criteria point out, the contribution that A consumer's viewpoint advertising and other promotional material make to Andrew Chetley rational drug use. If that contribution is negligible, then the advertising is unnecessary and could even Research Consultant and be considered harmful, in the sense that it is not in Freelance Journalist the best interests of public health.

For several years, the World Health Organization If the WFPMM is really prepared to focus only on has been encouraging the rational use of medi­ the three main messages it identifies, then all OTC cines. It was with this aim in mind that, in 1988, advertising in the future could take the following WHO updated and expanded its resolution on form: "A new/reformulated product for (indication), ethical and scientific criteria for pharmaceutical called (brand name), which contains (INN for all advertising (1) into the Ethical Criteria for Medicinal active ingredients), is now available. Ask your Drug Promotion (2). pharmacist or doctor for details about the use­ One form of promotion, advertising of over-the- fulness and safety of this drug. If, after consultation, counter (OTC) products to the general public, you decide to use the product, please read the warrants careful consideration. Does this label/leaflet carefully." advertising enable consumers to make rational choices in dealing with self-medication? Such advertising, of course, would not be designed to persuade consumers with partial information, According to the World Federation of Proprietary suggestive illustrations, clever headlines and Medicine Manufacturers (WFPMM) it cannot: "Our slogans and it would not contain illustrations, research and common knowledge of advertising graphics, or images of people who, having taken demonstrates that advertising is an ineffective the product, then look happy, more active, more means of communicating full and proper informa­ able to cope with life. Unfortunately, however, there tion on OTC medicines" (3). The WFPMM is little likelihood that such advertising would ever maintains that including detailed information about be agreed to by the OTC manufacturers. There is the product in any public advertising "simply considerable evidence that manufacturers are not reduces the effectiveness of the main messages interested in providing useful information to help which are: the name of the product, what it can be consumers make rational choices. used for and an express invitation to read the label or leaflet as appropriate" (4). The latest study, called A searching look at advertisements comes from Consumers Inter­ The "name" being talked about is the brand name— national (formerly the International Organisation of not the International Nonproprietary Name (INN) or Consumers Unions - IOCU) and the Scienceshop generic name. Its "use" refers to the provision of for Medicines at Groningen University in the one or more possible indications, without any Netherlands. The study analyses magazine and evidence of the efficacy of the product compared to newspaper advertisements for OTC medicines and other drug and non-drug therapies. The third health products in 11 industrialized countries (5). It message about reading the label or enclosed compared the advertisements to the requirements leaflet, although a good idea, will still not provide of the European Union (EU) Directive on the the consumer with comparative information. And Advertising of Medicinal Products for Human Use the consumer has to purchase the product to get and the WHO Ethical Criteria. The study was access to even this somewhat limited information. carried out two weeks before the EU directive was With the purchase, the goal of the manufacturer - made a legal requirement in its member states; another sale - has been achieved. none the less, the provisions were widely known

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and the study provides a useful baseline from which included in a product. The WFPMM points out that to judge future compliance. the EU Directive requires this only in single- ingredient products. Others might reasonably Certainly there is room for improvement. The study assume that it is perhaps even more important to found that only three of the 183 advertisements provide the name of all the active ingredients in a contained all the required information and avoided multi-ingredient product. With some ingredients, all the prohibited items as set out in the two such as paracetamol, access to this information international standards. Other major findings were: could ensure that a consumer stays safely below the maximum recommended daily dosage and • 91 advertisements failed to include instructions for alive, rather than being hospitalized with an use, or advice to read the instructions; overdose and possibly dying.

• 53 advertisements failed to give the INN or This latest study provides another indication that generic name; stronger medicine may be needed to deal with the excesses of promotional practices. Without some • 41 advertisements made medical claims for constraints on OTC advertising, consumers will products not registered as medicines; have little or no protection from being led into irrational use of medicines. • 18 advertisements used a celebrity or well-known person to endorse and promote the product. References 1. World Health Assembly resolution WHA21.41. Official An interesting finding was that in some countries, Records of the World Health Organization, 1.11, 144 including the United Kingdom, the amount of space (1968). devoted to pictures or illustrations was much greater than that for text. In advertising terms, this 2. Ethical Criteria for Medicinal Drug Promotion. WHO means that advertisers are relying much more on a Geneva, 1988. ISBN 92 4 154239 X. picture to sell the product than the words. This has implications for the future direction of advertising 3. WFPMM. "WFPMM comments on IOCU Report on controls as existing guidelines focus on the words, OTC Drug Advertising", Press Release. September 1994. not the pictures. 4. Reinstein, J. "Statement to the 47th World Health Assembly on WHO Ethical Criteria for Medicinal Drug There are, of course, problems with studies of this Promotion". May 1994. type, although the methodology developed by researchers at Groningen is quite rigorous. A major 5. Kaldeway, H. et al. A searching look at advertisements, difficulty with all such studies is that a certain IOCU and the Scienceshop for Medicines. London and amount of interpretation is called for: judgements Groningen, 1994 have to be made about whether a particular way of presenting information is in line with both the spirit and letter of what are often very general guidelines. The manufacturer's viewpoint Jerome A. Reinstein Indeed, one criticism that the industry makes of the study involves the decision by the researchers to Director-General interpret the provision in the European Union World Federation of Proprietary Directive that "the information necessary for correct Medicine Manufacturers use of the medicinal product" included the provision of "contraindications, side effects and warnings" which the WHO Ethical Criteria already calls for. Because they so directly affect health, medicines Despite the industry's objections, such an and their advertising, especially advertising of interpretation seems reasonable, particularly if we nonprescription (OTC) medicines to the public, are are striving for rational use of drugs. highly regulated. In addition to government regulation, there are various guides to practice such as the WHO Ethical Criteria for Medicinal Drug Another criticism levelled at the study is that it Promotion, national codes and industry self- claims that the EU Directive calls for, as do the regulatory codes, which respect the intent of the WHO Ethical Criteria, the inclusion in advertise­ Ethical Criteria. And companies have their own ments of the names of all active ingredients internal standards.

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The WHO Ethical Criteria state, inter alia, other factors, such as advertising, which would "advertisements to the general public should help make the consumer aware of the availability of a people to make rational decisions on the use of product and what it can be used for or remind him drugs determined to be legally available without a or her of the product. Should the person ask for the prescription". Although the Ethical Criteria were medicine in a pharmacy or other outlet, the outer written mainly with prescription medicines and their package labelling can be read before purchase to promotion in mind, the interpretation of the clauses let the consumer know whether the product is on advertising to the general public by almost all suitable for his or her particular needs. Additional governments is mainly that the advertising material information may be available on a package leaflet. must be truthful and not misleading, and claims The label and the leaflet information must be made must be in line with the licence or monograph carefully written to be understood by the lay public, issued by the competent authority. The complete while still being accurate and complete, and information needed for proper use of a medicine is industry — with national governments — works contained in the drug information sheet as indicated towards this end. Thus the total information in the appendix to the WHO Ethical Criteria them­ package is a complex of a number of factors taken selves. This is supplied in labelling and/or in the in order, which allows the medicine to be leaflet of nonprescription medicines. appropriately utilized.

Governments and industry understand that con­ Consumer advertising of medicines is ill-served to sumer advertising is different from advertising to provide detailed comparisons of a product with professionals and thus the requirements must take competing products or with non-drug therapies. these differences into consideration. Advertising is This is instead the role of independent drug a low-involvement medium. Advertising experts bulletins and consumer organizations. In any event, know that the most an OTC can hope to communi­ advertising has, in all developed and most cate effectively is a recognition that the product developing countries, had either direct government exists and what it should be used for. Additionally, approval or the approval after examination by a the industry feels that there should be a reminder to delegated body according to an accepted self- always read the label/leaflet or to follow the regulation code. As a further control, misleading or directions carefully. The recent European Union false advertising can be brought to the attention of Directive now requires this reminder. In one major the government or other authority and stopped if European country where television advertising for earlier control mechanisms fail to work as they ten years required contraindications, warnings and should. The fact that this happens very seldom for side-effects to be scrolled throughout the 30- OTC advertising suggests that the system of second commercial, it was realized that this was controls works well. counterproductive and it is no longer required. Research in advertising has clearly shown that I believe it is demeaning to consumers to suggest overload of detailed information on the use of the that an OTC medicine advertisement with attractive product cannot be effectively communicated to the illustrations makes people go out and buy and use consumer in advertising (1, 2). a product without having read the label to decide whether this is the proper product for them to take. Needless to say, the advertising of a medicine is by In fact, if one experiences the symptoms described, brand name denoting a particular product of a an advertisement can spark curiosity and lead to particular manufacturer. The manufacturer's questioning in the pharmacy. A check on appro­ reputation is at stake and therefore great pains are priateness comes then, if it is needed. taken to guarantee the quality of the product which bears his brand name. In addition, evaluation and When a government authority has agreed that a regular review of drug registrations by governments given medicine is safe enough to be used without in most countries help assure that the quality, professional supervision, why should a consumer safety and efficacy are maintained to appropriate necessarily need to question the pharmacist or scientific standards. doctor for details about its usefulness and safety? The labelling has already been designed to be and There are several steps leading to a person taking is accepted as sufficient for most people's needs in an OTC medicine. The first, by far, is the successful making this decision. Obviously pharmacists, previous use of the product or its recommendation doctors and other health care professionals are by family, pharmacist or doctor. Then there come available for information, should people have

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additional questions. But it is surely not required in They find out about what products are available and all cases. Should it really happen, pharmacists and this gives them the choice to determine for doctors would be spending a good part of the time themselves which to purchase. Choice is one of the answering questions which are clearly answered five basic consumer rights in the United Nations already on labels and leaflets of products. This Charter on Consumer Protection, the others being would not be in the interest of the professionals, or access, information, redress and safety, all of which of governments, or, most importantly, of con­ are characteristic of advertised OTC medicines. sumers themselves. Research with consumers has shown repeatedly that people do read the label and Secondly, it is in the professionals' interest: doctors, that OTC medicines are used responsibly and because they will not have their time taken up with appropriately (3-5). minor ailments and can concentrate on more serious medical problems, and pharmacists The recent study by Consumers International because it increases their professional role. Since (formerly IOCU) on OTC advertising in 11 many OTC medicines are sold in pharmacies it developed countries (6) stated that "only three gives the pharmacists an opportunity to advise advertisements out of the 183 analysed completely consumers on medications they learn of through fulfilled the requirements" suggested by inter­ advertising. national "standards". There were a number of methodological faults with this study, but in any Thirdly, it is in governments' interest since OTC case, one must wonder that when all the advertise­ products are purchased with the consumers own ments for medicines (and not all of the advertise­ money which makes them careful about what they ments evaluated in the study were in fact for buy and does not engage the governments' health­ medicines) were according to national laws, care budget for minor ailments. It also encourages regulations and codes, why only three were self-reliance for less serious health problems. deemed completely acceptable. The fact is that essentially all of these advertisements were Finally it is in industry's interest because it allows acceptable by the regulations, criteria and codes of consumers to know that products which could be the country in which they appeared. useful to them are available and allows good products to continue on the market. Our industry feels that detailed information is necessary for the consumer. It is useful before References purchase of the product on the outside label and 1. Taylor Nelson Research, Information or Communica­ before taking the product which then includes the tion? A consumer study of television advertising. London, information on labels and leaflets. This is where 1990. detailed information about side-effects, warnings and contraindications is effectively communicated 2. Kepplinger, H.M. How far can advertising be used to to the user. While there is considerable information inform? Swiss Pharma, 12: 73-77 (1991). from consumer research to indicate that people use OTC medicines appropriately (3-5), there is little 3. Reinstein, J.A. Worldwide studies on self-medication: information to suggest that a significant amount of what do they show? Swiss Pharma, 13: 21-25 (1991). misuse occurs and is harmful. 4. BMRB. Everyday health care: a consumer study of self- medication in Great Britain. London, 1987. In whose interest is OTC advertising? 5. Heller Research Group. Self-medication in the '90s: It is in the interest of all the stakeholders: practices and perceptions. Washington, 1992. consumers, professionals, governments and industry. 6. Kaldeway, H. et al. A searching look at advertisements. IOCU and the Scienceshop for Medicines. London and It is first and foremost in the consumers' interest. Groningen, 1994.

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Reports on Individual Drugs

Commensal enterobacteria and of the controls but in only 3 children who received the supplement (P=0.025). prevention of rotavirus diarrhoea It is important to obtain confirmation of these results Acute diarrhoea remains a major cause of infant in a variety of settings, and particularly within morbidity and mortality in developing countries (1, developing countries where infantile diarrhoea 2). Most of these cases could be averted by breast­ poses the greatest threat. Meanwhile, when breast­ feeding and many lives could be saved by prompt feeding cannot be maintained for a child exposed to oral replacement of water and electrolyte loss by high risk of diarrhoea, the possibility of reducing the home use of oral rehydration salts. However, for as risk of potentially serious illness by dietary adjust­ long as diarrhoea constitutes a public health ment is a persuasive option. It is vital, however, to problem, there is need to explore the potential of ensure that the selected cultures remain uncon¬ new preventive approaches for specific groups of taminated. Where purity cannot be assured by children at high risk. observance of good manufacturing practices and efficient bacteriological monitoring, the danger of The feasibility of developing a vaccine against introducing into the gut the very pathogens that rotaviruses — which are probably the single most should be excluded clearly overrides any expec­ important cause of diarrhoea in children (3, 4) — is tation of therapeutic benefit. still under examination but not yet assured (5). Meanwhile, the possibility has been raised that the References risk of rotavirus diarrhoea might be reduced among 1. Snyder, J., Merson, M. The magnitude of the global hospitalized children who are denied the advantage problem of acute diarrhoeal disease: a review of active of breast-feeding by accelerating the development surveillance data. Bulletin of the World Health Organiza­ of the protective commensal intestinal flora. The tion, 60: 605-613 (1982). fermented milk products widely employed in many traditional diets are natural culture media for such 2. Ho, M., Glass, R., Pinsky, P. et al. Diarrheal deaths in American children: are they preventable? Journal of the bacteria. Among these are the anaerobic, acid- American Medical Association, 260: 3281-3285 (1988). producing organisms of the genus Bifidobacterium which are dominant in the flora of breast-fed infants 3. Middleton, P., Szymanski, M., Petric, M. Viruses (6). These have been claimed both to attenuate associated with acute gastroenteritis in young children. rotavirus infection and to reduce shedding (7), and American Journal of Diseases of Children, 131: 733-737 also, possibly, to exert a nonspecific antidiarrhoeal (1977). action (8). A similar protective effect against infantile diarrhoea has also been ascribed to 4. Yolken, R., Eiden, J. Rotavirus, enteric adenoviruses, Streptococcus thermophilus, which, by stimulating Norwalk viruses, caliciviruses, astroviruses, and other viruses causing gastroenteritis. In: Belshe, R. ed. lactase activity, facilitates the digestion of lactose Textbook of human virology, 2nd ed. Mosby Year Book, (9). St Louis, USA, 1991. pp. 804-821.

The potential of these two organisms to reduce the 5. Glass, R., Gentsch, J., Smith, J. Rotavirus vaccines: incidence of diarrhoea in hospitalized infants aged success by reassortment? Science, 265: 1389-1391 5 to 24 months who are not breast-fed has now (1994). been explored in a double-blind, placebo-controlled trial (10). The children were randomized to receive 6. Benno, Y., Sawada, K., Mitsuoka, T. The intestinal standard infant formula, or the same formula microflora of infants: composition of fecal flora in breast­ supplemented with pure cultures of Bifidobacterium fed and bottle-fed infants. Microbiology and Immunology, 28:975-986 (1984). bifidum and S. thermophilus. Eight of 26 children who received the control formula developed 7. Duffy, L, Zielezny, M., Riepenhoff-Talty, M. et al. diarrhoea, compared with only two of 29 who Effectiveness of Bifidobacterium bifidum in mediating the received the supplemented formula (P=0.035). clinical course of murine rotavirus diarrhoea. Pediatric Moreover, shedding of rotavirus was detected in 10 Research, 33: 983 (1993).

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8. Bullen, C, Tearle, P., Stewart, M. Resistance of breast survives exposure to gastric acid, and although it is fed infants to gastroenteritis. British Medical Journal, 2: rapidly cleared from the gut when treatment is 338-344 (1971). withdrawn, it has been shown to colonize the colon for as long as daily administration is maintained 9. Marteau, P., Flourie, B., Pochart, P. et al. Effect of microbial lactase activity in yogurt on the intestinal (18). It has been claimed to be of value in antibiotic- absorption of lactose. British Journal of Nutrition, 64: 71 - associated diarrhoea (19), and it may reduce the 79 (1990). pathogenicity of C. difficile through a specific mechanism, either by interfering with the production 10. Saavedra, J., Bauman, N., Oung, I. et al. Feeding of or elimination of specific toxins (20), or by liberating Bifidobacterium bifidum and Streptococcus thermophilus a protease that disrupts receptor sites for these to infants in hospital for prevention of diarrhoea and toxins (21). shedding of rotavius. Lancet, 344: 1046-1049 (1994). The clinical potential of S. bulardii as a com­ Saccharomyces boulardii: a plement to a standard antimicrobial regimen in treating C. difficile-associated disease has been valuable adjunct in recurrent demonstrated in a double-blind, randomized, placebo-controlled study (22) involving 124 patients Clostridium difficile disease? with active disease, half of whom had recurrent Clostridium difficile is now recognized to be the bouts of diarrhoea. Patients received a 4-week leading cause of nosocomial intestinal infections in course of therapy consisting either of standard oral adults. It is a pathogen that is rarely encountered antimicrobials alone, or of antimicrobials together outside hospitals, although from time to time, it has with S. boulardii (1 g/day for 4 weeks). been held responsible for outbreaks in nursing homes (1, 2). The infections — which range from No significant difference in response to treatment uncomplicated diarrhoea and nonspecific colitis to was found among patients treated for an initial potentially fatal conditions including pseudo­ episode of infection. Recurrence rates in each of membranous colitis, toxic megacolon and intestinal these two groups over the subsequent 4-week perforation (3, 4) — spread rapidly in the hospital period were 19.3% and 24.2% respectively. environment (3-5). However, marked differences in response to the two treatments were noted among patients with Transmission is facilitated by widespread use of recurrent disease. Further relapse occurred within a antibiotics which reduce the population of com­ period of four weeks in 64.7% of the patients who mensal organisms in the gut flora (4, 6, 7). Most received antimicrobials alone, but only among patients can be cured by standard parenteral 34.6% of those who additionally received regimens of vancomycin hydrochloride or metroni­ S. boulardii. dazole — the only antibiotics to which C. difficile is clinically susceptible (3, 8, 9). However, relapses This simple and apparently innocuous treatment, are common within a matter of days or weeks after if it is confirmed to reduce the incidence of relapse completion of treatment (10-12) and these patients among patients with recurrent episodes of are subsequently at high risk of repeated episodes C. difficile-associated disease, would hold con­ of diarrhoea and colitis (3, 13) that are commonly siderable clinical value. However, it will be unresponsive to further antimicrobial therapy. Not important, in confirmatory studies, to extend the only does C. difficile carry multiple genes that period of post-treatment surveillance in order to confer antimicrobial resistance to a very wide show whether S. boulardii is contributing to a spectrum of substances (14), but repeated use of definitive cure or simply extending a period of wide-spectrum antimicrobials, by inhibiting the symptom-free remission. normal gut flora, favours its recolonization (3, 7). References Evidence has now been presented that some of 1. Bender, B., Laughton, B., Gaydos, C. et al. Is these patients may be helped if standard anti­ Clostridium difficile endemic in chronic care facilities? microbial therapy is complemented by treatment Lancet, 2: 11-13 (1986). aimed to promote growth of the normal intestinal flora (15-17). Saccharomyces boulardii — a yeast 2. Bennett, R., Greenough, W. Clostridium difficile which grows on the lychee tree — has been diarrhoea: a common — and overlooked — nursing home proposed for this purpose. It is exceptional in that it infection. Geriatrics, 45: 77-87 (1990).

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3. Fekety, R., Shah, A. Diagnosis and treatment of 17. Schwann, A., Sjolin, S., Trottestam, U. et al. Relapsing Clostridium difficile colitis. Journal of the American Clostridium difficile diarrhoea by administration of a non­ Medical Association, 269: 71-75 (1993). toxic strain. European Journal of Clinical Microbiology, 6: 51-53 (1987). 4. McFarland, L, Mulligan, M., Kwok, R., Stamm, W. Nosocomial acquisition of Clostridium difficile infection. 18. Klein, S., Elmer, G., McFarland, L. et al. Recovery and New England Journal of Medicine, 320: 204-210 (1989). elimination of the biotherapeutic agent, Saccharomyces boulardii, in healthy human volunteers. Pharmaceutical 5. Clabots, C, Johnson, S., Olsen, M. et al. Acquisition of Research, 10: 1615-1619 (1993). Clostridium difficile by hospitalized patients: evidence for colonized new admissions as a source of infection. 19. Surawicz, C, Elmer, G., Speelman, P. et al. Preven­ Journal of Infectious Diseases, 166: 561-567 (1992). tion of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterology, 96: 981- 6. Mulligan, M., Rolfe, R., Finegold, S., George, W. 988 (1989). Contamination of a hospital environment by Clostridium difficile. Current Microbiology, 3: 173-175 (1979). 20. Elmer, G., McFarland, L. Suppression by Saccharo­ myces boulardii of toxigenic Clostridium difficile over­ 7. Nord, C, Edlund, C. Impact of antimicrobial agents on growth after vancomycin treatment in hamsters. Antimicro­ human intestinal microflora. Journal of Chemotherapy, 2: bial Agents and Chemotherapy, 31: 129-131 (1987). 218-237 (1990). 21. Pothoulakis, C, Kelly, C, Joshi, M. et al. Saccharo­ 8. Young, G., Ward, P., Bayley, N. et al. Antibiotic- myces boulardii inhibits Clostridium difficile toxin A binding associated colitis due to Clostridium difficile: double-blind and enterotoxicity in rat ileum. Gastroenterology, 104: comparison of vancomycin with bacitracin. Gastroenterol­ 1108-1115 (1993). ogy, 89: 1038-1045 (1985). 22. McFarland, L, Surawicz, C, Greenberg, R. et al. A 9. Kelly, C, Pothoulakis, C, LaMont, J. Clostridium randomized placebo-controlled trial of Saccharomyces difficile colitis. New England Journal of Medicine, 330: boulardii in combination with standard antibiotics for 257-262 (1994). Clostridium difficile disease. Journal of the American Medical Association, 271: 1913-1918 (1994). 10. Bartlett, J., Tedesco, F., Schull, S. et al. Symptomatic recurrence after oral vancomycin therapy of antibiotic- associated pseudomembranous colitis. Gastroenterology, ACE inhibitors and non-diabetic 78:431-434 (1980). chronic renal failure 11. Walters, B., Roberts, R., Stafford, R., Seneviratne, E. Recurrence of antibiotic-associated colitis: endogenous Over the past decade, raised blood pressure has persistence of C. difficile during vancomycin therapy. Gut, been shown to accelerate impairment of renal 24:206-212 (1983). function in patients with chronic renal insufficiency (1), and reduction of the resting pressure towards 12. Fekete, R., Silvam, J., Kauffman, C. et al. Treatment the normal range has been found to slow the rate of of antibiotic associated Clostridium difficile colitis with oral functional impairment (2-4). Moreover, among vancomycin: comparison of two dosage regimens. American Journal of Medicine, 86: 15-19 (1989). patients with diabetic nephropathy, angiotensin- converting enzyme (ACE) inhibitors are more 13. Young, G., Ward, P., Bayley, N. et al. Antibiotic- effective in retarding the progression of the disease associated colitis due to Clostridium difficile: double-blind than other antihypertensive agents (5-7). This comparison of vancomycin with bacitracin. Gastroenterol­ beneficial response — which has been demon­ ogy, 89: 1038-1045 (1985). strated largely in studies of captopril — has tentatively been attributed to a direct effect of ACE 14. Roberts, M., McFarland, L, Mullany, P., Mulligan, M. inhibitors on the permeability of renal glomeruli. Characterization of the genetic basis of antibiotic These drugs selectively reduce the fractional resistance in Clostridium difficile. Journal of Antimicrobial clearance of high-molecular-weight dextrans (8), an Chemotherapy, 33: 419-429 (1994). effect which is apparently independent of changes 15. Gorbach, S., Chang, T., Goldin, B. Successful in systemic blood pressure (9). treatment of relapsing Clostridium difficile diarrhoea in six patients. Lancet, 2: 1519 (1987). Until recently, no clinical evidence had been presented to indicate whether ACE inhibitors offer 16. Tvede, M., Rask-Madsen, J. Bacteriotherapy for comparable advantage over other antihypertensive chronic relapsing Clostridium difficile diarrhoea in six agents to patients with renal failure secondary to patients. Lancet, 1: 1156-1160 (1989). other diseases. Given that the clinical progression

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of chronic renal disease, once initiated, is similar This concern, perhaps, explains the authors' regardless of its cause, it has seemed reasonable reluctance — having presented results decisively to make this assumption (19), which has now been favouring use of ACE inhibitors — from recom­ confirmed by the results of a retrospective analysis mending their wide use for all patients with chronic (11) and two open randomized trials in which renal failure. Instead, they call for further studies to enalapril has been used (12, 13). explore the performance of these drugs in specific nephropathies. None the less, on the basis of the The larger and more recent of these studies is a findings now published, many clinicians who are multicentre trial undertaken in France that involved able efficiently to monitor the progress of their 100 hypertensive outpatients with chronic renal patients, will feel bound to carefully weigh the failure (initial serum creatinine 200-400 (µmol/L) potential benefits and hazards of administering resulting, most frequently, from primary glomerulo­ ACE inhibitors to any patient who presents with nephritis or interstitial nephritis (4). Renal function progressively deteriorating renal function. and blood pressure were monitored over three References years during which time the patients received either an ACE inhibitor (enalapril 5-10 mg/day) or a 1. Brazy, P., Stead, W., Fitzwilliam, J. Progression of renal beta-adrenergic blocking agent (either acebutolol insufficiency: role of blood pressure. Kidney International, 400 mg/day or atenolol 100 mg/day). Furosemide 35:670-674 (1989). and, if necessary, a calcium antagonist or a 2. Alvestrand, A., Gutíerrez, A., Bucht, H., Bergström, J. centrally-acting drug were added to the regimen Reduction of blood pressure retards the progression of when the diastolic pressure remained persistently chronic renal failure in man. Nephrology, Dialysis and above 90 mmHg. Ten of 52 patients (19%) in the Transplantation, 3: 624-631 (1988). enalapril group and 17 of 48 patients (35%) who received beta-adrenergic blocking agents develop­ 3. Brazy, P., Fitzwilliam, J. Progressive renal disease: role ed endstage renal failure (relative risk 3.5; 95% of race and antihypertensive medications. Kidney confidence interval 1.5 to 7.6) within the three-year International, 37: 1113-1119 (1990). period. 4. Hannedouche, T., Albouze, G., Chauveau, P. et al. Effects of blood pressure and antihypertensive treatment A comparable result has been obtained in a some­ on progression of advanced chronic renal failure. what smaller study undertaken in North America American Journal of Kidney Disease, 21 (suppl .2): 131- (12). This study showed that, over a two-year 137 (1993). period, the median fall in glomerular filtration rate (measured by plasma clearance of chromium-51 5. Parving, H., Hommel, E., Smidt, U. Protection of kidney EDTA) was some one-third lower in the enalapril function and decrease in albuminuria by captopril in group than in the control group. A similar trend, insulin-dependent diabetics with nephropathy. British Medical Journal, 297: 1086-1091 (1988). observed in the French study, failed to achieve significance, possibly because of wide intra- 6. Björck, S., Mulec, H., Johnsen, S. et al. Renal protec­ individual variations in sequential measurements of tive effect of enalapril in diabetic nephropathy. British inulin clearance (14). Medical Journal, 304: 339-343 (1992).

In both studies it was found that, among patients 7. New perspectives on ACE inhibitors: diabetic nephro­ with glomerular disease, urinary protein excretion pathy. WHO Drug Information, 8: 4-7 (1994). decreased significantly within the enalapril group throughout the first year of treatment. This finding 8. Morelli, E., Loon, N., Meyer, T. et al. Effects of angiotensin-converting enzyme inhibition in diabetic may have particular relevance since it has been glomerulonephropathy. Diabetes, 39: 76-82 (1990). suggested that reduction in proteinuria itself tends to reduce glomerulosclerosis and preserve renal 9. Pinto, J., Walker, J., Turner, C. et al. Renal response to function (15). lowering of arterial pressure by angiotensin-converting enzyme inhibition or diuretic therapy in insulin-dependent ACE inhibitors, however, are not without danger in diabetic patients with nephropathy. Kidney International, patients with moderate to severe renal failure. Two 37:516 (1990). of the patients taking enalapril in the French study developed hyperkalaemia. The authors stress the 10. Hostetter, T., Olson, J., Rennke, H. et al. Hyper- need for careful monitoring, prompt correction of filtration in remnant nephrons: a potentially adverse metabolic acidosis, and early administration of response to renal ablation. American Journal of Physiol­ furosemide to any patient considered to be at risk. ogy, 241: F85-93 (1981).

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11. Mann, J., Reisch, C, Ritz, E. Use of angiotensin- controls. Overall, a slight but marginally significant converting enzyme inhibitors for the preservation of kidney rising trend in risk of breast cancer was demon­ function. Nephron, 55 (suppl 1): 38-42 (1990). strated with increasing duration of use. But even among women who had used oral contraceptives 12. Kamper, A., Strongaard, S., Leysac, P. Effects of for a total of 12 years or more, the 95% confidence enalapril on the progression of chronic renal failure. interval for the relative risk still included unity (RR American Journal of Hypertension, 5: 423-430 (1992). 1.3; 95% Cl 0.9-1.9). 13. Hannedouche, T., Landais, P., Goldfarb, B. et al. Randomized controlled trial of enalapril and beta blockers Subgroup analyses undertaken on women in in non-diabetic renal failure. British Medical Journal, 309: different age bands, however, demonstrated that 833-837 (1994). the increased risk was distributed unevenly throughout the sample: 14. Davis, D., Shock, N. The variability of measurement of inulin and diodrast tests of kidney function. Journal of • For women who were aged between 36 and 45 Clinical Investigation, 29: 491-495 (1950). years when breast cancer was diagnosed, no association with any previous use of oral 15. Remuzzi, A., Bertani, T. Is glomerulosclerosis a consequence of altered glomerular permeability to contraceptives was found. This finding accords macromolecules? Kidney International, 38: 384-394 with the mass of evidence that use of oral (1990). contraceptives by women in the middle of their fertile years has no effect on the risk of breast cancer (10).

Oral contraceptives and • Among women aged under 36 years at the time of breast cancer: more insight diagnosis, usage for more than 4 years doubled the risk of breast cancer (RR 2.1; 95% Cl 1.0-4.5) into a complex association and this risk tended to increase with greater duration of use (P=0.08). As expected, women in More than 50 studies have now been published that the youngest age group had started using oral explore the risk of breast cancer among users of contraceptives at an earlier age and, within this oral contraceptives, and articles appear at frequent group, use before the age of 20 years was intervals that provide updated overviews of the associated with greater risk than subsequent use. evidence (1-4). It is widely agreed that, if these These results support previous findings (5, 6, products constitute a risk, it is largely incurred by 11,12) concerning the influence of very early use two specific subgroups of users: women who have of oral contraceptives on the risk of breast cancer, used these products over many years (5) and those but whether this increased risk persists into who started to use them early in their reproductive subsequent decades of life remains unclear. At life (6-8). least two other studies have suggested, on limited An exploration of the association between long- evidence, that the increased risk is transient (13, sustained use of oral contraceptives and risk of 14). None the less, it is of the highest importance breast cancer presenting in women of different age that the first cohorts of teenage users of oral groups has recently been undertaken in the contraceptives be monitored for steroid-related Netherlands using the case-control approach (9). cancers over several decades. The results of the study are of considerable importance. Not only do they depict the association • An excess risk of similar magnitude was shown between contraceptive use and breast cancer as among women aged 46-54 years at diagnosis complex, but they identify issues that require to be who had used oral contraceptives for more than carefully monitored in future studies and that may 12 years (RR 2.3; 95% Cl 1.1-4.7). eventually presage a need for a general reappraisal of contraceptive practice. In this older group, the excess risk was also strongly correlated with recent use of oral contra­ Over 900 women with breast cancer diagnosed at ceptives. These results are supported by a recent ages ranging from 20 to 54 years were paired by Canadian study (15), but they do not support earlier age with randomly selected controls. Some 85% of expectations that oral contraceptives might induce these women had used oral contraceptives at some breast cancer only after a prolonged latent period time. The mean duration of use was 7.1 years (16). However, data generated in the same study among the cases and 6.6 years among the on younger women who had used contraceptives

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for 4 years or more, suggest that clinical expression contraceptives, since even a small increase in of the risk occurs, in this group, only after a latency incidence within the age group most vulnerable to of some 10 years. breast cancer would assume considerable public health importance; and Analyses of relative risks associated with different formulations of oral contraceptives generated • further examination of the increased risk found to unexpected findings. After 8 years use, a significant be associated with prolonged use of oral excess risk of breast cancer was found among contraceptives before the age of 20 years, women using low-dose preparations (RR 3.0; 95% particularly in order to establish how this risk may Cl 1.5-6.1). No such trend was detected among be influenced by the use of low-estrogen-dose women who had used high-dose preparations. In preparations, and to investigate whether this other studies, estrogen dose has either appeared to group of women remains at increased risk in later be without effect (17, 18) or to have been positively decades. correlated with increased risk (11, 19). The case has been argued that, even if long-term In the Netherlands, the apparent increase in risk use of oral contraceptives increases the incidence associated with low-dose preparations could not be of breast cancer up to the age of 35, overall explained by the use of specific progestogens. The mortality among users and non-users remains authors suggest that these findings might result virtually identical (10). If, however, this excess risk from incomplete suppression of ovarian activity in is extended into later life, and if verification is forth­ some women taking low-dose preparations (20), coming that use of oral contraceptives by older but they emphasize the need for confirmation of women, and use of low-dose preparations in their findings before any firm conclusions can be general, is also positively associated with risk of drawn. breast cancer, then need may arise for a major reassessment of contraceptive practice. Only two of seven progestogens studied were found to be associated with significantly increased References risk: norethisterone and norethisterone acetate, used mainly in combination with high doses of 1. Romieu, I., Berlin, J., Colditz, G. Oral contraceptives estrogen, and desogestrol, used exclusively with and breast cancer: a review and meta-analysis. Cancer, low-dose ethinylestradiol. Again the authors stress 66: 2253-2263 (1990). the need for cautious interpretation of results 2. Thomas, D. Oral contraceptives and breast cancer: a involving multiple comparisons, particularly in the review of the epidemiologic literature. Contraception, 43: absence of any a priori hypothesis, and in the 597-642 (1991). knowledge that norethisterone acetate, etynodiol acetate, noretynodrel, and lynestrenol are all 3. Rushton, L, Jones, D. Oral contraceptive use and ultimately metabolized to norethisterone. None the breast cancer risk: a meta-analysis of variations with age less, they point to other studies in which use of at diagnosis, parity and total duration of oral contraceptive preparations containing norethisterone (acetate) use. British Journal of Obstetrics and Gynaecology, 99: has been associated with the highest risk of breast 239-246 (1992). cancer (11, 16, 18). 4. Malone, K., Daling, J., Weiss, N. Oral contraceptives in relation to breast cancer. Epidemiologic Reviews, 15: 80- The reassuring aspect of this study is that it 97 (1993). supports the already considerable body of evidence that women who use oral contraceptives throughout 5. Meirik, O., Lund, E., Adami, H. et al. Oral contraceptive the middle years (25-39 years) of their fertile use and breast cancer in young women. Lancet, 2: 650- lifespan are not at increased risk of breast cancer. 653 (1986). At the same time, it has strengthened earlier misgivings that use of these preparations either 6. Pike, M., Henderson, B., Krailo, M. et al. Breast cancer early or late in the fertile years does increase the in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet, 2: risk of this disease. Given these trends, the authors 926-930 (1983). propose that subsequent epidemiological studies should focus on one or both of two issues: 7. McPherson, K., Vessey, M., Neil, A. Early oral contra­ ceptive use and breast cancer: results of another case • verification of the increased risk in older women control study. British Journal of Cancer, 56: 653-660 apparently associated with recent use of oral (1987).

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8. Romieu, I., Willett, W., Colditz, G. et al. Progressive study of oral contraceptive use and risk of breast cancer in DMPA and breast cancer: women. National Journal of Cancer, 81: 1313-1321 a largely reassuring analysis (1989). Depot medroxyprogesterone acetate (DMPA), a 9. Rookus, M., van Leewen, F. for the Netherlands Oral Contraceptives and Breast Cancer Study Group. Oral potent progestogen, has been used as a long- contraceptives and risk of breast cancer in women aged acting injectable contraceptive for over 20 years. 24-54 years. Lancet, 344: 844-851 (1994). Until recently, controversy on whether its undoubt­ ed potential to cause malignant mammary tumours 10. Vessey, M. An overview of the benefits and risks of in beagle dogs (1) holds relevance to its medicinal combined oral contraceptives. In: Mann, R. ed. Oral use as a contraceptive agent delayed its accept­ contraceptives and breast cancer. Royal Society of ance in the United States and many other countries Medicine, London, 1990. pp 121-132. (2). It is now widely considered that the beagle 11. UK National Case-Control Study Group. Oral contra­ provides an inappropriate model for assessing the ceptive use and breast cancer risk in young women. effects of progestogens on the human breast (3, 4). Lancet, 1: 973-982 (1989). However, in the last analysis, direct epidemiological confirmation of long-term safety in human use was 12. Bernstein, L, Pike, M., Krailo, M., Henderson, B. seen to be essential (5). Update of the Los Angeles study of oral contraceptives and breast cancer: 1981-1983. In: Mann, R., ed. Oral Within the past five years, relevant data have been contraceptives and breast cancer, Royal Society of obtained from case-control studies undertaken Medicine, London, 1990. pp 169-180. respectively in New Zealand (6), and in three 13. Paul, C, Skegg, D., Spears, G. Oral contraceptives countries representative of different regions of the and risk of breast cancer. International Journal of Cancer, developing world — Kenya, Mexico and Thailand 46: 366-373 (1990). (7). Overall, these two studies provided no evidence of a significant association between use 14. Wingo, P., Lee, N., Ory, H. et al. Age-specific differ­ of DMPA and breast cancer. Indeed, they were ences in the relationship between oral contraceptive use sufficiently reassuring to permit the US Food and and breast cancer. Obstetrics and Gynecology, 78: 161 - 170 (1991). Drug Administration to approve a preparation of DMPA for contraceptive use in 1992. None the less, 15. Risch, H., Howe, G. Menopausal hormone usage and in both studies there was some evidence of breast cancer in Saskatchewan: a record-linkage cohort increased risk — which fell short of statistical study. American Journal of Epidemiology, 139: 670-683 significance — among women who first used DMPA (1994). when they were aged under 25 years, women 16. McPherson, K., Coope, P., Vessey, M. Early oral under 35 years with diagnosed breast cancer, and contraceptive use and breast cancer: theoretical effects of women who had used DMPA shortly before latency. Journal of Epidemiology and Community Health, diagnosis of breast cancer. 40: 289-294 (1986). Given the similar design of the two studies, it was 17. Vessey, M., McPherson, K., Villard-Mackintosh, L., considered acceptable to pool the data and to Yates, D. Oral contraceptives and breast cancer: latest findings in a large cohort study. British Journal of Cancer, rework the results. This, it was hoped, would enable 59: 613-617 (1989). these factors and their various interrelationships to be reassessed with greater confidence. The results 18. Thomas, D., Noonan, E. for WHO Collaborative Study of this re-examination of the data have now been of Neoplasia and Steroid Contraceptives. Breast cancer published (8). The estimated overall relative risk of and specific types of combined oral contraceptives. British breast cancer among the women who had used Journal of Cancer, 65: 108-113 (1992). DMPA was close to unity (relative risk 1.1; 95% confidence interval 0.97-1.4). Among other factors 19. Ewertz, M. Oral contraceptives and breast cancer risk shown to be associated with breast cancer were in Denmark. European Journal of Cancer, 28A: 1176- early menarche, single marital status, late age at 1181 (1992). birth of first child, nulliparity and low parity, family 20. van der Vange, N. Effects of seven low-dose history of breast cancer, history of benign breast combined oral contraceptives on ovarian function, disease, and late menopause. Among these, the measured by ultrasound examination and peripheral only factor that appreciably confounded the endocrine parameters. In: Chamberlain, G., ed. association between use of DMPA and the risk of Contemporary Obstetrics and Gynaecology, London, breast cancer was age at first live birth. Subsequent 1987. pp 315-326.

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analyses were adjusted accordingly. Although use possibility that DMPA may accelerate the growth of of oral contraceptives was also examined as a occult cancers when they seek advice on the potentially confounding factor, no analysis was relative risks and advantages of available methods undertaken to explore any excess risk within the of contraceptive. cohort that may have been independently associated with use of these preparations. References

The striking finding to emerge from this reanalysis 1. Jordan, A. Toxicology of depot medroxyprogesterone is that the excess risk of breast cancer associated acetate. Contraception, 49: 189-201 (1994). with DMPA is unlikely to be primarily a function of the age at which the product was first used or the 2. Weisz, J., Ross, G., Stolley, P. Report of the Public time over which it was taken (although there were Board of Inquiry on Depot-Provera. Food and Drug relatively few long-term users). Instead, it appears Administration, Rockville, Maryland, USA, 1984. to be related to recent or current use of the product. 3. World Health Organization. Depot-medroxyprogester¬ Surprisingly, the increased risk in women who one acetate (DMPA) and cancer: Memorandum from a started DMPA within the previous five years was WHO meeting. Bulletin of the World Health Organization, evident exclusively among those who had received 71: 669-676 (1993). only one injection (relative risk 3.1; 95% confidence interval 1.8-5.2), and was not more pronounced 4. Meirick, O. Updating DMPA safety: four background among those who used the product over prolonged papers for a WHO meeting. Contraception, 49:185-230 periods. (1994). If these results are accepted as reliable, they lead 5. Michal, F. ed. Safety requirements for contraceptive to the conclusion that a single injection of DMPA steroids. Cambridge University Press, Cambridge, 1989. suffices to exert the full effect of the hormone on the clinical expression of breast cancer. This is 6. Skegg, D., Spears, G. Depot medroxyprogesterone plausible since a single injection of DMPA exerts a (Depot-Provera) and risk of breast cancer. British Medical Journal, 299: 759-762 (1989). potent progestogenic effect extending over a period of several months. It is proposed that the effects of 7. WHO Collaborative Study of Neoplasia and Steroid DMPA on risk of breast cancer are analogous to Contraceptives. Breast cancer and depot medroxyproges­ those of pregnancy. A short-term increase in the terone acetate: a multinational study. Lancet, 338: 833- risk of breast cancer has been described following 838 (1991). both full-term pregnancy, and even pregnancy terminated by abortion at three months (9-11). The 8. Skegg, D., Noonan, E., Paul, C. et al. Depot medroxy­ hypothesis is not novel, since it has previously been progesterone acetate and breast cancer: a pooled proposed to explain temporal aspects of the analysis of the World Health Organization and New Zealand Studies. Journal of the American Medical apparent association between oral contraceptives Association, 273: 799-804 (1995). and breast cancer (12, 13). 9. Brussi, P., Negri, E., La Vecchia, C. et al. Short-term Two characteristics of the results obtained in this increase in breast cancer risk following a full-term study are striking: the short latency with which pregnancy. British Medical Journal, 297: 1096-1098 cases of breast cancer have followed single (1988). injections of DMPA, and the lack of any overall increase associated with the use of DMPA in the 10. Lambe, M., Hsieh, C, Trichopoulos, D. et al. Transient increase in the risk of breast cancer after giving birth. New cohort as a whole. The biological mechanism that is England Journal of Medicine, 331: 5-9 (1994). advanced to explain this temporal relationship is that DMPA does not promote tumour formation, but 11. Daling, J., Malone, K., Voigt, L. et al. Risk of breast that it may either enhance the late stages of such cancer among young women: relationship to induced promotion or accelerate the growth of pre-existing abortion. Journal of the National Cancer Institute, 86: early tumours. 1584-1592 (1994).

The authors conclude that use of DMPA as a 12. Romieu, I., Willett, W., Colditz, G. et al. Prospective contraceptive should not be restricted on grounds study of oral contraceptive use and risk of breast cancer in women. Journal of the National Cancer Institute, 81: of breast cancer. They suggest, however, that 1313-1321 (1989). prospective users should be informed of the

21 Reports on Individual Drugs WHO Drug Information Vol. 9, No. 1, 1995

unparalleled array of questions concerning the 10. Selwyn, P., Scell, B., Alcabes, P. et al. High risk of benefits, risks and overall cost-effectiveness of a active tuberculosis in HIV-infected drug users with wide range of therapeutic and prophylactic inter­ cutaneous anergy. Journal of the American Medical ventions (13). Association, 268: 504-509 (1992). References 11. Girard, P-M., Landman, R., Gaudebout, C. et al. Dapsone-pyrimethamine compared with aerosolized 1. Powderly, W. Cryptococcal meningitis and AIDS. pentamidine as primary prophylaxis against Pneumo­ Clinical Infectious Diseases, 17: 837-842 (1993). cystis carinii pneumonia and toxoplasmosis. New England 2. Saag, M., Powderly, W., Cloud, G. et al. Comparison of Journal of Medicine, 328: 1514-1520 (1993). amphotericin B with fluconazole in the treatment of AIDS- associatied cryptococcal meningitis. New England Journal 12. Nightingale, S., Cameron, W., Gordin, F. et al. Two of Medicine, 326: 86-89 (1992). controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in the acquired 3. Chuck, S., Sande, M. Infections with Cryptococcus immunodeficiency syndrome. New England Journal of neoformans in the acquired immunodeficiency syndrome. Medicine, 328: 828-833 (1993). New England Journal of Medicine, 321: 794-799 (1989). 13. Wheat, L, Goldman, M. Antifungal prophylaxis in 4. Galgiani, J. Fluconazole, a new antifungal agent. AIDS: should it be the standard of care? AIDS Clinical Annals of Internal Medicine, 113: 177-179 (1990). Care, 6: 27-30 (1994). 5. Powderly, W., Saag, M., Cloud, G. et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of Corrigendum cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. New England Journal of The article entitled "When should cysticidal drugs Medicine, 326: 793-798 (1992). be prescribed in cerebral cysticercosis?" published in Volume 8, Number 4, pp 197-198 (1994) of this 6. Cotton, D., Weinberg, D. Survey results: treatment journal contained an important error. decisions in HIV care. AIDS Clinical Care, 4: 85-91 (1992). It was stated that the dosage of both praziquantel 7. Nightingale, S., Cal, S., Peterson, D. et al. Primary and albendazole was 50 mg/kg/day. The dosage of prophylaxis with fluconazole against systemic fungal albendazole should have read 15 mg/kg/day. It is infections in HIV-positive patients. AIDS, 6: 191-194 important that this dosage should not be exceeded. (1992). 8. Quagliarello, V., Viscoli, C, Horwitz, R. Primary A further article on the use of these substances in prevention of cryptococcal meningitis by fluconazole in cysticercosis will be included in the Number 2, 1995 HIV-infected patients. Lancet, 345: 548-552 (1995). issue of WHO Drug Information. 9. Centers for Disease Control. Recommendations for prophylaxis against Pneumocystis carinii pneumonia in adults and adolescents infected with human immuno­ deficiency virus. Morbidity and Mortality Weekly Report, 41 (RR-4): 1-11 (1992).

24 WHO Drug Information Vol. 9, No. 1, 1995

General Information

Acinetobacter. a paradigm for prescribed with confidence for the empirical treat­ ment of Acinetobacter infection (18). In some hospital-acquired infection outbreaks, only the carbapenem antibiotic, imipenem, has been identified as effective (12). The array of life-support facilities available in Even imipenem has been ineffective in two intensive-care units in large general hospitals saves separate outbreaks of infection in the intensive care many lives. However, the dangers of concentrating unit of a New York hospital. Isolates showed that patients highly vulnerable to acute bacterial these strains were susceptible only to polymyxin B infections in an environment where broad-spectrum and sulbactam (11, 19). One of these outbreaks is antibiotics are intensively used is only now notable in that it was preceded by an outbreak of becoming evident. Not only is the emergence of cefalosporin-resistant Klebsiella infections that antibiotic-resistant strains favoured, but the required treatment with imipenem (20). It is the conditions may also be created for a harmless selective pressure generated by this exposure that organism to shift to a parasitic mode of existence. is assumed to have resulted in the emergence of Acinetobacter have long been recognized as a the imipenem-resistant strain of Acinetobacter. genus of widely-distributed free-living saprophytic The susceptibility of these isolates to the beta- bacteria, but reports began to appear towards the lactamase inhibitor, sulbactam, was unexpected end of the 1970s which associated them with and remains unexplained. Already, however, serious respiratory infections among patients in imipenem-resistant strains of Acinetobacter have intensive-care units (1-4). These species flourish in been identified which are also resistant to the hospital environment. They have been isolated sulbactam, leaving topical irrigation of open wounds from habitats as varied as the skin of healthy with polymyxins as the only feasible therapeutic people (5), and non-sterile pharmaceutical products option (21). (6). During outbreaks of infection, they have been detected in patients' mattresses (7), room References humidifiers (8), ventilator circuits, resuscitation bags and Wright respirometers (9, 10). Initially, it was 1. Markhan, S., Telfer-Brunton, W. Acinetobacter assumed that all members of the genus are calcoaceticus — a pathogen? Journal of Infectious potential pathogens, but it now seems that most, if Diseases, 6: 95-96 (1983). not all, outbreaks of serious and often fatal hospital- acquired infections (13) are caused by a specific 2. Myer, K., Zinner, S. Bacterial pathogen of increasing subtype, Acineto-bacter baumannii. significance in hospital-acquired infections. Reviews of Infectious Diseases, 7 (suppl 3): 371-379 (1985). Typically, the patients involved in these outbreaks have developed pneumonia or tracheobronchitis, 3. Bergogne-Berezin, E., Joly-Guillot, M., Vieu, J. but cases of meningitis, and of bloodstream, urinary Epidemiology of nosocomial infections due to Acineto­ tract and wound infections are also on record (13, bacter calcoaceticus. Journal of Hospital Infection, 10: 105-113 (1987). 14). Isolates obtained from these cases were initially commonly susceptible to cefalosporins, 4. Bergogne-Berezin, E., Joly-Guillot, M. Hospital infection aminoglycosides, and extended-spectrum peni­ with Acinetobacter spp.: an increasing problem. Journal of cillins (15). However, strains have since emerged Hospital Infection, 18 (suppl. A): 250-255 (1991). that are resistant to multiple antibiotics (15, 17) and these are rapidly becoming dominant. Outbreaks 5. Rosenthal, S., Al-Khoja, M., Darrell, J. The skin as the are becoming both more numerous and more source of Acinetobacter and Moraxalla species occurring resistant to treatment, and it is ominous that in blood cultures. Journal of Clinical Pathology, 32: 497- resistance to first-line antimicrobials has been 499 (1979). reported to develop during the course of a single outbreak (3, 16). 6. De la Rosa, M., Mosso, M., Garcia, M. et al. Resistance to antimicrobial agents of bacteria isolated from non- sterile pharmaceuticals. Journal of Applied Bacteriology, Beta-lactam agents and aminoglycosides — with 74: 570-577 (1993). the exception of amikacin — can no longer be

25 General Information WHO Drug Information Vol. 9, No. 1, 1995

7. Sheretz, R., Sullivan, M. An outbreak of infections with 19. Go, E., Urban, C, Burns, J. et al. Clinical and Acinetobacter calcoaceticus in burn patients: contamina­ molecular epidemiology of acinetobacter infections tion of patients' mattresses. Journal of Infectious sensitive only to polymyxin B and sulbactam. Lancet, 344: Diseases, 151: 252-258 (1985). 1329-1332 (1994).

8. Smith, P., Massanari, R. Room humidifier as a source 20. Meyer, K., Urban, C, Eagan, J. et al. An outbreak of of acinetobacter infections. Journal of the American klebsiella infection resistant to late generation cephalo­ Medical Association, 56: 169-173 (1977). sporins. Annals of Internal Medicine, 119: 353-358 (1993). 21. Wood, C, Reboli, A. Infections caused by imipenem- 9. Hartstein, A., Rashad, A., Liebler, J. et al. Multiple resistant Acinetobacter calcoaceticus biotype anitratus. intensive care unit outbreak of Acinetobacter Journal of Infectious Diseases, 168: 1602-1603 (1993). calcoaceticus (subspecies anitratus) respiratory infection and colonization associated with contaminated, reusable ventilator circuits and resuscitation bags. American Journal of Medicine, 85: 624-631 (1988). Hydroxyurea and sickle-cell disease: encouraging response 10. Cunha, B., Kilmk, J., Gracewski, J. et al. A common source of outbreak of acinetobacter pulmonary infections in a multicentre study traced to Wright respirometers. Postgraduate Medical Journal, 56: 169-173 (1977). Valuable progress is being made in the manage­ ment of the major beta-haemoglobinopathies, 11. Urban, C, Go, E., Mariano, N. et al. Effect of sickle-cell anaemia and thalassaemia. The finding sulbactam on infections caused by imipenem-resistant that several different types of drug can switch Acinetobacter calcoaceticus biotype anitratus. Journal of haemoglobin synthesis to favour production of Infectious Diseases, 167: 448-451 (1993). normal fetal haemoglobin provides hope that effective suppressive therapy can be developed 12. Seifert, H., Baginski, R., Schulze, A et al. Antimicrobial which may ultimately become accessible to a high susceptibility of acinetobacter species. Antimicrobial Agents and Chemotherapy, 37: 750-753 (1993). proportion of those children who suffer from these diseases. 13. Dijkshoorn, L, van Dalen, R., van Ooyen, A. et al. When sickle-cell anaemia was last discussed in this Endemic acinetobacter in intensive care units: epidemiol­ ogy and clinical impact. Journal of Clinical Pathology, 46: journal in 1993 (1), it was to describe how use of 533-536 (1993). prophylactic and therapeutic administration of antibiotics and use of pneumococcal and Haemo­ 14. Siegman-lgra, Y., Bar-Yosef, S., Gorea, A. et al. philus influenzae type b vaccine had reduced death Nosocomial acinetobacter meningitis secondary to rates from septicaemia among affected infants and invasive procedures: report of 25 cases and review. young children resulting from impaired splenic Clinical Infectious Diseases, 17: 843-849 (1993). function (2-4). At that time, little could be done to prevent the underlying anaemic crises and veno- 15. Okpara, A., Maswoswe, J. Emergence of multidrug- occlusive events that result in the strokes and resistant isolates of Acinetobacter baumannii. American chronic organ damage which characterize the Journal of Hospital Pharmacy, 51: 2671-2675 (1994). disease. 16. Rolston, K., Bodey, G. In vitro susceptibility of Sickled red-blood cells, which are more fragile than acinetobacter species to various antimicrobial agents. Antimicrobial Agents and Chemotherapy, 30: 769-770 normal red cells, increase blood viscosity and (1986). frequently block capillaries. They behave in this way because they contain a genetically-determined 17. Traub, W., Spohr, M. Antimicrobial drug susceptibility abnormal haemoglobin (HbS) which polymerizes of clinical isolates of acinetobacter species (Acinetobacter and aggregates in rod-like structures as oxygen baumannii, Acinetobacter haemolyticus, genospecies 3, tension falls. The incidence of clinically significant and genospecies 6). Antimicrobial Agents and Chemo­ veno-occlusive events associated with sickling can therapy, 33: 1617-1619 (1989). be ameliorated in severely anaemic patients by an open-ended programme of intermittent blood 18. Vila, J., Marcos, A., Marco, F. et al. In vitro antimicro­ transfusion aimed to reduce the proportion of HbS bial production of beta-lactamases, aminoglycoside- in peripheral blood by some 50%. However, the modifying enzymes, and chloramphenicol acetyltrans- ferase by — and susceptibility of clinical isolates of — benefits of blood transfusion are seriously offset by Acinetobacter baumannii. Antimicrobial Agents and the inevitable risks of infection, iron overload and Chemotherapy, 37: 138-141 (1993). allo-immunization (5, 6).

26 WHO Drug Information Vol. 9, No. 1, 1995 General Information

All of these difficulties can be circumvented by the USA and the results are highly encouraging. transplanting allogenic bone marrow. Highly The trial — a randomized, placebo-controlled study encouraging results have been reported (7) but this involving some 300 young adults with moderate to is a high-cost option which will remain available severe sickle-cell anaemia enrolled at 21 centres only to a privileged minority of children. Of wider across the United States — was halted prematurely relevance is the discovery that polymerization of after some three years because the patients allo­ HbS, which is the immediate cause of sickling, is cated to hydroxyurea were shown to have gained inhibited in the presence of normal fetal haemo­ decisive benefit (18). Daily administration of globin (HbF) (8). The possibility of stimulating hydroxyurea at the maximum tolerated dose had expression of HbF pharmacologically arose when it halved the frequency of painful crises, of blood was found, in 1982, that 5-azacytidine increases transfusions, and of the "acute chest syndrome" (a HbF levels in primates (9). Other substances have life-threatening complication characterized clinically since been shown to share this property, including by chest pain and fever) by some 50% throughout butyric acid and butyrate derivatives, sodium the observed period of treatment. phenylacetate and other phenyl-fatty acids, and some cytotoxic agents, including hydroxyurea (10). It is reassuring that the only evidence of toxicity Because red cells containing HbF survive longer in noted during the course of this trial was reversible patients with sickle-cell disease, HbF levels in the bone marrow depression. Concerns had previously peripheral blood can rise as high as 20%, when as been expressed that serious drug-related effects little as 4% is produced within the bone marrow might occur even in the short term (19). Given that (11). hydroxyurea is a mutagenic substance with terato­ genic and carcinogenic potential (20), its longer- Thus far, interest in anti-sickling agents has term effects will not become evident for many focused largely on hydroxyurea. Its cytotoxic effect years. All of the patients admitted to this trial were in vivo results from its conversion into a free radical aware of the risks implicit in this therapy, of the nitroxide. This diffuses into and kills dividing cells need to maintain treatment, and of the need to by inactivating the enzyme ribonucleotide reductase practise an effective method of contraception for as and selectively inhibiting DNA synthesis (12). This long as they take hydroxyurea. All now have the effect has already been used in the treatment of option of continuing treatment, in which case their polycytaemia vera and other myeloproliferative progress and their health status will be reviewed disorders. Its unanticipated value in sickle-cell annually. disease was first recognized when it was found that cytotoxic agents — which interfere with DNA As yet, the approved indications for hydroxyurea in replication in the bone marrow — at the same time the United States are limited to melanoma, resistant reprogramme erythroid progenitors by an chronic myelocytic leukaemia, ovarian cancer, and unexplained mechanism to switch from producing polycythemia vera. No application has as yet been adult haemoglobin to HbF (13). lodged by the manufacturer, Bristol-Myers Squibb, to extend its use to sickle-cell disease, but At doses reasonably well tolerated in the short discussions are in hand with the the US Food and term, daily oral administration of hydroxyurea Drug Administration regarding the data that needs induces a brisk reticulocyte response in the majority to be generated for this purpose (18). of patients with sickle-cell disease (14-16). In turn, this results in circulating HbF levels of some 10- References 15%. However, individual responses are unpre­ dictably variable. It may ultimately prove possible 1. Sickle-cell disease: a trend towards less intensive to potentiate the response by combining hydroxy­ management. WHO Drug Information, 7: 120-122 (1994). urea with non-cytotoxic agents known to alter the 2. Gaston, H., Verter, J., Woods, G. et al. Prophylaxis with kinetics of maturation of erythroid cells, including oral penicillin in children with sickle-cell anemia. New sodium butyrate, erythropoietin and other growth England Journal of Medicine, 314: 1593-1599 (1986). factors — but this remains uncertain (16, 17). 3. Editorial. Penicillin prophylaxis for babies with sickle- cell disease. Lancet, 2: 1432-1433 (1986). To be of practical therapeutic interest, hydroxyurea must be shown to promote the expression of HbF in 4. John, A., Ramlal, A., Jackson, H. Prevention of a sustained manner at dosages well tolerated in the pneumococcal infection in children with homozygous longer term. The first multicentre study designed to sickle-cell disease. British Medical Journal, 288: 1567- test this requirement has now been undertaken in 1570 (1984).

27 General Information WHO Drug Information Vol. 9, No. 1, 1995

5. Transfusion in management and therapy of sickle-cell 20. Charache, S. Experimental therapy of sickle-cell disease. Charache, S., Lubin, B., Reid, C. eds. (NIH disease: use of hydroxyurea. American Journal of publication 85-2117). National Institutes of Health, Pediatric Hematology and Oncology, 16: 62-66 (1994). Bethesda, MD. USA. 1985. 6. Serjeant, G. Clinical judgement and sickle-cell disease. New England Journal of Medicine, 329: 501-502 (1993). Progress in managing beta-thalassaemia: 7. Vermylen, C, Cornu, G. Bone marrow transplantation in sickle-cell anaemia. Blood Reviews, 7: 1-3 (1993). iron chelation and beyond

8. Rodgers, G., Dover, G., Ukesaka, N. et al. Augmenta­ Thalassaemia, like sickle-cell disease, is one of the tion by erythropoietin of the fetal-hemoglobin response to hereditary haemoglobinopathies. It exists principally hydroxyurea in sickle-cell disease. New England Journal among peoples of Mediterranean descent, and it is of Medicine, 328: 73-80 (1993). caused by one or another of a large number of discrete mutations that have been described in the 9. Lavelle, D., DeSimone, J., Heller, P. Fetal hemoglobin single gene that expresses beta-globin. Decreased reactivation in baboon and man: a short perspective. production of beta-globin results, in turn, in com­ American Journal of Hematology, 42: 91-95 (1993). pensatory production and accumulation of unstable 10. Fibach, E., Prassana, P., Rodgers, G., Samid, D. alfa-globin chains, impaired erythropoiesis and Enhanced fetal hemoglobin production by phenylacetate shortened red cell survival. and 4-phenylbutyrate in erythroid precursors derived from normal donors and patients with sickle-cell anemia and Children who are homozygous for this abnormal beta-thalassemia. Blood, 82: 2203-2209 (1993). gene can be protected against life-threatening anaemia and major deficiencies in growth and 11. Perrine, S., Olivieri, N., Fallen D. et al. Butyrate development by repeated blood transfusion. derivatives: new agents for stimulating fetal globin However, this approach creates an excessive iron production in the beta-globin disorders. American Journal load, which eventually gives rise — frequently of Pediatric Hematology and Oncology, 16: 67-71 (1994). during the first two decades of life — to haemochromatosis. This is characterized by 12. Yarbro, J. Mechanism of action of hydroxyurea. progressive multi-organ failure, and particularly, by Seminars in Oncology, 19: 1-10 (1992). signs of hepatic, pancreatic and cardiac 13. Dover, J., Charache, S. Hydroxyurea induction of fetal dysfunction. hemoglobin synthesis in sickle-cell disease. Seminars in Oncology, 19: 61-66 (1992). Because, in contrast to sickle-cell anaemia, homo­ zygous beta-thalassaemia has a clearly defined 14. Rogers, G. Spectrum of fetal hemoglobin responses in phenotype, prenatal diagnosis and genetic sickle-cell patients treated with hydroxyurea: the National counselling have been used with success to reduce Institutes of Health experience. Seminars in Oncology, 19: 67-73 (1992). the incidence of the disease (1). In patients with normal liver function, bone marrow grafts using 15. el-Hasmi, M., Warsy, A., al-Momen, A., Harakati, M. tissue from an HLA-identical related donor have Hydroxyurea for the treatment of sickle-cell disease. Acta resulted in a 90% three-year survival rate — but Haematologica, 88: 170-174 (1992). also in an immediate death rate of some 3-5% (2). Unfortunately, however, this involves high-cost 16. Goldberg, M., Brugnara, C, Dover, G. et al. Hydroxy­ technology which has little relevance within the less urea and erythropoietin therapy in sickle-cell anemia. Seminars in Oncology, 19: 74-81 (1992). affluent countries where the disease is most prevalent. 17. Rodgers, G., Dover, G., Uyesaka, N. et al. Augmenta­ tion by erythropoietin of the fetal-haemoglobin response to Lifelong transfusions coupled with iron chelation, hydroxyurea in sickle-cell disease. New England Journal which reduces the risk of haemochromatosis by of Medicine, 328: 73-80 (1993). increasing urinary iron excretion (3), is a more realistic, albeit costly option for greater numbers of 18. Marwick, C. Trial halted as sickle-cell treatment proves children. At present, deferoxamine, a trihydroxamic itself. Journal of the American Medical Association, 273: acid derived from a strain of streptomyces, is the 611 (1995). only such agent that has been tested in routine practice (4). However, this substance has the 19. Vichinsky, E., Lubin, P. A cautionary note regarding important disadvantage that it must be administered hydroxyurea in sickle-cell disease. Blood, 83: 1124-1128 parenterally, either intravenously, intramuscularly or (1994).

28 WHO Drug Information Vol. 9, No. 1, 1995 General Information

subcutaneously. When injections can be given 5. Cohen, A., Martin, M., Schwartz, E. Depletion of regularly, it has been shown to be generally excessive liver iron stores with desferrioxamine. British beneficial in ameliorating organ dysfunction (5-9), Journal of Haematology, 58: 369-373 (1984). improving growth and sexual maturation (10, 11), and extending survival (12, 13). None the less, the 6. Marcus, R., Davies, S., Bantock, H. et al. Desferrioxamine to improve cardiac function in iron- response to such treatment has at best been overloaded patients with thalassaemia major. Lancet, 1: unpredictable and sometimes virtually lacking (6). 392-393 (1984).

More recent long-term assessment of relatively 7. Wolfe, L, Olivieri, N., Sallan, D. et al. Prevention of large cohorts of patients has shown that the cardiac disease by subcutaneous deferoxamine in prognosis for survival deteriorates sharply within patients with thalassemia major. New England Journal of two groups of patients: those who begin chelation Medicine, 312: 1600-1603 (1985). therapy relatively late in the course of their disease and those who receive relatively little deferoxamine 8. De Sanctis, V., Zurlo, M., Senesi, E. et al. Insulin- dependent diabetes in thalassemia. Archives of Diseases in relation to their transfused iron load (14, 15). In of Childhood, 63: 58-62 (1988). these groups, irreversible myocardial damage from iron overload has been the dominant cause of 9. Freeman, A., Giles, R., Berdoukas, V. et al. Sustained death. normalization of cardiac function by chelation therapy in thalassemia major. Clinical and Laboratory Haematology, If chelation therapy is to work, two needs must be 11:299-307 (1989). met. Iron toxicity must be diagnosed early before it causes symptoms, and care must be taken to 10. Borgna-Pignatti, C, De Stefano, P., Zonta, L. et al. Growth and sexual maturation in thalassemia major. ensure that deferoxamine is administered regularly Journal of Pediatrics, 106: 150-155 (1985). (1). Administration will be greatly simplified if development of a promising orally-active agent is 11. Bronspiegel-Weintrob, N., Olivieri, N., Tyler, B. et al. successfully concluded (16). In the long term, Effect of age at the start of iron-chelation therapy on however, efforts need to be directed to approaches gonadal function in beta-thalassemia major. New England that dispose of the need for transfused blood and Journal of Medicine, 323: 713-719 (1990). the risks inevitably associated with its use. Various agents now under development that have been 12. Zurlo, M., De Stephano, P., Borgna-Pignatti, C. et al. found to induce the production of fetal haemoglobin Survival and causes of death in thalassaemia major. in patients with sickle-cell anaemia (see page 26), Lancet, 2:27-30 (1989). may well have broader application in thalassaemia 13. Ehlers, K., Giardina, P., Lesser, M. et al. Prolonged and other beta-haemoglobinopathies (17). A more survival in patients with beta-thalassemia major treated precise definition of their therapeutic potential holds with deferoxamine. Journal of Pediatrics, 118: 540-545 interest for considerable numbers of patients. (1991).

References 14. Olivieri, N., Nathan, D., MacMillan, J. et al. Survival in medically treated patients with homozygous beta- 1. Dover, G., Valle, D. Therapy for beta-thalassemia: a thalassemia. New England Journal of Medicine, 331: 574- paradigm for the treatment of genetic disorders. New 578 (1994). England Journal of Medicine, 331: 609-610 (1994). 15. Brittenham, G., Griffith, P., Nienhuis, A. et al. Efficacy of deferoxamine in preventing complications of iron 2. Lucarelli, G., Galimberti, M., Polchi, P. et al. Marrow overload in patients with thalassemia major. New England transplantation in patients with thalassemia responsive to Journal of Medicine, 331: 567-573 (1994). iron-chelation therapy. New England Journal of Medicine, 329:840-844 (1993). 16. Olivieri, N., Koren, G., Matsui, D. et al. Reduction of tissue iron stores and normalization of serum ferritin 3. Sephton Smith, R. Iron excretion in thalassaemia major during treatment with the oral iron chelator L1 in after administration of chelating agents. British Medical thalassemia intermedia. Blood, 79: 2741-2748 (1992). Journal, 2: 1577-1580 (1962). 17. Stamatoyannopoulos, J., Nienhuis, A. Therapeutic 4. Brittenham, G. Development of iron-chelating agents for approaches to hemoglobin switching in treatment of clinical use. Blood, 80: 569-574 (1992). hemoglobinopathies. Annual Reviews of Medicine, 43: 497-521 (1992).

29 WHO Drug Information Vol. 9, No. 1, 1995

Regulatory Matters

Source: Committee on Safety of Medicines. Current Cyproterone acetate Problems in Pharmacovigilance, Vol. 21, 1995. and hepatic reactions United Kingdom — Cyproterone acetate is an anti- High-potency pancreatins androgen used for a variety of purposes, including treatment of prostatic cancer, severe hypersexuality and bowel strictures and sexual deviation in the male. Together with the United Kingdom — The Committee on Safety of estrogen, ethinylestradial, it is also used at con­ Medicines has advised doctors that unless special siderably lower dosage as a hormone treatment for reasons exist, patients with cystic fibrosis should acne in women. not use high-potency pancreatins.

Abnormalities of liver function, including jaundice This statement supplements a warning first issued and hepatitis, have previously been associated with in December 1993 concerning seven cases of ileo- its use, and evidence of serious dose-related caecal stricture in children who had been treated hepatic toxicity with prolonged use has recently with these enzyme supplements (1-3). Since then, been reported by the Committee on Safety of a further six cases have been described in the UK Medicines (1). In all, 96 reports have been received and similar cases have been reported from North of patients who developed hepatic reactions, America. Among the British children, twelve were including hepatitis, cholestatic jaundice and hepatic boys aged between 2 and 13 years. The stricture failure. almost always affected the ascending colon, and in some cases fibrosis extended from the ileo-caecal All but five of these reactions occurred in elderly valve to the transverse colon. men who had been receiving cyproterone acetate for prostatic cancer over a period of several The mechanism of the reaction remains unknown, months, usually at the highest recommended dose but investigations are in hand to establish its of 300 mg daily. Having regard to this pattern of frequency and to identify risk factors. The toxicity, the Committee recommends that use of Committee stresses the need to monitor carefully cyproterone acetate in prostatic cancer should be all patients who have received these products, and restricted to: to consider the possibility of large bowel stricture, should symptoms suggestive of gastrointestinal • short courses to cover the testosterone flare obstruction arise. associated with LHRH agonists. References • treatment of hot flushes after orchidectomy or use of LHRH agonists. 1. WHO Drug Information, 8 (2): 68 (1994).

• patients who have not responded to, or who are 2. Smyth, R., et al. Strictures of ascending colon in cystic intolerant of, other treatments. fibrosis and high-strength pancreatic enzymes. Lancet, 343:85-86 (1994). Liver function tests should be conducted before 3. Letters to the editor. Lancet, 343: 109-110 (1994). treatment and whenever symptoms or signs are suggestive of hepatic impairment. Treatment should normally be stopped if evidence of hepatotoxicity Metformin gains approval in USA develops. United States of America — The Food and Drug These concerns and precautions do not apply to Administration has issued a note to explain its the use of cyproterone in women for the treatment decision, taken in response to an advisory of acne or hirsutism at dosages of the order of 2 mg committee recommendation in March 1994, to daily. approve the biguanide hypoglycaemic agent,

30 WHO Drug Information Vol. 9, No. 1, 1995 Regulatory Matters

metformin (Glucophage®, Lipha Pharmaceuticals/ 2. WHO Drug Information, 8: 27 (1994). Bristol Myers), for patients with type-II diabetes mellitus not responding adequately to dietary 3. United States Federal Register, 42: 23170-23174 regimens alone (1). The Agency had earlier (1977). decided to make metformin hydrochloride available 4. University Group Diabetes Program. Effects of hypo­ to clinical investigators for treating patients with glycemic agents on vascular complications in patients non-insulin-dependent diabetes mellitus who met with adult onset diabetes. IV: A preliminary report on stringent protocol criteria (2). phenformin results. Journal of the American Medical Association, 217: 777-784 (1971). Metformin was not approved for use in the USA when international concern about the safety of 5. Hall, G., Crowley, M., Bloom, A. Oral treatment of biguanides arose in the 1970s. At that time it diabetes: a trial of phenethyldiguanide. British Medical became apparent that the more widely-used Journal, 2: 71-74 (1958). congener, phenformin, was associated with cases 6. Craig, J., Miller, M., Woodward, H., Merik, E. Influence of potentially fatal lactic acidosis (3) and, less of phenethylbiguanide on lactic, pyruvic and citric acids in certainly, with an increased incidence of cardio­ diabetic patients. Diabetes, 9: 186-193 (1960). vascular deaths (4). 7. Walker, R., Linton, A., Thomson, W. Mode of action and The propensity of phenformin to promote subclinical side-effects of phenformin hydrochloride. British Medical degrees of ketonuria and acidosis which persisted Journal, 2: 1567-1569 (1960). in the presence of substantial doses of insulin had been recognized at the time of its development in 8. Olíva, G. Lactic acidosis. American Journal of Medicine, 48: 209-225 (1970). the 1950s (5-7). Only some 20 years later was an association established between routine clinical use 9. Bengtsson, K., Karlberg, B., Lindgren, S. Lactic of the drug and deaths from severe lactic acidosis acidosis in phenformin-treated diabetics. Acta Medica (8-15), and this resulted in its withdrawal in many Scandinavica, 191: 203-208 (1972). countries. The less widely-used congener, bufor¬ min, was shown on the basis of German data, to be 10. Assan, R., Heuclin, C, Girard, J. et al. Phenformin- associated with similar risk (16-18). induced lactic acidosis in diabetic patients. Diabetes, 24: 791-800 (1975). It was initially assumed that this hazard would be 11. Brach, B., Blackard, W., Rothschild, H. A review of shared by all biguanides (19). However, no deaths due to suspected lactic acidosis at a large restrictive regulatory action was taken in connection metropolitan hospital. Southern Medical Journal, 68: 202- with metformin in any of the many countries in 205 (1975). which it was registered: reassuring evidence was offered that it exerted less effect on blood lactate 12. Conlay, L., Loewenstein, J. Phenformin and lactic levels (20, 21) and that it was associated with few acidosis. Journal of the American Medical Association, of the cases of acidosis reported to national drug 235: 1575-1578 (1976). monitoring centres (22). 13. Fulop, M., Hoberman, H. Phenformin-associated metabolic acidosis. Diabetes, 25: 292-296 (1976). The importance of metformin is that it reduces blood sugar levels by a distinctive mechanism, and 14. Gale, E., Tattersall, R. Can phenformin-induced lactic in the absence of functional pancreatic beta-cells acidosis be prevented? British Medical Journal, 2: 972- (23). It has been used extensively in the treatment 975 (1976). of late-onset diabetes, particularly in patients who fail to respond adequately to diet and sulfonylureas. 15. Wise, P., Chapman, M., Thomas, D. et al. Phenformin As a condition of marketing in the USA, the and lactic acidosis. British Medical Journal, 1: 70-72 manufacturer will conduct a postmarketing study (1976). involving some 10 000 patients with a view to assessing potential risks associated with acidosis 16. Clavadetscher, P., Bischof, P., Wegmann, T. Lactat- and adverse cardiovascular events. Acidose nach Buformin-Medikation, Deutsche medizinische Wochenschrift, 101: 238-241 (1976).

References 17. Thimme, W., Buschmann, H., Dismann,. W., Amft, R. Biguanidtherapie und Lactatacidose. Medizinische Klinik, 1. Food and Drug Administration. FDA approves new 71: 1429-1433 (1976). diabetes drug. Talk Paper T94-64, 1994.

31 Regulatory Matters WHO Drug Information Vol. 9, No. 1, 1995

18. Luft, D., Muller, P. Laktazidose bei Biguanid- A special paediatric subcommittee will be estab­ behandelten Diabetikern, Medizinische Welt, 28: 378-383 lished within the FDA to monitor the implementation (1977). of the new regulation and to draft policies, regula­ 19. Albert, K., Nattrass, M. Lactic acidosis. Lancet, 2: 25- tions and guidelines consonant with its aims. The 29 (1977). agency will work in collaboration with paediatric pharmacology research units funded by the 20. Phillips, P., Thomas, D., Harding, P. Oral hypo¬ National Institute of Child Health and Human glycaemic agents — dangers and contraindications. Development to ensure that relevant studies are Medical Journal of Australia, 1: 155 (1977). conducted on selected products. It will also ensure 21. Alexander, W., Marples, J. Biguanides and lactic that requisite paediatric information is developed for acidosis. Lancet, 1:191-192 (1977). new drugs under investigation which have potential use in diseases of childhood. 22. Phenformin and lactic acidosis. WHO Drug Informa­ tion Bulletin, PDT/DI/77.2, (1977). Source: Federal Register, 13 December 1994.

23. Nielsen, R., Swanson, H., Tanner, D. et al. Effects on blood sugar of a new potent hypoglycemic compound. Pimozide and cardiac arrhythmias Archives of Internal Medicine, 101:211-215 (1958). United Kingdom — In 1990 the Committee on Safety of Medicines first issued a warning that New requirements serious cardiac arrhythmias had been associated for paediatric labelling with use of the antipsychotic drug, pimozide. At that time it recommended that: United States of America — Since 1979 the Food and Drug Administration has required all newly • treatment with pimozide should be started at a low proposed paediatric indications for drug products to dose (usually 2-4 mg daily) and any increase in be supported by evidence obtained from clinical dose must be made slowly (maximum increments studies involving children. With a view to avoiding of 2-4 mg daily at intervals of at least one week) non-essential involvement of children in formal up to a maximum of 20 mg daily. trials, this requirement will now be relaxed at the discretion of the FDA, to enable such claims to be • pimozide should not be prescribed for patients based upon extrapolation of results obtained in with pre-existing prolongation of the QT interval or studies on adults when other information — and in patients with a history of cardiac arrhythmias. particularly pharmacokinetic and safety data — An ECG should thus be performed prior to starting support paediatric use. treatment.

Proposed indications supported by such data will The Committee continues to receive reports of be considered only when the course of the disease serious cardiac reactions associated with use of and the effects of the drug are sufficiently similar in pimozide (1). A total of 40 has now been received adults and children to permit confident extra­ since pimozide first became available in 1971, and polation. 16 of these have been fatal. The Committee The rule additionally provides for the FDA to consequently now additionally recommends that: request a manufacturer to present information on the use of a specific product in children, particularly • patients on pimozide should have an annual ECG. when the product is known to be of therapeutic If the QT interval is prolonged, treatment should importance in paediatric practice, or when its use is be reviewed and either withdrawn or the dose known to be associated with a specific hazard to reduced under close supervision. children. • concurrent treatment with the following drugs Manufacturers are expected to re-examine existing should be avoided: other antipsychotic drugs, statements on the paediatric use of their products including depot preparations; tricyclic having regard to additional relevant information antidepressants; other drugs that are known to obtained in adults. Should they consider an amend­ prolong the QT interval, including some anti­ ment to be necessary, they are required to submit malarials, anti-arrhythmic agents, and certain an application for supplementary labelling within a antihistamines; and diuretics and other drugs that period of two years. cause electrolyte disturbances.

32 WHO Drug Information Vol. 9, No. 1, 1995 Regulatory Matters

Pimozide is not the only antipsychotic agent that disulfiram, the only other product approved for may prolong the QT interval. Sudden deaths have treatment of alcoholism in the USA, naltrexone been associated with other such agents when used does not interact with alcohol. It seems to assist at high dosage or in combination. A Working Party abstention in patients who are actively collaborating set up by the Royal College of Psychiatrists has in a treatment plan. recently produced guidelines on maximum recommended doses which are now included in the This effect has been demonstrated in two placebo- British National Formulary (No. 28, 1994). controlled double-blind trials supported by the National Institute of Alcohol Abuse and Alcoholism. Source; Committee on Safety of Medicines. Current In both studies a positive effect was obtained when Problems in Pharmacovigilance, Vol. 21, February 1995. a 12-week course was administered at a dose of 50 mg daily to patients receiving social and psycho­ HIV test using oral fluid samples therapeutic care. United States of America — The Food and Drug Serious adverse reactions appear to be uncommon. Administration has approved a testing system that Nausea, which is usually mild and transient, has detects HIV antibody in oral fluids, which comprises been reported by about 10% of treated patients. a collecting device and an enzyme-linked immuno­ The product labelling, however, is required to sorbent assay (ELISA) test. include a boxed warning indicating that there is a risk of liver damage if the recommended dose is The test does not provide a definitive diagnosis of exceeded. The product is contraindicated in HIV infection. When a subject provides a positive patients with acute hepatitis or liver failure, and sample on two or more occasions, a blood doctors are advised to consider carefully and specimen should be taken for confirmatory testing. monitor its use in patients with active liver disease. The oral system is less sensitive and less specific Patients will also be told that a large dose of heroin than available blood tests. It is estimated to provide or any other narcotic substance will interact with some 23 false positive results in every 1000 tests naltrexone to cause serious injury, and possibly undertaken on high-risk subjects. False negative coma or death. results occur with a frequency of about 14:1000 in Source: Nightingale, S. From the Food and Drug these subjects. Administration. Journal of the American Medical Associa­ tion, 273: 613 (1995). The system is not intended for home use or for screening blood donors. It is available only on prescription and doctors are required to sign a Use of quinacrine for female statement that they will assume specified responsibilities intended to assure proper use of the sterilization arouses concern system, including the training of staff who will World Health Organization — In the wake of collect the specimens. Training and self-audit recent controversy concerning the instillation of the materials are provided to laboratories that wish to antimalarial drug, quinacrine into the uterus as a become accredited to test the specimens. method of female sterilization (1-4), WHO's Special Programme of Research, Development and Source: Nightingale, S. From the Food and Drug Research Training in Human Reproduction has Administration. Journal of the American Medical Associa­issued a public statement to support its view that tion, 273: 613 (1995). "toxicology testing of quinacrine must be completed before further studies are carried out in women, and Naltrexone approved as an adjunct retrospective studies of the women already treated with quinacrine must be continued and completed" in the treatment of alcoholism (5). United States of America — The Food and Drug Interest in the method was first aroused in 1980 Administration has approved naltrexone hydro­ when preliminary clinical data were published to chloride for use in the treatment of alcohol show that intrauterine instillation of a sclerosant dependence. Naltrexone, a pure opioid antagonist, dose of quinacrine has the potential to occlude the was already marketed as an adjunct for the Fallopian tubes (6). Extensive experience of the treatment of narcotic dependency. Unlike

33 Regulatory Matters WHO Drug Information Vol. 9, No. 1, 1995

approach was reported in 1993 (7), and the WHO Clozapine and myocarditis Programme estimates that, in all, some 70 000 women in several developing countries, particularly Statement received from Sandoz Pharmaceuticals, in South and South-East Asia, have now been United Kingdom, on 3 January 1995. sterilized in this way. WHO's concern at this use is centred on three issues: lack of understanding of Worldwide — With reference to an item in WHO exactly how the treatment affects the Fallopian Drug Information, Vol. 8, 1994, p. 66, prompt action tube; inadequate toxicological testing to establish has been taken by Sandoz Pharma Ltd. regarding the safety of administering quinacrine by this route; the occurrence of myocarditis during clozapine and lack of approval of the method by any national treatment. It is currently recommended that if drug regulatory authority. clinical suspicion of myocarditis is high, then anti­ psychotic medication, including clozapine, should Existing studies on quinacrine, it believes, have not be stopped (1). provided consistent information: protocols, methods Myocarditis is difficult to diagnose and is reported of instillation, and the dosage of quinacrine as an incidental finding in 10% of routine necrop­ administered have each varied substantially. In sies (2). This, together with the difficulty of some centres, women were given supplementary distinguishing between viral myocarditis and drug- nonsteroidal anti-inflammatory drugs. Limited induced myocarditis clinically, resulted in the toxicological testing of quinacrine completed more formulation of a checklist based on advice from than a decade ago is considered inadequate to leading cardiologists in the United Kingdom. The satisfy contemporary standards. In particular, WHO purpose of this checklist is to help in the assess­ emphasizes, the full range of genotoxicity studies ment of these complex cases particularly as these that would now be required by major drug regu­ patients are often on multiple medications. It will not latory agencies has not been applied. only help to confirm the diagnosis of myocarditis, but will also assess if there is any possible asso­ References ciation between myocarditis and clozapine therapy and look at possible etiological risk factors. 1. Death of a study: WHO, what, and why. Lancet, 343: 987-988 (1994). To provide the basis of a prospective survey, which started in January 1994, this checklist is sent to 2. Hieu, D.T. Quinacrine method of family planning (letter). every psychiatrist who reports a suspected case of Lancet, 343: 1040 (1994). myocarditis in a patient receiving clozapine. This 3. Letters to the Editor. Quinacrine family-planning may provide a better understanding of the true method. Lancet, 343: 1425-1427 (1994). etiology of these cases. The use of clozapine is restricted to treatment- 4. Benagiano, G. Sterilization by quinacrine (letter). Lancet, 344: 689 (1994). resistant schizophrenia; such patients are likely to have had a long exposure to phenothiazines which 5. UNDP/UNFPA/WHO/World Bank Special Programme are themselves a potential cause of cardiac lesions of Research, Development and Research Training in (3). Human Reproduction. Scientific review body voices concern at use of quinacrine for sterilization. Progress in The results of this prospective survey will be sent to Human Reproduction Research, Geneva, No. 31. (1994). the Medicines Control Agency after analysis in mid- 1995. Of the cases reported so far during the first 6. Zipper, J., Cole, L., Goldsmith, A. et al. Quinacrine 10 months of 1994, there have been no confirmed hydrochloride pellets: preliminary data on a nonsurgical cases of clozapine-induced myocarditis. method of female sterilization. International Journal of Gynaecology and Obstetrics, 18: 275-279 (1980). Sources 1. Current Problems in Pharmacovigilance, 19:9-10, 1993. 7. Hieu, D.T., Tan, T., Tan, D. et al. 31 781 cases of non­ surgical female sterilization with quinacrine tablets in 2. Peters, N.S. Myocarditis: a controversial disease. Vietnam. Lancet, 342: 213-217 (1993). Journal of the Royal Society of Medicine, 84:1-2 (1991). 3. Kerwin, R. Adverse reaction reporting and new antipsychotics. Lancet, 342: 1440 (1993).

34 WHO Drug Information Vol. 9, No. 1, 1995

Essential Drugs

Rheumatoid arthritis NSAIDs act by inhibiting the formation of inflam­ matory mediator substances including prosta­ Rheumatoid arthritis is a chronic progressive glandins. Many different products are available, and inflammatory disease involving joints and other it remains impossible to predict which will be most tissues. It occurs in some 1-3% of adults world­ effective in a given patient. It is often necessary to wide. It is five times more common in women than try several different products in sequence in order in men, and its incidence increases up to the age of to select, on an empirical basis, one that is well 60. Clinically, it is typified by a symmetrical, tolerated and effective. Only one orally- destructive and deforming polyarthritis affecting administered NSAID should be prescribed at a time small and large peripheral joints. It is associated and the lowest effective dosage should be with a systemic disturbance and it is characterized prescribed. Paracetamol is sometimes used as a by the presence of circulating antiglobulin anti­ supplement. It has been claimed to augment the bodies (rheumatoid factors). The inflammatory analgesic effect. Because it has no anti-inflamma­ process, which eventually results in crippling tory effect, paracetamol has little other application disablement, usually follows a remitting course, but in the management of rheumatoid arthritis. it may be rapidly progressive. It is advisable to use ibuprofen in the first instance The pathological basis of the condition remains because it has been associated with the lowest risk uncertain, but it seems to be associated with T of adverse effects. Conversely, azapropazone is lymphocyte activation in genetically-predisposed generally regarded as having significantly greater individuals. The inappropriate chronic inflammatory toxicity; it should be reserved for patients who have response damages the synovial tissue lining the not responded to other NSAIDs. It should never be joints. This may first become apparent as an acute prescribed for patients with a history of peptic episode of pain, stiffness and symmetrical swelling ulceration. Patients over 60 years of age requiring of a number of peripheral joints. In other cases, the treatment over extended periods should not take patient may complain of malaise and general more than 600 mg daily. Other widely-used fatigue well before the joints become affected. As compounds, including indometacin, ketoprofen, the disease advances, muscle atrophy and joint naproxen, diclofenac and piroxicam are associated destruction limit movement and lead to deformities. with intermediate risk. Extra-articular signs of the disease occur most Gastrointestinal disturbances are the most fre­ commonly in the ocular, cardiovascular, renal, quently reported adverse effects. Inhibition of the haemopoietic and nervous systems. cytoprotective effect of prostaglandins on the gastric mucosa can result in dyspepsia, peptic Management ulceration and haemorrhage. NSAIDs should The management of rheumatoid arthritis is directed consequently never be given to patients with active to relief of symptoms, suppression of active disease gastrointestinal ulceration. Disruption of the and conservation or restoration of function in the regulatory effect of prostaglandins on renal blood affected joints. flow can reduce filtration and result in acute or chronic renal failure. Hepatic dysfunction, blood Pain is controlled and inflammation suppressed in disorders, anaphylaxis and other allergies have the first instance with acetylsalicylic acid and, when also been shown to be associated with use of these this fails, with another nonsteroidal anti-inflamma­ drugs. tory drug (NSAID) to which a slow-acting anti­ rheumatic drug (SAARD) may be added. Physical Administration of a histamine H2-receptor blocking therapy, including general and specific exercises, agent or misoprostol may enable patients who are educational programmes and psychological support vitally dependent on NSAIDs for effective relief of are also important in preserving joint function. pain and stiffness to recommence treatment with an Surgical interventions, including total joint replace­ NSAID following gastrointestinal haemorrhage ment, may ameliorate severe handicap. without high risk of recurrence.

35 Essential Drugs WHO Drug Information Vol. 9, No. 1, 1995

If significant symptoms and signs of inflammation arthritis. They are sometimes administered at lower persist after several weeks of intensive NSAID dosage over longer periods in combination with therapy, use of SAARDs should be considered. slow-acting antirheumatic drugs. However, because These are a diverse group of substances which of the danger of inducing Cushing's syndrome, they include aminoquinolones, sulfasalazine, penicill­ should be used only when other drugs have proved amine, methotrexate and organic gold compounds. ineffective in controlling severe progressive They share the potential to slow the rate of disease. The smallest effective dose should be functional deterioration. Treatment should be used and continuous attempts should be made to started early in the course of the disease before gradually reduce the daily requirement. A relatively significant joint damage has occurred. However, high dose — used together with cyclophosphamide specialist training is required to ensure they are or other immunosuppressive drug — may be used safely and to best advantage. needed to control severe vasculitis. Otherwise, the dose should not exceed the equivalent of 10 mg Chloroquine and hydroxychloroquine are relatively prednisolone daily. A small evening dose is often inexpensive, but they are not as effective as the effective in relieving morning stiffness in elderly other agents. Because long-term therapy (par­ patients. ticularly with chloroquine) can result in retinopathy, ophthalmological examinations need to be conducted at the outset of treatment and at three- ACETYLSALICYLIC ACID monthly intervals for as long as treatment is tablet: 100-500 mg continued. suppository: 50-150 mg Sulfasalazine is effective, but it is poorly tolerated Acetylsalicylic acid has anti-inflammatory, anal­ by perhaps one quarter of patients treated. Nausea, gesic, antipyretic, antithrombotic and antirheumatic vomiting, abdominal pain, and a wide range of activity. In part, these effects result from inhibition cutaneous reactions are frequently reported. of the synthesis of endogenous prostaglandins. In Hepatotoxicity may also occur. rheumatoid arthritis, acetylsalicylic acid relieves symptoms but it does not affect the underlying Penicillamine is no longer extensively used. It is disease process. not satisfactorily effective in the longer term, and it is associated with a high incidence of serious The compound is hydrolysed partly in the gut and adverse effects including rashes, proteinuria and partly in the liver, and it is excreted mainly in the blood dyscrasias. urine, both as free salicylic acid and as inactive metabolites. The plasma half-life of salicylic acid is Intramuscular gold compounds are still widely used. of the order of three hours and is strongly dose- They are among the most effective substances, and dependent. may delay or prevent progression of erosion in some patients. However, severe mucocutaneous, Uses bone marrow and renal toxicity limit their accept­ Control of pain and suppression of inflammation in ability. rheumatoid arthritis. Methotrexate has become the most widely pre­ scribed drug of this group. At the dosages used for Dosage and administration rheumatoid arthritis, it is well tolerated in the short Adults: 300 mg - 1 g every 4 hours. term, but because there is a risk of hepatic and Administration with food or a full glass of water pulmonary toxicity in the longer term, patients must reduces gastric irritation. remain under close supervision throughout treatment. Contraindications Other immunosuppressive drugs, including aza¬ • Hypersensitivity to acetylsalicylic acid. thioprine, have been used with success in resistant cases. Cyclophosphamide is reserved for patients • Bleeding disorders, anticoagulant therapy, with severe systemic complications, and particularly haemorrhagic stroke, active peptic ulcer or gastritis. for life-threatening rheumatoid vasculitis. • Chronic renal insufficiency. Corticosteroids remain the most potent anti­ inflammatory substances used in rheumatoid • Haemophilia or hypoprothrombinaemia.

36 WHO Drug Information Vol. 9, No. 1, 1995 Essential Drugs

Precautions Co-administration of acetylsalicylic acid and cortico­ Symptoms of hypersensitivity are more likely to steroids greatly increases the risk of gastrointestinal occur in patients with asthma, urticaria or chronic bleeding. rhinitis; and in patients who have developed a rash or anaphylactic phenomena after exposure to other Overdosage nonsteroidal anti-inflammatory agents. Acute ingestion of 20-25 g by an adult can be lethal and smaller quantities can cause serious toxicity. A mild haemolytic reaction may occur in patients with glucose-6-phosphate dehydrogenase Characteristic early symptoms of overdosage deficiency. include nausea and vomiting, abdominal pain and To avoid the risk of haemorrhage, acetylsalicylic tinnitus which may ultimately progress to deafness. acid should not be administered within 7 days of an These are followed by flushing, sweating and elective surgical operation. hyperventilation with respiratory alkalosis. In severe cases, metabolic acidosis and coma supervene. Acetylsalicylic acid must at all times be kept out of the reach of children. Activated charcoal is the preferred treatment for salicylate poisoning with an initial dose of 50 g for Use in pregnancy adults which can be repeated every four hours until Occasional use of acetylsalicylic acid carries no symptomatic improvement occurs. Hyperthermia, apparent risk during early pregnancy. However, it dehydration, acidosis and potassium deficiency should not be taken during the last three months of should be corrected symptomatically. pregnancy since it has been reported to prolong labour and contribute to perinatal bleeding in the Whole blood transfusion may be necessary in the mother and child. event of spontaneous haemorrhage. No advantage is obtained by administering vitamin K supple­ Adverse effects ments. Hypersensitivity reactions, which may occasionally be severe, include urticaria, angio-oedema, pruri­ Sodium bicarbonate may be administered to tus, and anaphylactic phenomena. alkalinize the urine and to promote urinary Gastrointestinal effects, which include dyspepsia, excretion. However, when the serum salicylate heartburn, epigastric distress and nausea, are concentration is dangerously high or when serious common and sometimes severe. Gastrointestinal complications develop, such as unresponsive bleeding can result from acute mucosal erosion or acidosis, impaired urinary output, pulmonary reactivation of peptic ulceration. Bleeding is oedema, persistent seizures or coma, haemo¬ commonly occult but occasionally profuse and even dialysis may offer the only hope of survival. fatal. Storage Inhibition of platelet aggregation may result in Acetylsalicylic acid tablets should be kept in tightly prolongation of bleeding time. Leukopenia, thrombo­ closed containers. If an odour of acetic acid is cytopenia, purpura and pancytopenia have rarely perceptible on opening the container, the tablets been reported. should be discarded. Suppositories should be stored below 15° C. Hearing disturbances such as tinnitus, vertigo and mental confusion may occur with high dosage. IBUPROFEN Drug interactions Concomitant use of NSAIDs increases the tablet: 200 mg, 400 mg, 600 mg incidence of adverse gastrointestinal effects but suppository: 500 mg does not enhance the therapeutic effect. oral solution: 20 mg/ml

The therapeutic action of anticoagulants may be Ibuprofen is a nonsteroidal anti-inflammatory agent potentiated. (NSAID) with analgesic, anti-inflammatory and Conversely, the efficacy of uricosuric agents and antipyretic actions. It acts by inhibiting prosta­ spironolactone may be reduced. glandin synthesis. In rheumatoid arthritis, ibuprofen and other NSAIDs relieve symptoms but they do

37 Essential Drugs WHO Drug Information Vol. 9, No. 1, 1995

not affect the underlying disease process. Whereas some cases of reversible amblyopia have been the analgesic action of a single dose lasts 6-8 reported. hours, the maximum benefit in patients with rheumatoid arthritis may be obtained only after Ibuprofen inhibits platelet aggregation and bleeding several months of regular use. Whenever possible, time is prolonged. the decision to start treatment with an NSAID and the subsequent monitoring of its effects should be Reversible acute renal failure has been provoked. undertaken by a specialist rheumatologist. Rarely, papilliary necrosis or interstitial fibrosis has been reported. Ibuprofen is largely metabolized in the liver. It has a plasma half-life of 2 hours and is excreted by the Rarely reported reactions include aseptic menin­ kidneys. gitis, exacerbation of connective-tissue disorders, fluid retention and hepatic damage. Uses To control pain and suppress inflammation in Drug interactions rheumatoid arthritis. Concomitant use of acetylsalicylic acid or other NSAIDs increases the incidence of gastrointestinal Dosage and administration adverse effects but does not enhance the thera­ Adults: 400-3600 mg daily in divided doses, as peutic effect. determined by the response. Administration with food or water may reduce Overdosage gastric irritation. Rectal absorption is slow and Dizziness, nystagmus, apnoea, and hypotension incomplete but suppositories may be of value in leading to loss of consciousness are symptoms of patients unable to take oral dosage forms overdosage. Gastric lavage and supportive measures are necessary. Most patients recover Contraindications without serious sequelae. Hypersensitivity to acetylsalicylic acid or any NSAID including asthma, angioedema, urticuria or rhinitis. Storage Peptic ulceration. Preparations of ibuprofen should be stored in well- closed containers, protected from light. Precautions Particularly careful consideration should be given to using NSAIDs in the elderly and in patients with a INDOMETACIN history of peptic ulcer or bleeding disorder. Dys­ capsule or tablet: 25 mg pepsia may be reduced by taking each dose capsule: 50 mg together with food or milk. suppository: 100 mg Patients with impaired renal function should be oral solution: 5 mg/ml monitored carefully throughout treatment. injection: 50 mg/10 ml

Use in pregnancy Indometacin, a nonsteroidal anti-inflammatory Safe use in pregnancy has not been established. agent (NSAID) with analgesic, anti-inflammatory Ibuprofen should be used only when the need of and antipyretic effects. Its action in rheumatoid the mother outweighs any possible risk to the fetus. arthritis is qualitatively identical to that of ibuprofen.

Adverse effects It is rapidly and almost completely absorbed from Among the NSAIDs, ibuprofen is associated with the gastrointestinal tract. The plasma half-life is 5- the least overall risk of adverse effects. 10 hours. It is metabolized in the liver and excreted as metabolites and unchanged drug in the bile and Gastrointestinal adverse reactions including dys­ urine. pepsia, peptic ulceration, and haemorrhage usually necessitate withdrawal of treatment (see p. 35). Uses Hypersensitivity reactions (particularly angioedema, To control pain and suppress inflammation in bronchospasm and rash), dizziness, headache and rheumatoid arthritis.

38 WHO Drug Information Vol. 9, No. 1, 1995 Essential Drugs

Dosage and administration Uses Adults. 100-200 mg daily in divided doses Slowing of disease progression in rheumatoid arthritis Contraindications, precautions, use in pregnancy and adverse effects Dosage and administration As for ibuprofen. Adults: 3.5 mg/kg up to a maximum of 250 mg daily. Indometacin has been claimed to have more severe effects on the central nervous system than other Contraindications NSAIDs. It may aggravate psychiatric disorders, Known hypersensitivity. epilepsy or parkinsonism. Severe headache, depression and disorientation have been described Precautions with higher doses. Baseline renal function should be measured, since the need for dosage reduction should be Drug interactions considered in patients with renal impairment. Concomitant use of acetylsalicylic acid or other NSAIDs increases the incidence of adverse Hepatic function should be carefully monitored gastrointestinal effects but does not enhance the throughout treatment in patients with pre-existing therapeutic effect. hepatic disease. Serum concentrations of lithium are elevated when given with indometacin. An ophthalmic examination should be carried out before treatment is started and subsequently at Indometacin may reduce the diuretic and anti­ three monthly intervals to detect dose-related hypertensive effects of furosemide, thiazides and deposition of pigment and scotomata. In patients potassium-sparing diuretics. with normal renal function ocular toxicity rarely occurs at daily dosages less than 3.5 mg/kg. Overdosage Nausea, vomiting, headache, dizziness, mental Use in pregnancy confusion, disorientation and lethargy are symp­ No untoward effects have been demonstrated, but toms of acute overdosage. treatment is best deferred, when possible, until after Gastric lavage and supportive treatment is the first trimester of pregnancy. necessary. Adverse effects Storage Transient headaches and gastrointestinal symp­ Preparations should be stored in tightly closed toms are occasionally troublesome. containers, protected from light. Corneal deposits are common and reversible; accommodation defects and irreversible retinopa­ CHLOROQUINE thy are unlikely to occur at recommended dosages. tablet: 100 mg, 150 mg base (as Chloroquine may precipitate a severe exacerbation phosphate or sulfate ) of psoriasis.

Chloroquine is a 4-aminoquinoline antimalarial Overdosage drug. In common with other slow-acting anti­ Acute chloroquine poisoning is often fatal; the rheumatic drugs, chloroquine gradually improves lethal dose may be as low as 50 mg chloroquine symptoms and suppresses serological markers of base/kg. Nausea, vomiting and drowsiness, which active rheumatoid arthritis. It also slows the occur rapidly, are followed by slurring of speech, progression of the disease, but it is uncertain agitation, visual impairment, breathlessness due to whether it modifies the ultimate outcome. pulmonary oedema, cardiac dysrhythmias, convul­ It is absorbed efficiently from the gastrointestinal sions and coma. tract and peak plasma concentrations occur within 2-3 hours. The drug and its metabolites can be Emesis must be induced, or gastric lavage detected in the plasma for up to 2 months and in undertaken, as rapidly as possible if the patient is the urine for up to 4 months after a single dose. seen within a few hours of ingestion. Otherwise

39 Essential Drugs WHO Drug Information Vol. 9, No. 1, 1995

treatment is symptomatic and is directed Analysis of urine for presence of protein should be particularly to sustaining cardiovascular and performed at weekly intervals and subsequently respiratory function. Diazepam may help to control every four weeks. convulsions. Adverse reactions Storage Allergic reactions occur in about one-third of Tablets should be kept in well-closed containers, patients. Most common is a generalized skin rash. protected from light and moisture. Rarely, myositis, myasthenia or drug-induced lupus erythematosus has been reported. PENICILLAMINE Gastrointestinal effects include anorexia, nausea, epigastric pain and dyspepsia. Taste impairment is capsule or tablet: 250 mg common. Penicillamine is a monothiol chelating agent which Adverse haematological reactions include is a degradation product of all penicillins. Its leukopenia, thrombocytopenia and bone marrow mechanism of action in the treatment of rheumatoid depression. arthritis may be related to inhibition of collagen formation. Its effect in slowing the progression of Proteinuria, a sign of immune complex nephritis, the disease is similar to that of intramuscular gold. sometimes resolves on adjustment of dosage. However, it is less effective in the longer term, and it is associated with a higher incidence of adverse Drug interactions effects. The absorption of penicillamine is reduced by iron.

It is readily absorbed from the gastrointestinal tract, Storage metabolized in the liver, and excreted in the urine Tablets and capsules should be stored in tightly and faeces as inactive disulfides. closed containers.

Uses Treatment of active rheumatoid arthritis unrespon­ SULFASALAZINE sive to acetylsalicylic acid and NSAIDs. tablet: 500 mg Dosage Sulfasalazine is composed of sulfapyridine and 5- Adults: 125 mg daily for one month and sub­ aminosalicylic acid joined by a diazo bond. When sequently increased to 250 mg, 500 mg, and 750 administered in enteric-coated formulations, it is mg daily at four to six week intervals. split in the colon into its component parts.

Contraindications Uses History of penicillamine-induced agranulocytosis, Treatment of active rheumatoid arthritis aplastic anaemia or severe thrombocytopenia. unresponsive to acetylsalicylic acid and NSAIDs. It Renal impairment. is probably less effective than intramuscular gold or Lupus erythematosus. penicillamine, but it is better tolerated. Pregnancy. Dosage and administration Precautions Adults: 500 mg daily in an enteric-coated formula­ Patients should be monitored closely for allergic tion-increased by 500 mg increments every 2-4 reactions. Patients hypersensitive to penicillins may weeks to a total dose of 2-4 g daily. Maintenance react similarly to penicillamine but cross-sensitivity dose is generally 2 g daily. appears to be rare. Contraindications Thrombocytopenia, which is common and often Known hypersensitivity to sulfonamides or salicy­ dose related, can occur early and is sometimes lates. Severe hepatic impairment. severe. Patients should be instructed to report immediately symptoms of fever, sore throat or Precautions unusual bleeding. The blood count should be monitored at the start of treatment and at monthly intervals thereafter.

40 WHO Drug Information Vol. 9, No. 1, 1995 Essential Drugs

Liver function tests should be carried out at regular Uses intervals. Treatment of severe active rheumatoid arthritis.

Adverse effects Dosage and administration Almost 25% of patients have to discontinue therapy Adults: 7.5 -15 mg weekly either orally or intra­ due to toxicity. muscularly. Nausea, headache, loss of appetite and fever are common adverse effects. Contraindications Pre-existing blood dyscrasias, chronic liver disease, Folate deficiency is common; adequate dietary pregnancy. intake should be assured. Hypersensitivity reactions include generalized skin Precautions rashes and urticaria and, occasionally, life-threaten­ A complete blood count and liver function test ing Stevens-Johnson syndrome or anaphylaxis. should be performed before starting therapy and every four weeks for the first year and thereafter at Patients with glucose-6-phosphate dehydrogenase three-monthly intervals. deficiency are at particular risk of haemolytic anaemia. Renal function tests should be measured every three months. Bone-marrow depression occurs rarely; toxic hepa­ titis has been reported; reversible oligospermia and Adverse effects male infertility have been described. Unwanted effects occur commonly, but are usually mild or transient in the dosage recommended for Use in pregnancy rheumatoid arthritis. Safe use in pregnancy has not been demonstrated. It should be used only when the need of the mother Gastrointestinal adverse effects include stomatitis, outweighs any possible harm to the fetus. nausea, vomiting and abdominal pain.

Drug interaction Pulmonary hypersensitivity presents with cough, Sulfasalazine can impair the absorption of digoxin fever and dyspnoea. Most patients recover on and an interval of 2-3 hours should elapse between withdrawal of treatment, but some develop pul­ oral administration of these drugs. monary fibrosis. The risk of cumulative hepatic Overdosage toxicity is more remote. Some rheumatologists Emesis and gastric lavage may be of value within a advise liver biopsy to detect possible early signs few hours of overdosage. Otherwise, treatment is of fibrosis and cirrhosis after a cumulative dose of supportive. 1.5 g (about three years' treatment). Storage Bone-marrow suppression is rare at the doses used Tablets should be stored in well-closed containers. in rheumatoid arthritis.

Drug interactions METHOTREXATE Concomitant administration of tetracycline and tablet: 2.5 mg (as sodium salt) chloramphenicol decreases methotrexate absorp­ powder for injection: 50 mg (as sodium tion. salt) in vial Toxicity may be increased by concomitant Methotrexate is a folic acid antagonist. In the doses administration of salicylate or another nonsteroidal used in rheumatoid arthritis it does not produce anti-inflammatory agent, and by use of other systemic immunosuppression. antifolate compounds.

Absorption from the gastrointestinal tract is Storage variable. Some patients respond better to intra­ Tablets and powder for injection should be stored in muscular therapy. Clinical improvement usually well-closed containers, protected from light. appears earlier than with gold or penicillamine.

41 Essential Drugs WHO Drug Information Vol. 9, No. 1, 1995

PREDNISOLONE Use in pregnancy Corticosteroids should not be administered during tablet: 5 mg, 25 mg pregnancy unless the need outweighs any possible injection: 5 mg (as sodium phosphate risk of harm to the fetus. Adrenal development may or succinate) in vial be impaired and a relationship with cleft palate and other abnormalities may exist, particularly in the Prednisolone is a synthetic glucocorticoid with case of fluorinated compounds. Dosage should be minimal mineralocorticoid properties. Its therapeutic kept as low as possible, but requirements may be effect results from inhibition of macrophage accu­ raised slightly in replacement therapy as a result of mulation, suppression of capillary-wall permeability increased binding of corticosteroids to plasma and oedema formation and reduction of fibroblast proteins during pregnancy. proliferation and collagen deposition. It is readily absorbed from the gastrointestinal tract, is exten­ Corticosteroids are secreted into breast milk and sively protein bound and has a plasma half-life of breast-feeding should be avoided. about 8 hours. Adverse effects Uses The adverse effects of long-term systemic Suppression of active rheumatoid arthritis in corticosteroids include osteoporosis, cataracts, patients unresponsive to any other treatment. poor wound healing, gastrointestinal bleeding, hyperglycaemia, hypertension, and increased risk Dosage and administration of infection. Quiescent tuberculosis may be The lowest dosage to produce an acceptable reactivated, and psoriasis may be exacerbated on clinical response should be used. Dosage should withdrawal of therapy. not exceed 7.5-10 mg daily. Drug interactions Contraindications Hepatic enzyme inducers including phenobarbitone, Prednisolone should not be used unless other anti­ phenytoin and rifampicin may accelerate the inflammatory and disease-modifying drugs have metabolism of prednisolone. proved unsuccessful. Known hypersensitivity. Active peptic ulcer. The response to oral anticoagulants may be altered. Inhibition is characteristic, but isolated Prednisolone should not be used in patients with reports of potentiation are on record. presumed viral or bacterial infections because corticosteroids increase susceptibility to, and mask The incidence of gastrointestinal ulceration is the symptoms of infection. increased if acetylsalicylic acid or nonsteroidal anti­ inflammatory drugs are administered concomitantly. Precautions Patients must understand the importance of The risk of hypokalaemia is increased when cortico­ following dosage instructions rigorously. Should steroids are taken concomitantly with potassium- they feel unexpectedly unwell, they should losing diuretics. immediately seek medical advice. If this is not Overdosage possible, they should double the next scheduled In the event of a single large overdosage, specific dose of corticosteroid. treatment is unlikely to be required. The response of the pituitary-adrenal axis to stress Symptomatic treatment is indicated for reactions is reduced and may remain depressed for many due to chronic poisoning. months after withdrawal. Dosage may need to be Storage doubled or reinstituted temporarily during this Tablets should be stored in well-closed containers. period if infection occurs. Prednisolone sodium phosphate injection should be Bone pain, and particularly backache, may be protected from light. Freezing should be avoided. indicative of osteoporosis.

The information in this section is subject to consultation prior to definitive publication. Comments, which are invited at this stage, should be referred to:

Division of Drug Management & Policies, World Health Organization 1211 Geneva 27, Switzerland

42 SELECTED WHO PUBLICATIONS OF RELATED INTEREST

Price* (Sw. fr.) The use of essential drugs Sixth report of the WHO Expert Committee WHO Technical Report Series, No. 850 1995 (138 pages) 21.-

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The International Pharmacopoeia, third edition Volume 1: general methods of analysis. 1979 (223 pages) 24.- Volume 2: quality specifications. 1981 (342 pages) 36.- Volume 3: quality specifications. 1988 (407 pages) 64.- Volume 4: tests, methods and general requirements. 1994 (360 pages) 85.-

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Further information on these and other World Health Organization publications can be obtained from Distribution and Sales, World Health Organization, 1211 Geneva 27, Switzerland

* prices in developing countries are 70% of those listed here.