WHO DRUG INFORMATION VOLUME 11- NUMBER 3 • 1997 RECOMMENDED INN LIST 38 INTERNATIONAL NONPROPRIETARY N A M E S F O R P H A R M A C E U T I C A L SUBSTANCES WORLD HEALTH ORGANIZATION • GENEVA Volume 11, Number 3, 1997 World Health Organization, Geneva WHO Drug Information Contents Essential Drugs WHO Model Formulary Antiprotozoal drugs General Policy Issues Drugs used in amoebiasis 144 The dangers of counterfeit and substandard Diloxanide 144 active pharmaceutical ingredients 123 Drugs used in giardiasis Metronidazole 145 Drugs used in leishmaniasis 145 Quality Assurance Issues Meglumine antimoniate & The importance of analytical procedures sodium stibogluconate 146 in regulatory control 128 Pentamidine 147 Amphotericin B 148 Drugs used in trypanosomiasis 148 Reports on Individual Drugs Melarsoprol 148 Simplified treatment for leprosy 131 Pentamidine 149 Should antibiotics be indicated for children Suramin sodium 149 with acute otitis media? 131 Eflornithine 151 Acetylsalicylic acid: confirmed efficacy Drugs used in American trypanosomiasis 151 after stroke 132 Benznidazole 151 Antiretroviral therapy for HIV: latest guidelines 134 Nifurtimox 152 General Information ATC/DDD Classification Biological standardization: report of the 153 Expert Committee 138 (temporary) Recent Publications and Documents Regulatory Matters Drugs for the elderly 155 Irinotecan-associated mortality 141 Rapid examination methods against counterfeit HIV protease inhibitors associated with and substandard drugs 155 diabetes 141 Countering counterfeiting 155 Valvular heart disease associated with Malaria: a manual for community health fenfluramine and phentermine 141 workers 156 Withdrawal of antidiarrhoeal paediatric product 142 Guidelines for the management of Dangerous products promoted on the Internet 142 drug-resistant tuberculosis 156 Health risks of herbal products containing ephedrine 142 Photoallergic and phototoxic reactions Recommended International associated with fibrates 143 Restriction on sale of high-dose vitamin B6 Nonproprietary Names: List 38 157 products 143 First-year safety reports with triple component pertussis vaccine 143 i WHO Drug Information Vol. 11, No. 3, 1997 General Policy Issues The dangers of counterfeit In countries where there is strong regulation, counterfeits are fewer in number, but highly and substandard active sophisticated. Where the risk of detection is lower, pharmaceutical ingredients the infringements increase in number and the misrepresentations become more crude. In the WHO was first alerted to the circulation of counter- developing countries, it is the essential life-saving feit pharmaceuticals at the Conference of Experts drugs such as antibiotics and antiparasitics that are on the Rational Use of Drugs held in Nairobi, in most commonly counterfeited. Many developing 1985. Since then, concern about the situation has countries are heavily reliant on imports of finished been voiced repeatedly by delegations at the World dosage forms and active pharmaceutical ingredi- Health Assembly and this has been reflected in ents. As a result of the attention that has repeatedly several resolutions. The most important was been drawn to the extent of counterfeit and adopted in May 1988 (1) and requested WHO "to substandard products, including APIs, circulating initiate programmes for the prevention and within these countries, the WHO Certification detection of the export, import and smuggling of Scheme is being extended to include active falsely labelled, spurious, counterfeited or pharmaceutical ingredients. substandard pharmaceutical preparations and to cooperate with the Secretary-General of the United It must be underscored that, at present, the legal Nations in such cases when the provisions of status of APIs differs fundamentally from that of international drug treaties are violated". finished dosage forms. APIs are not subject to marketing authorization, although they are regulat- The WHO Secretariat has implemented these ed indirectly through the drug master file (DMF). resolutions through its normative activities as well However, this mechanism is only applied in highly as in the formulation of guidelines. It has set out to developed countries and, even there, marketing stimulate collaboration between regulatory authori- and labelling are not always regulated. Finished ties, and a data base has been created within WHO dosage forms, on the other hand, are subject to which contains some 700 case reports on counter- marketing authorization, and their labelling is strictly feit finished dosage forms. Information and news regulated and requires display of the marketing are exchanged regularly with other interested authorization holder, even when this is not the parties and drug alerts are circulated to drug manufacturer. regulatory authorities. Particular importance is placed on the promotion of training for drug Because of the present lack of regulation of APIs, it regulators and inspectors in those countries which is unclear whether the definition manufacture and are most vulnerable to counterfeiting and related manufacturer — as set out, for example, in the activities. WHO/GMP text (3) and in Directive 75/319/EEC — The report of a WHO/IFPMA workshop held in 1992 also covers APIs. If it does, the opportunity arises (2) defines a counterfeit medicine as one which is for a company or an individual involved in “partial deliberately and fraudulently mislabelled with manufacture” — perhaps only repackaging — to respect to identity and/or source. This definition is place their name on the label without further also relevant to active pharmaceutical ingredients reference to the manufacturer responsible for the (APIs) and underscores the need to establish their chemical synthesis. In many instances, this practice true origin and to have this information reflected on provides a means to deliberately obscure the true the label. Furthermore, it has become evident that provenance and quality of the material. both developed and developing countries alike are confronted with similar problems. Counterfeits can Case reports range from highly sophisticated copies which are The following reports on counterfeit APIs have been almost indistinguishable from the authentic branded provided to WHO, and several of them clearly product, to potentially dangerous substandard or illustrate the problem of labelling. spurious preparations sold under branded or generic labels. 123 General Policy Issues WHO Drug Information Vol. 11, No. 3, 1997 Australia that the value-added nature of the work conducted In February 1997, the Therapeutic Goods Ad- in Western Europe was greater than 50% of the ministration of Australia drew the attention of the cost of the drug provided to Australia and hence the Pharmaceutical Inspection Convention (PIC-PIC/S) company was entitled to claim that it was “made” in Committee of Officials (4) to the practice of sub- that particular country. No action could be taken stitution. The following cases, concerning APIs since the Australian companies had not committed manufactured and supplied from Asia, are drawn an offence, and no prosecution of the overseas from the evidence provided. companies from within Australia was possible. However, because of lack of regulation of either the An API, sulfamethoxazole, manufactured in India manufacturing process, de novo synthesis, or and delivered to an Australian firm, was partially repackaging, and the routing of subsequent substituted with sugar in the same particle size. The exports, it is unlikely that the authorities in any of substitution involved three of every 10 containers in the countries involved would have had a basis for the delivery. In another incident, inferior grade and legal intervention. rejected APIs were deliberately being placed at the bottom of every third or fourth drum. During sub- Many similar cases involve substitution, dilution or sequent investigations, it came to light that this adulteration, including the addition of subpotent substitution often takes place immediately following material to normal material in such a way as to be departure of the consignment from the premises of just able to pass pharmacopoeial specifications, the legitimate manufacturer. Substitution racket- and the switching of technical grade for pharma- eers also gain access to sophisticated packaging ceutical grade substances. technology, including access to “tamper-proof” security devices through co-opting company United States of America employees into providing packaging information, or Information has also been received from the US examples of the security, or the actual packaging Food and Drug Administration's Office of Criminal material from either the manufacturing plant or the Investigation (5) regarding recent cases involving printer of the labels. APIs. The following investigation was carried out Information on this particular situation was passed jointly with the US Customs Service. on to all members of the PIC-PIC/S, and inspector- ates were requested to report any similar problems In 1991, chemists at SmithKline Beecham Labora- occurring in their own country. They were also tories notified the FDA of the delivery of counterfeit asked whether a provision for “top, middle and oxytetracycline at their Animal Health Facility in bottom” sampling of each container of API received Nebraska. Investigations discovered a conspiracy from specified countries should be implemented. to import and distribute counterfeit bulk drugs. As a consequence, a company and three individuals