International Nonproprietary Names for Pharmaceutical Substances

INFORMATION

VOLUME 13 - NUMBER 3 1999

RECOMMENDED INN LIST 42 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES

WORLD HEALTH ORGANIZATION • GENEVA WHO Drug Information Vol. 13, No. 3, 1999

General Policy Issues

Disaster relief and drug supply Large-scale national and international humanitarian aid operations are now launched with increasing rapidity in response to urgent needs for survival. Governments, organizations and aid agencies have acquired a significant amount of experience in coordinating the complicated logistical support indispen- sable to the success of operations aimed at relief of disaster-stricken victims. Through these efforts, donations of shelter, food and medicines soon arrive in large quantities.

The availability of drugs is an important aspect of effective health care. In emergency situations, appropriate drug donations are of crucial importance for maintaining a basic level of health services. Recently, during the Balkans crisis, the international community reacted promptly by sending large quantities of drugs and medical supplies and WHO played an important role in facilitating interaction between the national authorities and aid agencies.

Emergency situations and that country does not exist. Furthermore, although import authorizations are not obligatory in the case controlled medicines of benzodiazepines under the relevant international treaty (2), an increasing number of governments In large-scale disasters, great numbers of people extend the same import-export control measures to suffer hardship not only from malnutrition and psychotropic substances in response to a resolution infectious disease but from physical injuries and of the Economic and Social Council. extreme psychological distress. The medicines they need include strong analgesics to relieve pain from This is a real problem because the government of a injuries, and anxiolytics to calm the symptoms of disaster-stricken country is often so overwhelmed mental trauma associated with suffering. by other urgent matters that it no longer has the infrastructure to issue import authorizations — even Many of the medicines needed to deal with these more so when the disaster affects central adminis- situations are subject to strict international control trative services. Equally, when a civil war is fought, and, until recently, these measures have hampered the drug control authorities of the existing govern- the timely provision of controlled medicines to ment may not be ready to issue an import authori- disaster-stricken peoples. Fortunately, this is no zation for drugs to be sent to the other part of the longer the case for situations such as that prevail- country. Thus, there are a number of situations ing in the Balkans. where import authorizations are impossible. Most of the strong analgesics — opioids such as The WHO Expert Committee on the Use of Essen- morphine and pethidine — are controlled narcotic tial Drugs first discussed this problem in 1991 as a drugs. The majority of anxiolytics — benzodiaze- result of problems encountered by humanitarian aid pines such as diazepam and oxazepam — are also organizations (3). In 1994, the Expert Committee on under international control as psychotropic sub- Drug Dependence recommended that the matter be stances. The international drug control treaties brought to the attention of the UN Commission on require certain import-export control measures to Narcotic Drugs (4). Through subsequent discus- be applied to these substances during movement sions in 1996 at the United Nations Commission on across international boundaries. For example, Narcotic Drugs and, later that year, at the World opioid analgesics cannot be exported without first Health Assembly, an international consensus was having an import authorization (1). If the control established to support the application of simplified authority of the importing country is not functional or import-export control procedures in emergency cannot issue an import authorization for any rea- situations (5, 6). son, a legal means of sending opioid analgesics to

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Through a consultative process, which included 8. World Health Organization and the Ministry of Health, discussions with the International Narcotics Control Bahrain. Proceedings of the Eighth International Confer- Board (INCB) and national drug regulatory officials ence of Drug Regulatory Authorities (ICDRA), 1996. at the Eighth International Conference of Drug Regulatory Authorities (ICDRA) held in Bahrain in Drug donations to Albania 1996 (8), WHO has developed Model Guidelines for the International Provision of Controlled Medicines Because of the country's unsettled history, the for Emergency Medical Care (7). The Guidelines Albanian health sector has been heavily dependent have opened the way for competent humanitarian on drug donations for some time. Consequently, organizations to provide controlled medicines procedures have been set up to ensure the appro- across international boundaries in emergency priateness and quality of donations, including situations without import authorizations. distribution of official guidelines and a reference drug list setting out the most needed products. Application in Kosovo Within this system, import permission for drug The Model Guidelines have proved to be of impor- donations is delivered through the Pharmaceutical tant practical utility in the Kosovo crisis. Although Department of the Ministry of Health in Tirana and United Nations agencies began to provide health donors are requested to channel donations through and other services in Kosovo after the cease-fire a state-owned wholesaler for distribution to the agreement, there was no national authority in Albanian public health facilities (1). Kosovo legally competent to issue import authorizations. Nor was it practical for the Yugoslav Govern- The distribution of drugs for primary care is organ- ment in Belgrade to issue import authorizations for ized through the Health Insurance Scheme and drugs to be used only in Kosovo. Under these covers an estimated 70% of the population. At the circumstances, the Danish Medical Agency applied hospital level only 20% of the needs of drugs and the Model Guidelines to approve the shipment of medical supplies are covered by the state system. controlled medicines to Pristina in Kosovo for use The Albanian health system was therefore not well by the field office of the United Nations High Com- placed to cover the drug needs of an additional one missioner for Refugees. It is likely that other na- million refugees in the spring of 1999 as a result of tional authorities have done the same. the Kosovo crisis.

References During the crisis, the international community responded promptly to refugee needs and essential 1. Single Convention on Narcotic Drugs, 1961, as drugs to provide for 1.5 million people were sent in amended by the 1972 protocol amending the single convention on narcotic drugs, 1961. United Nations, 80- the form of new emergency health kits. The pre- 43678. packed kits are an ideal way to donate drugs at the beginning of an emergency. The authorities created 2. Convention on psychotropic substances, 1971. United a fast track system for use by international humani- Nations, V. 93-88220. tarian organizations having the proven capacity and 3. World Health Organization. WHO Expert Committee on infrastructure to deal with importation, storage and the Use of Essential Drugs, Fifth report. WHO Technical distribution of drug donations independently. Import Report Series, No. 825, 1992. permission was granted directly at major entry points by inspectors from the Pharmaceutical 4. World Health Organization. WHO Expert Committee on Drug Dependence, Twenty-ninth report. WHO Technical Department of the Ministry of Health. Report Series, No. 856, 1995. WHO and the international health community made 5. Resolution 7 (XXXIX) in United Nations Commission on every effort to assist Albania in managing its esca- Narcotic Drugs, Report on the Thirty-Ninth Session. lating health needs and in facilitating availability of United Nations, E/CN.7/1996/19, 1996. medicines to refugee populations. WHO's task was to assist the Ministry of Health in improving man- 6. World Health Organization. Resolution WHA49.1. agement of drug donations and drug supply in Resolutions & Decisions of the 49th World Health Assem- general and to coordinate interagency work both for bly. WHA49/1996/REC/1 (1996). Albanian nationals and for refugees. In April 1999, 7. World Health Organization. Model Guidelines for the because of growing concern about the appropriate- International Provision of Controlled Medicines for Emer- ness and quality of the drugs donated to Albania, gency Medical Care. WHO/PSA/96.17 (1996). the WHO Regional Office for Europe issued a press

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release entitled "Drug donations for Kosovo refu- 3. No mention of expiry date (43.5%). gees: WHO says follow the guidelines" (1). It was also decided to undertake a rapid assessment and 4. Insufficient remaining shelf-life (41% less than survey of drug donations. The survey was based on one year to expiry). application of the Albanian Guidelines for Drug Donations with regard to documentation and sam- 5. Presence of free samples, physician samples ples. Many instances of inappropriate donations and demonstration packs for drug stores and were identified. supermarkets. Returned-to-pharmacy drugs (18%).

During the month of May 1999, 160 import authori- 6. Drugs unknown in Albania (15%). zations were issued by the Albanian Pharmaceuti- cal Department. This did not include the drug 7. Absence of (consignment) packing lists. donations entering Albania using the fast track administrative arrangements. Thus, they were not It is therefore strongly recommended that donors included in the evaluation. Unconfirmed estimates respect recipient requests and follow national suggest that only 20% of donations went through guidelines or, in their absence, the Interagency the normal administrative procedure. Guidelines for Drug Donations (2) as described on page 155. The survey demonstrated that only 25% of donations complied with the Albanian Guidelines. The References following problems were identified: 1. World Health Organization. WHO calls for good dona- 1. Drugs donated without a specific request (80%). tion practice during emergencies as it issues new Guide- lines. Press Release, WHO/45. 3 September 1999.

2. No mention of the International Nonproprietary 2. World Health Organization. Guidelines for Drug Dona- Name (INN)/generic name (44%). tions. WHO/EDM/PAR/99.4 (1999).

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Reports on Individual Drugs

Leishmaniasis: will new technology Standard treatment consists of intralesional injections of the antimonial compounds, sodium sti- provide a breakthrough? bogluconate and meglumine antimoniate. Clinical trials are currently under way to evaluate the effi- F. Modabber, UNDP/World Bank/WHO Spe- cacy of topical paromomycin. cial Programme for Research and Training in Tropical Diseases Although less common, diffuse cutaneous leishma- Leishmaniasis is endemic in tropical and subtropi- niasis is progressively chronic, difficult to treat and cal regions and remains a serious public health relapse is frequent. Treatment is based on standard problem in 88 countries where an estimated 350 antimonial therapy, pentamidine, or liposomal million people are at risk. The geographic distribu- amphotericin B. tion of leishmaniasis is limited only by the presence of the vector — the infected female sandfly — Mucocutaneous leishmaniasis leads to disfiguring which is capable of transmitting over 20 different lesions on the face which later destroy the mucous species of Leishmania parasite. membranes of the nose, mouth and throat. Coun- tries most affected are Bolivia, Brazil and Peru. It is now apparent that the prevalence and impact of Extended courses of standard treatment may be leishmaniasis have been grossly underestimated needed to deal with this form of leishmaniasis, and the recent expanded use of surveillance involving administration of pentamidine or liposomal centres demonstrates that urbanization, man-made amphotericin B. Antigens liberated from dead environmental changes and human immunodefi- parasites sometimes induce severe inflammation ciency virus (HIV) infection are contributing to during the early phases of treatment and emer- increased transmission and prevalence in many gency use of corticosteroids may be needed to countries (1). control pharyngeal or tracheal oedema.

Drug treatment Visceral leishmaniasis is fatal if left untreated, while Leishmaniasis is manifested in a variety of clinical even in treated patients mortality can still be around forms having the potential to incapacitate, mutilate 15%. Parasites infect the reticulo-endothelial sys- or kill. Clinically, it is heterogeneous because the tem and cause gross hepatosplenomegaly with parasite may be contained in or near the point of pancytopenia. Most patients die from intercurrent inoculation, while in more diffuse forms it becomes infections. Countries most affected are Bangladesh, widely disseminated. This occurs as a conse- Brazil, India, Nepal and Sudan. quence of infected cells re-entering the circulatory system as macrophages. It is thus the intensity of Conventional treatment is based on parenteral the local inflammatory response that determines the antimonial compounds administered for 28 days. degree to which the disease remains localized. In Many patients tend to relapse after this treatment HIV-infected patients, both leishmaniasis and HIV and parasites frequently develop resistance to are locked in a vicious circle of mutual reinforce- antimony. Other drugs used include amphotericin ment with leishmaniasis accelerating the onset of B, liposomal amphotericin B, allopurinol, paromo- acquired immunodeficiency syndrome (AIDS) and mycin, pentamidine, dapsone, rifampicin and inter- associated opportunistic infections. feron gamma or combinations.

Cutaneous leishmaniasis accounts for 50–75% of Many of the treatments mentioned above need to all new cases and is characterized by chronic be administered parenterally and may elicit severe inflammatory infiltration, focal necrosis and fibrosis, adverse reactions requiring careful monitoring. producing profuse skin lesions covering the face, Treatment costs are high and therapeutic efficacy arms and legs often leading to permanent scars of antimonials is often limited or compromised by and debility. Countries most affected are Afghani- resistance. In this situation, new oral drugs are stan, Algeria, Brazil, Islamic Republic of Iran, Peru, urgently needed, particularly for children. Saudi Arabia and Syrian Arab Republic.

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The new orally administered drug, miltefosine was multidose injections of heat-killed Leishmania major formerly developed as an antitumour agent. It has antigen (ALM) plus BCG has been demonstrated in shown activity against Leishmania and will soon clinical trials in the Islamic Republic of Iran (5). A enter phase III clinical trials in India for the treat- recently completed phase III trial of a single injec- ment of visceral leishmaniasis. Parenteral paromo- tion of ALM plus BCG demonstrated protection mycin has also been shown in limited phase III against anthroponotic cutaneous leishmaniasis in trials to be more effective than sodium stibogluco- second year follow-up (6). Multiple injections of this nate and has a better safety profile. vaccine are currently being evaluated in phase III trials in Iran, and a field trial of a similar killed Many countries now depend on the direct agglutina- vaccine has recently been completed in Ecuador, tion test (DAT) for the serological diagnosis of where cutaneous leishmaniasis was reduced by visceral leishmaniasis. DAT has proven to be a 73% (7). Other field trials are ongoing in Brazil, simple, cheap and reliable test particularly in epi- Colombia and Venezuela. demic situations such as those recently experi- enced in Eritrea, Ethiopia and Sudan. A simple Second generation vaccine trials dipstick test using recombinant antigen (K-39) has Recombinant molecules or genetically engineered proven useful for diagnosis of clinical visceral organisms are still undergoing preclinical develop- leishmaniasis (2) ment. Vaccines involving genetically engineered, live attenuated promastigotes and subunit, recom- Vaccine development binant vaccines involving as many as 10 antigens The costs associated with effective leishmaniasis have each demonstrated partial protection in animal control remain prohibitive. Current strategies in- models. In each case, adjuvants were required for clude vector control, use of impregnated bednets, vaccine efficacy. Most recently, DNA vaccines health education and treatment. The variety in encoding leishmanial antigens have produced epidemiology of the different forms of leishmaniasis partial protection in murine models. However, these and location makes it impossible to apply a single vaccines were administered subcutaneously with- control measure globally. Development of an afford- out adjuvant (8). able and effective vaccine is thus the most desir- able solution for controlling the disease. The over- Future developments whelming cross-reactive antigens in all pathogenic The Parasite Genome Committee of WHO's Tropi- Leishmania and the presence of molecules that cal Disease Research Programme was set up in cross protect against different species appear to 1994 as a consortium to coordinate research on the justify present efforts to develop a single-strain analysis and mapping of genomes of five tropical vaccine (3). parasites, including L. major (8).

Vaccine development is considered feasible in The Leishmania genome, with its relatively small particular because long-lasting immunity to reinfec- size, is likely to be the first target parasite to be tion has been demonstrated in patients recovering completely sequenced. The aim is to have 45% of from leishmaniasis. Furthermore, Leishmania spp. the Freidlin strain of the L. major genome share many dominant antigenic determinants. It is sequenced by the year 2000 with completion two none the less important to define what is expected years later. The main challenge to research is to of a vaccine. This would need either to completely find ways of blocking or disrupting development at a block infection in the host or to protect against high crucial stage in the parasite life cycle. Data are parasite load to prevent transmission (4). being released onto the Internet as they become available (9). First generation vaccine trials Composed vaccines of killed parasite with or with- References out BCG as adjuvant are presently in clinical trial. The rationale for using whole-cell killed vaccine 1. UNAIDS/World Health Organization. Leishmania & HIV includes ease of preparation, efficacy when used in Gridlock. WHO/CTD/LEISH/98.9. Add.1. UNAIDS/98.23 with certain adjuvants in animal models (3) and (1998). demonstrated safety and immunogenicity in hu- 2. Sundar, S., Reed, S.G., Singh, V.P. et al. Rapid accu- mans. Increased recovery was noted when com- rate field diagnosis of Indian visceral leishmaniasis. pared with chemotherapy. The safety of single and Lancet, 351: 563–565 (1998).

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3. Bahar, K., Dowlati, Y., Shidani, B. et al. Comparative controlled trial to determine the safety and efficacy safety and immunogenicity trial of two killed Leishmania of oral zidovudine (ZDV) and the efficacy of oral major vaccines with or without BCG in human volunteers. nevirapine (NVP) for the prevention of vertical Clinics in Dermatology, 14(5): 489–495 (1996). transmission of HIV from infected pregnant women to their newborns. However, following the an- 4. Modabber, F. Vaccine: the only hope to control leish- nouncement of encouraging results from a trial in maniasis. In: Molecular and Immune Mechanisms in the Pathogenesis of Cutaneous Leishmaniasis. Eds. Tapia, Thailand involving use of ZDV to reduce HIV mater- F.J., Caceres-Dittmar, G., Sanchez, M.A. R.G. Landes nal transmission (3), the placebo arm was dropped Company, 1996. after 49 enrolled mothers had given birth.

5. Sharifi, I., Fekri, A.R, Aflatonian, M.R. et al. Rand- In a run-up open label, phase I/II trial (HIVNET omized vaccine trial of single dose of killed Leishmania 006), safety, pharmacokinetics, tolerance, antiretro- major plus BCG against anthroponotic cutaneous leishma- viral activity and infant HIV infection status were niasis in Bam, Iran. Lancet, 351: 1540–1543 (1998). evaluated after giving a single dose of nevirapine to HIV-infected pregnant women during labour and to 6. Convit, J., Castellanos, P.L., Rondon, A. et al. Immuno- therapy versus chemotherapy in localized cutaneous their newborns during the first week of life. Nevirap- leishmaniasis. Lancet, 1: 401–405 (1987). ine was well tolerated and no serious adverse events were observed. Potent antiretroviral activity 7. Armijos, R.X., Weigel, M.M., Aviles. H. et al. Field trial was demonstrated in women at one week of dosing of a vaccine against New World cutaneous leishmaniasis and was maintained above the target in infants at in an at risk child population: safety, immunogenicity and age 7 days (4). efficacy during the first 12 months of follow-up. Journal of Infectious Diseases, 177: 1352–1357 (1998). Within HIVNET 012, both zidovudine and nevirapine demonstrated low rates of serious and non- 8. World Health Organization. Tropical Disease Research. Progress 1997–1998. Fourteenth Programme Report. serious adverse events. Long-term toxicity and the UNDP/World Bank/WHO Special Programme for Re- impact of these regimens on long-term survival and search and Training in Tropical Diseases. (1999). possible transmission through breastfeeding are unknown. For this reason, follow-up of HIVNET 012 9. Genome on the Web. http://www.ebi.ac.uk/parasites/ infants to 18 months of age remains a high priority. leish/html. Data from a trial carried out from 1994 to 1997 to measure the frequency, timing and risk factors of HIV transmission through breast milk, suggest that Nevirapine and vertical the risk of HIV infection is highest in the early transmission of HIV months of breastfeeding (5). The recent HIVNET 012 study has confirmed a In parts of sub-Saharan Africa, up to 30% of preg- highly effective and safe drug regimen for reducing nant women can be HIV-infected and perinatal maternal transmission of human immunodeficiency transmission rates are in the order of 25–35%. If virus (HIV) to newborns that is both simple to widely implemented, single dose nevirapine given administer and affordable in developing countries at delivery could protect some 300 000 to 400 000 (1). newborns in developing countries annually from maternal HIV infection. Nevirapine used in this way Interim results from the study carried out in Uganda is currently 70 times cheaper than the short course demonstrate that a single oral 200 mg dose of the ZDV regimen used in the Thailand study. It is antiretroviral, nevirapine, given to an HIV-positive feasible that all women living in areas of high mother at onset of labour and a single 2 mg/kg HIV prevalence could receive the drug during dose given to the newborn within 72 hours of birth labour, even in the absence of an established HIV reduced transmission by 47% in a breastfeeding diagnosis. population within the first 14 weeks of life compared with a short course of zidovudine (600 mg Despite the apparent simplicity of administration, orally at onset of labour, 300 mg every 3 hours until efficacy and low wholesale cost of nevirapine, delivery, and 4 mg/kg orally twice daily to infants for obstacles to implementation remain. Health centres 7 days following birth) (2). offering counselling and HIV testing are not avail- HIVNET 012 was originally designed as a 1500- able to many pregnant women in developing coun- person randomized double-blind phase III placebo- tries and the majority of deliveries take place out-

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side the health care system. The trial also found 5. Miotti, P.G., Taha, T.E.T., Kumwenda, N.I. et al. HIV that many women refuse counselling or testing and transmission through breastfeeding. Journal of the Ameri- may not return for test results. can Medical Association, 282: 744–749 (1999).

A subsequent cost-effectiveness analysis has been 6. Marseille, E., Kahn, J.G., Mmiro, F. et al. Cost effectiveness of single-dose nevirapine regimen for mothers and made of a hypothetical cohort of 20 000 pregnant babies to decrease vertical HIV-1 transmission in sub- women in sub-Saharan Africa and compared Saharan Africa. Lancet, 354: 803–808 (1999). HIVNET 012 with other short-course antiretroviral regimens (5). Two implementation strategies were tested: (i) counselling and HIV testing before treat- Spironolactone: severe heart ment (targeted) or (ii) nevirapine for all pregnant women (universal). failure cut by one-third A new study has shown that adding spironolactone, For universal treatment, within a 30% HIV sero- an aldosterone receptor antagonist, to standard prevalence setting, the HIVNET 012 regimen would therapy for severe heart failure can reduce the risk avert 603 cases of HIV in babies, cost US$183 333 of death by 30% and hospitalization by 35%. These and generate 15 862 disability-adjusted life years highly encouraging results were found at interim (DALYs). The associated cost-effectiveness ratios analysis and the trial, which was carried out in 15 were $138 per case averted or $5.25 per DALY. countries, was discontinued early after a mean For targeted treatment with 30% seroprevalence follow-up period of only 24 months (1). HIVNET 012 would cost $141 922 and avert 476 cases at $298 per case averted or $11.29 per In a double-blind, randomized, placebo-controlled DALY. The HIVNET 012 regimen could be cost- study, 1663 patients with severe heart failure and a effective in high seroprevalence settings. In lower left ventricular ejection fraction of no more than seroprevalence areas where multidose regimens 35% were enrolled. All were treated with an angio- are not cost effective, nevirapine therapy could also tensin-converting enzyme (ACE) inhibitor, a loop have a major public health impact at a reasonable diuretic or digoxin. Of these, 822 were assigned to cost. receive 25 mg of spironolactone daily and 841 to receive placebo. The primary endpoint was death References from all causes. Spironolactone was found to be efficacious following 284 deaths compared to 386 1. National Institute of Allergy and Infectious Diseases. A phase IIB randomized, controlled trial to evaluate the deaths in the placebo group. This 30% reduction in safety, tolerance and HIV vertical transmission rates the risk of death among patients was attributed to a associated with short course nevirapine (NVP) vs. short lower risk of death from progressive heart failure course zidovudine (ZDV) in HIV infected pregnant women and sudden death from cardiac causes. and their infants in Uganda. Preliminary report. www.niaid.nig.gov/newsroom/simple/exec.htm. 23 August Although the exact cause of reduction in risk of 1999. death remains speculative, it is postulated that an aldosterone receptor antagonist can prevent pro- 2. Guay, L.A., Musoke, P., Fleming, T. et al. Intrapartum gressive heart failure by averting sodium retention and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission and myocardial fibrosis and prevent sudden death of HIV-1 in Kampala, Uganda: HIVNET 012 randomized from cardiac causes by averting potassium loss and trial. Lancet, 354: 795 (1999). by increasing the myocardial uptake of norepineph- rine. Additionally, spironolactone may avert myocar- 3. Centers for Disease Control and Prevention. Adminis- dial fibrosis by blocking the effects of aldosterone tration of zidovudine during late pregnancy to prevent on the formation of collagen (3, 4). Researchers in perinatal HIV transmission — Thailand 1996–1998. the trial thus propose that the effect of spironolac- Morbidity and Mortality Weekly Report, 47: 151–153 tone was largely cardioprotective and the reduction (1998). in the risk of hospitalization may be attributable to 4. Musoke, P., Guay, L.A., Bagenda, D. et al. A phase I/II the ability of spironolactone to reduce myocardial study of the safety and pharmacokinetics of nevirapine in and vascular fibrosis. HIV-I infected pregnant Ugandan women and their ne- onates (HIVNET 006). AIDS, 13: 479–486 (1999). The fact that spironolactone significantly reduced the risk of both morbidity and death among high-

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risk patients in the study with only a very low inci- 2. Weber, K.T. Aldosterone and spironolactone in heart dence of serious hyperkalaemia can be attributed to failure. New England Journal of Medicine, 341: 753–755 previous efforts in determining the effective safe (1999) dose of spironolactone when used in conjunction 5. Macfdyen, R.J., Barr, C.S., Struthers, A.D. Aldosterone with an ACE inhibitor (5). blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in Given the increasing prevalence of heart failure and heart rate in heart failure patients. Cardiovascular Re- the high burden of mortality and morbidity associ- search, 35: 30–34 (1997). ated with this disease, every patient should be 6. Brilla, C.G., Matsubara, L.S., Weber, K.T. Anti-aldoster- given treatment of proven benefit. Simplifying the one treatment and the prevention of myocardial fibrosis in increasingly complex therapy for heart failure might primary and secondary hyperaldosteronism. Journal of require an objective marker of cardiac dysfunction Molecular Cell Cardiology, 25: 563–575 (1993). or stress, and studies in progress should soon elucidate this option (6). 7. The RALES Investigators. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart References failure (the Randomized Aldactone Evaluation Study (RALES). American Journal of Cardiology, 78: 902–907 1. Pitt, B., Zannad, F., Remme, W.J. et al. For the Rand- (1996). omized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in 8. Richards, A.M., Nicholls, M.G. Aldosterone antagonism patients with severe heart failure. New England Journal of in heart failure. Lancet: 354: 789 (1999). Medicine, 341: 709–717 (1999)

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Current Topics

The growing importance Many different drug donation scenarios exist, such as during emergencies or as a complement to of drug donations development aid in acute situations. Donations may be corporate (either direct or through private volun- The Partnership for Quality Medical Donations tary organizations), government aid, or aimed (PQMD) is an umbrella organization representing a directly at single health facilities. Although there are number of US-based pharmaceutical companies legitimate differences between these scenarios, and nongovernmental organizations. Its aim is to basic rules for an appropriate donation apply to all. endorse and implement the Interagency Guidelines The principal objective of the Guidelines is to define for Drug Donations (1) which have been published good donation practices. as part of WHO efforts to ensure that only drugs appropriate to the needs of the recipient country are Monitoring since 1996 has indicated that many donated. donor countries, recipient countries and numerous aid agencies have modified their donation practices The signatories of the PQMD are AmeriCares, in line with the Guidelines. Although a number of Catholic Medical Mission Board, Interchurch Medi- recipients using the guidelines reported an improve- cal Assistance, International AID, MAP Interna- ment in drug donation quality and found it easier to tional, Project Hope, Abbott Laboratories, Becton- refuse unwanted donations, problems were still Dickinson, Bristol Myers Squibb Company, Johnson identified and numerous examples of inappropriate & Johnson, Eli Lilly and Company, Merck & Co., drug donations were reported. A global survey Inc., Pfizer Inc., Pharmacia & Upjohn, SmithKline carried out by WHO indicated that the following Beecham and Wyeth-Ayerst Laboratories. Any areas still need improvement. other organizations willing to endorse the Guide- lines are invited to contact [email protected] and • Drugs are not relevant to the situation, disease will be listed on the Essential Drugs and Other pattern or level of care possible. They are often Medicines Homepage under http://www.who.int/ unknown to local health professionals and do not dap/edmguidelines.html. comply with locally agreed drug policies and standard treatment guidelines. Good drug donation practice Originally published in 1996, the Interagency • Many donated drugs arrive unsorted and labelled Guidelines for Drug Donations (1) have recently in a language which is not understood locally. been revised in collaboration with 15 major United Some donated drugs come under trade names not Nations and international emergency relief agen- registered for use in the recipient country, and cies*. The purpose of the guidelines is to provide an lack identification through an International Nonpro- advisory tool to be used as a basis for national or prietary Name (INN) or generic name. institutional guidelines. The Guidelines are not proposed as international regulations. • The quality of the drugs does not always comply with standards in the donor country. For example, drugs may have expired before they reach the patient, or the donation may be made up of drugs *Caritas Internationalis, Churches' Action for Health of the or free samples returned to pharmacies by pa- World Council of Churches, International Committee of the tients or health professionals in the donor country. Red Cross, International Federation of Red Cross and Red Crescent Societies, International Pharmaceutical • The donor agency sometimes ignores local ad- Federation, Joint United Nations Programme on HIV/ ministrative procedures for receiving and distribut- AIDS, Médecins sans Frontières, Office of the United ing medical supplies. The distribution plan of the Nations High Commissioner for Refugees, Oxfam, donor agencies may conflict with the wishes of Pharmaciens sans Frontières, United Nations Children's national authorities. Fund, United Nations Development Programme, United Nations Population Fund, World Bank.

155 Current Topics WHO Drug Information Vol. 13, No. 3, 1999

• Donated drugs may have a high declared value 2. World Health Organization. Interagency Guidelines for (the market value in the donor country rather than safe disposal of unwanted pharmaceuticals in and after the world market price). In such cases, import emergencies. WHO/EDM/PAR/99.2 (1999). taxes and overheads for storage and distribution may be unnecessarily high, and the (inflated) value of the donation may be deducted from the Importance of fixed-dose combina- government drug budget. tions in tuberculosis control • Drugs may be donated in the wrong quantities, Despite recommendations by WHO and the Inter- and some stocks may have to be destroyed. This national Union against Tuberculosis and Lung is wasteful and creates problems of disposal at Disease (IUATLD) to use fixed-dose combination the receiving end. (FDC) tablets for treatment of tuberculosis, more than 75% of rifampicin used in the public sector Unwanted pharmaceuticals globally is administered as single-drug tablets (1). and their disposal The recently published Interagency Guidelines for The justification for recommending that FDCs Safe Disposal of Unwanted Pharmaceuticals in and replace single-drug tablets as the primary treatment after Emergencies (2) is a consensus document for tuberculosis is that they simplify treatment, produced as a complement to the Interagency minimize prescription errors and increase patient Guidelines described above. It should be used by and physician compliance. Furthermore, drug national authorities, environmental and waste supply management is facilitated and the risk of management authorities and those involved in the misuse of rifampicin for conditions other than safe disposal of unusable pharmaceuticals in or tuberculosis is reduced. FDCs prevent the out-of- following emergencies. stock situations where some drugs are being con- tinued in isolation while new stocks of others are The Guidelines are based on experience gained being awaited. Most importantly, by preventing from the safe disposal of unwanted and unusable monotherapy and by delivering the correct drug drugs, such as those which accumulated during the doses, FDCs are expected to reduce the emer- war in Bosnia and Herzegovina. Quantifying phar- gence of drug-resistant tuberculosis (2). maceutical waste is not easy; it is reported that almost 60% of the approximately 32 000 tonnes of Several factors that hinder introduction of FDCs medical supplies donated to Bosnia and and the expansion of their use include higher prices Herzegovina between 1992 and 1996 were consid- (particularly of the three- and four-drug FDCs), lack ered to be inappropriate. By mid-1996 there were of proof of bioavailability of rifampicin, protectionist an estimated 17 000 tonnes of unusable drugs measures which favour locally produced single- stockpiled in warehouses and clinics throughout the drug tablets, fears of complications and adverse country. drug reactions, and inappropriate FDC formulations. The guidelines describe a number of disposal methods which involve minimal risks to public Since the use of substandard FDCs may result in health and the environment and can be used by treatment failures and emergence of drug-resistant countries with limited resources and equipment. tuberculosis, a major concern is quality. In order to Among these are the possibility of returning unus- address this, a system of quality assurance based able drugs to the manufacturer, particularly those on a WHO protocol for assessment of rifampicin representing disposal problems, such as bioavailability is currently being set up and WHO antineoplastics. Other methods include landfill, and partners are in the process of recruiting labora- immobilization/encapsulation, inertization, dis- tories to take part in a global network. So far, two charge into sewers, incineration and chemical reference laboratories have been evaluated and decomposition. certified according to the recently developed procedures for ensuring laboratory proficiency for the References evaluation of bioavailability. An inexpensive screen- ing tool to detect substandard FDCs, thin layer 1. World Health Organization. Interagency Guidelines for chromatography, may become a valuable supple- Drug Donations. WHO/EDM/PAR/99.4 (1999). ment to the more expensive quality assurance

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measures such as bioavailability testing (3). Phar- pressure (BP)≥ 160 mm Hg or sustained diastolic maceutical specifications for FDCs are under BP ≥ 100 mm Hg despite nonpharmacological preparation. measures. In diabetic patients, the corresponding values of BP are ≥ 140 and ≥ 90 mm Hg. The The WHO survey showed that in the public sector minimum acceptable level of control is <150/<90 approximately 24% of tuberculosis patients are mm Hg and optimal level <140/85 mm Hg although treated with the two-drug FDC and that these are these levels will be difficult to achieve in some now available at the same price or lower than the hypertensive patients. sum of prices of the separate single-drug tablets (1). It is expected that an eventual fall in prices will A low dose of thiazide diuretics or beta-adrenore- also make FDCs affordable in the settings where ceptor antagonists is recommended as first-line they are most needed. In the meantime, the most treatment unless there is a contraindication or a costly alternative of all is to ignore the issue of drug compelling indication for another drug class. In quality. Creating resistance because of poor quality older subjects, diuretics or long-acting dihydropyrid- drugs will prove to be much more expensive for the ine calcium channel blockers are preferred to beta- future than investing in making quality anti-tubercu- adrenoreceptor antagonists. Specific advice is losis drugs available today. given on the management of hypertension in ethnic subgroups, for those suffering from diabetes melli- References tus or chronic renal disease and in women during 1. Norval, P., Blomberg, B., Kitler, M. Estimate of the pregnancy, oral contraceptive use and hormone global market for rifampicin-containing fixed-dose combi- replacement therapy. nation tablets. International Journal of Tuberculosis and Lung Disease, 3 S1–S9 (in press). Although drugs approved for treating hypertension lower blood pressure, the purpose of treatment is to 2. Sbarbaro, J., Blomberg, B., Chaulet, P. Fixed dose reduce the risk of devastating hypertensive compli- combination formulations for tuberculosis treatment. International Journal of Tuberculosis and Lung Disease, 3: cations such as myocardial infarction, stroke and 51–53 (in press). heart failure. However, few antihypertensive drugs have consistently provided evidence of gains which 3. Kenyon, T.A., Kenyon, A.S., Kgarebe, B.V. et al. are applicable to public health. Since the 1993 Detection of substandard fixed-dose combination tubercu- guidelines, three long-term double-blind clinical losis drugs using thin layer chromotography. International trials have compared the major classes of Journal of Tuberculosis and Lung Disease, 3 S3 (in press). antihypertensives (thiazides, beta-adrenoreceptor antagonists, calcium channel blockers, angiotensin- converting enzyme (ACE) inhibitors and alpha- Guidelines for the adrenoreceptor antagonists). Overall, they have showed no consistent or important differences as treatment of hypertension regards antihypertensive efficacy, side effects or The British Hypertension Society has updated its quality of life. A difference in average responses 1993 version of guidelines for treatment of hyper- was found between drug classes related to age and tension using new evidence which has emerged ethnic grouping. For most hypertensives, a combi- from recent clinical trials. The guidelines empha- nation of antihypertensive drugs is required to size the crucial role of non-pharmacological meas- achieve the recommended targets for blood pres- ures to lower blood pressure in all hypertensive and sure control. borderline hypertensive cases. The recommended preventive measures include weight control, re- Other drugs that reduce cardiovascular risk must duced salt and fat intake, limited alcohol consump- also be considered. These include acetylsalicylic tion, dynamic exercise and increased consumption acid for secondary prevention of cardiovascular of fruit and vegetables. To reduce overall cardio- diseases. The British recommendation is to include statins for hypertensive patients with a total serum vascular risk, patients should also stop smoking in ≥ order to lower serum cholesterol, reduce saturated cholesterol 5 mmol/L and established vascular fat intake and increase consumption of polyunsatu- disease. rated and mono-unsaturated fats and fish. Reference: Ramsay, L.E., Williams, B., Johnston, G.D. et al. Guidelines for management of hypertension: report of Initiation of antihypertensive drug therapy is pro- the third working party of the British Hypertension Society. posed in people with sustained systolic blood Journal of Human Hypertension, 13: 569–592 (1999).

157 Current Topics WHO Drug Information Vol. 13, No. 3, 1999

International comparator products List A (below) sets out 147 products from the WHO Model List of Essential Drugs (2) where a compara- for bioequivalence testing tor product has so far been identified. It includes the manufacturer who is the innovator ("company") and Multisource (generic) products need to meet the the national market where the manufacturer in same quality, safety and efficacy standards as the question considers its product meets the best original, brand-name, or innovator product they safety, quality, efficacy and labelling standards resemble (1). In order to comply with regulatory ("primary market"). List B is a compilation of the requirements, in vivo comparative bioequivalence remaining essential drugs for which a comparator and pharmacodynamic studies are often required to product has yet to be selected. demonstrate evidence of interchangeability. Many countries have already selected their own reference A full explanatory text with detailed instructions and or comparator products against which to carry out including Lists A and B will be published in the these studies, which are generally based on the forthcoming Thirty-sixth Report of the WHO Expert innovator or first marketed product. Committee on Specifications for Pharmaceutical Preparations. Related background information can For those countries looking for advice on how to also be obtained from: Quality Assurance and identify a reference product on the local market, Safety of Medicines, Department of Essential Drugs WHO has collected information from drug regula- and Medicines Policy, World Health Organization, tory authorities and the pharmaceutical industry in 1211 Geneva 27, Switzerland. the form of a list of comparator products. Inclusion of products in the list does not imply endorse- Reference ment or recommendation by WHO in any way. 1. World Health Organization. Multi-source Pharmaceuti- It is expected that the list will be of most value to cal Products: WHO Guideline on Registration Require- those regulatory agencies in countries with limited ments to Establish Interchangeability. Technical Report resources. In view of the growing number of generic Series No. 863 (1996). products requiring assessment for marketing au- 2. World Health Organization. The Use of Essential Drugs. thorization and the need for in vivo comparative Eighth report of the WHO Expert Committee. Technical bioequivalence studies, testing against a single Report Series, Number 882, 1998. comparator product on the WHO list could eliminate unnecessary repetition of studies.

List of Comparator Products (with reference to the WHO Model List of Essential Drugs)

Instructions for use of List A

1. It should be determined whether the innovator product is available on the local market. If so, manufacturers should ideally use this product to assess bioequivalence of the multisource pharmaceutical product in question.

2. If the innovator product is not available on the local market, List A may be consulted and the comparator product sought from the primary market.

3. If no innovator product can be identified or obtained from the primary market, a local market leader product may be used if quality, safety and efficacy are established.

4. Where no innovator product can be identified and there is no market leader product available, the proposed multisource pharmaceutical product should be manufactured in accordance with local, national or regional standards including, asapplicable, The International Pharmacopoeia and Multi-source Pharmaceutical Products: WHO Guideline on Registration Requirements to Establish Interchangeability.

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List of Comparator Products INN/INNm/ Model dosage form brand company primary common List section and strength name market(s) name albendazole 6.1.1 chewtab, 200 mg Zentel SmithKline Beecham France amiloride HCI 16 tab, 5 mg Midamor Merck Sharp & Dohme UK aminophylline 25.1 tab, 100 mg, Aminophylin BYK Gulden Lomberg Germany 200 mg, 125 mg amitriptyline HCI 24.2.1 tab, 25 mg Elavil Zeneca USA amoxicillin 6.2.1 cap, 250 mg, 500 mg Amoxil SmithKline Beecham UK amoxicillin 6.2.1 pwosp, 125 mg/5ml Amoxil SmithKline Beecham UK amoxicillin 6.2.1 tab, 250 mg, 500 mg Amoxil SmithKline Beecham UK atenolol 12.1, 2 & 3 tab,50 mg,100 mg Tenormin Zeneca UK atropine sulfate 21.5 eyd, 0.1%, 0.5%, 1% Atropin Ciba Vision (Novartis) Switzerland Dispersa benznidazole 6.5.5 tab, 100 mg Radanil Roche Argentina, Brazil, Switzerland biperiden HCI 9 tab, 2 mg Akineton Knoll Germany captopril 12.3 sctab, 25 mg Capoten Bristol-Myers Squibb USA carbamazepine 5 sctab, 100 mg, 200 mg Tegretol Novartis Switzerland chloramphenicol 6.2.2 cap, 250 mg Chloromycetin Parke-Davis USA chloramphenicol 6.2.2 oilspinj, 0.5 g/2 ml Chloromycetin Parke-Davis USA sodium succinate sodium succinate chloroquine 6.5.3 tab, 25 mg, 100 mg, Alaren Sanofi Winthrop USA phosphate a + b 150 mg, 500 mg Phosphate chlorphenamine 3 tab, 4 mg Chlortrimeton Schering-Plough USA H-maleate ciclosporin 8.1 cap, 25 mg Sandimmun Novartis Switzerland cimetidine 17.1 tab, 200 mg Tagamet SmithKline Beecham France ciprofloxacin HCI 6.2.2 tab, 250 mg Ciprobay Bayer Germany clofazimine 6.2.3 cap, 50 mg, 100 mg Lamprene Novartis Switzerland clomifene, citrate 18.6 tab, 50 mg Clomid Hoechst Marion Roussel USA clomipramine 24.4 cap, 10 mg, 25 mg Anafranil Novartis Switzerland clonazepam 5 sctab, 500 µg Rivotril Roche Switzerland cloxacillin 6.2.1 cap, 500 mg Penstaphon Bristol-Myers Squibb Belgium cloxacillin 6.2.1 pwosl, 125 mg/5 ml Tegopen Bristol-Myers Squibb USA cyclophosphamide 8.2 tab, 25 mg, 50 mg Endoxana ASTA Medica UK dapsone 6.2.3 tab, 25 mg, 50 mg, Dapsone Jacobus USA 100 mg desmopressin 10.2 nsp, 10 µg DDAVP Ferring USA acetate dexamethasone 18.1 & 3 tab, 500 µg, 4 mg Decadron Merck Sharp & Dohme USA diazepam 24.3 sctab, 2 mg, 5 mg Valium Roche USA doxazosin 12.3 tab, 1 mg, 2 mg, 4 mg Caldura Pfizer Germany doxycycline hyclate 6.2.2 cap, 100 mg Vibramycin Pfizer Germany doxycycline hyclate 6.2.2 tab, 100 mg Vibramycin Pfizer Canada epinephrine HCI 21.5 eyd, 2% Suprarenin Hoechst Marion Roussel Germany ergocalciferol 27 cap, 1.25 mg Drisdol Sanofi USA ergocalciferol 27 osl, 250 µg/ml Drisdol Sanofi USA ergocalciferol 27 tab, 1.25 mg Drisdol Sanofi USA ethinylestradiol 18.4 tab, 10 µg , 20 µg, Pregynon C Schering Germany 50 µg ethinylestradiol+ 18.3.1 tab, 30 µg+150 µg, Nordette-21 Wyeth-Ayerst USA levonorgestrel 30 µg+250 µg * This list is based on information collected by WHO from drug regulatory authorities and supplemented by information from pharmaceutical companies. It should be used in conjunction with the instructions provided.

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INN/INNm/ Model dosage form brand company primary common List section and strength name market(s) name

ethosuximide 5 cap, 250 mg Zarontin Parke-Davis USA ethosuximide 5 syr, 250 mg/5 ml Zarontin Parke-Davis USA etoposide 8.2 cap, 100 mg Vepesid Bristol-Myers Squibb Netherlands etoposide 8.2 inj, 20 mg/ml, 50 mg/ml Vepesid Bristol-Myers Squibb USA flucytosine 6.3 cap, 250 mg Ancobon ICN Pharmaceuticals USA fludrocortisone 18.1 tab, 100 µg Florinef Bristol-Myers Squibb USA acetate fluorouracil 13.5 oin, 5% Efudix Roche USA fluphenazine 24.1 inj, 25 mg/1 ml Prolixin Bristol-Myers Squibb USA decanoate depot Decanoate fluphenazine 24.1 inj, 25 mg/1 ml Prolixin Bristol-Myers Squibb USA enantate depot Enantate furosemide 16 tab, 40 mg Lasix Hoechst Marion Roussel Germany glyceryl trinitrate 12.1 sbtab, 500 µg Nitroglycerin Novartis Switzerland chcap, 800 µg Wander griseofulvin 6.3 cap,125 mg, 250 mg Grisactin Zeneca USA griseofulvin 6.3 tab,125 mg, 250 mg Fulcin Zeneca UK haloperidol 24.1 tab, 2 mg, 5 mg Haldol Janssen Belgium hydralazine HCI 12.3 pwinj, 20 mg Apresoline Novartis UK hydralazine HCI 12.3 tab, 25 mg ,50 mg Apresoline Novartis Netherlands hydrochlorothiazide 16 tab, 25 mg, 50 mg Hydrosaluric Merck Sharp & Dohme UK hydrochlorothiazide 12.3 tab, 25 mg Hydrosaluric Merck Sharp & Dohme UK ibuprofen 2.1 tab, 200 mg Nurofen Boots UK idoxuridine 21.1 eyd, 0.1% Herplex Allergan USA idoxuridine 21.1 eyo, 0.2% Herplex Allergan USA imipenem + 6.2.1 pwinj, 250 mg +250 mg, cilastatin Na 500 mg +500 mg Tienam Merck Sharp & Dohme Italy imipenem + 6.21 pwinj, 500 mg +500 mg Tienam Merck Sharp & Dohme Italy cilastatin Na insulin inj. (soluble) 18.5 inj, 40,80,100 IU/ml Actrapid Novo Nordisk Germany Zimbabwe insulin inj. (soluble) 18.5 inj, 40,80,100 IU/ml Novolin R Novo Nordisk USA, Japan insulin 18.5 inj, 40, 80,100 IU/ml Humulin L Eli Lilly USA intermediate-acting insulin, isophane 18.5 inj, 40,80,100 IU/ml Humulin N Eli Lilly USA ipratropium bromide 25.1 inh, 20 µg/ Atrovent Boehringer Ingelheim USA metered dose iron dextran 10.1 inj, 50 mg eq/ml Infed Shein USA isosorbide dinitrate 12.1 subling. tab, 5 mg Isordil Wyeth-Ayerst USA ivermectin 6.12 scored tab, 6 mg Stromectol/ Merck Sharp & Dohme Netherlands Mectizan ketoconazole 6.3 osp, 100 mg/5 ml Nizoral Janssen Belgium ketoconazole 6.3 tab, 200 mg Nizoral Janssen Belgium levamisole HCI 8.2 tab, 50 mg Ergamisol Janssen Belgium levamisole HCI 6.11 tab, 50 mg, 150 mg Ergamisol Janssen Belgium levodopa + 9 tab, 100 mg +10 mg, Sinemet Merck Sharp & Dohme Italy carbidopa 250 mg + 50 mg levonorgestrel 18.3 tab, 30 µg Microval Wyeth-Ayerst Germany lithium carbonate 24.2 cap, 300 mg Quilonum SmithKline Beecham Germany lithium carbonate 24.2 tab, 300 mg Quilonum SmithKline Beecham Germany mebendazole 6.11 chtab, 100 mg, 500 mg Vermox Janssen Belgium

* This list is based on information collected by WHO from drug regulatory authorities and supplemented by information from pharmaceutical companies. It should be used in conjunction with the instructions provided.

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INN/INNm/ Model dosage form brand company primary common List section and strength name market(s) name

medroxy- 18.7 tab, 5 mg Provera Pharmacia-Upjohn USA progesterone acetate medroxy- 18.31 inj, 150 mg/ml, Depo-Provera Pharmacia-Upjohn USA progesterone acetate depot mefloquine HCI 6.5.3 tab, 250 mg Lariam Roche Switzerland methyldopa 12.3 tab, 250 mg Aldomet Merck Sharp & Dohme Spain metoclopramide HCI 17.2 tab, 10 mg Primperan Synthélabo France miconazole nitrate 13.1 cre, 2% Daktarin Janssen Belgium miconazole nitrate 13.1 oin, 2% Daktarin Janssen Belgium nalidixic acid 6.2.2 tab, cap, 500 mg Neggran Sanofi Winthrop USA neostigmine bromide 20 tab, 15 mg Prostigmin Roche Germany niclosamide 6.1.1 chtab, 500 mg Yomesan Bayer Germany nifedipine 12.3 cap, 10 mg Adalat-10 Bayer Germany nifedipine 12.3 tab, 10 mg Adalat-T10 Bayer Germany nifurtimox 6.5.5 tab, 30 mg, Lampit Bayer Argentina 120 mg, 250 mg nitrofurantoin 6.2.2 tab, 100 mg Furadantin Proctor & Gamble UK, Ireland norethisterone 18.3.1 oilsl, 200 mg/ml Noristerat Schering South Africa, enantate nystatin 6.3 loz, 100000 IU Nystan Bristol-Myers Squibb UK nystatin 6.3 vag. tab, 100 000 IU Mycostatine Bristol-Myers Squibb France nystatin 6.3 tab,100 000 IU Mycostatine Bristol-Myers Squibb France nystatin 6.3 tab,500 000 IU Mycostatine Bristol-Myers Squibb USA oxamniquine 6.1.3 cap, 250 mg Mansil/ Vansi Pfizer Brazil oxamniquine 6.1.3 syr, 250 mg Mansil/ Vansil Pfizer Brazil paracetamol 2.1 sup, 100 mg, 125 mg, Ben-U-ron Bene Germany 250 mg, 500 mg, 1000 mg penicillamine 4.2 tab, 250 mg Depen Carter-Wallace USA penicillamine 4.2 cap, 250 mg Cuprimine Merck Sharp & Dohme USA phenobarbital 5 tab, 15 mg Luminaletten Desitin Germany phenobarbital 5 tab, 100 mg Luminal Desitin Germany phenoxymethyl- 6.2.1 pwosp, 250 mg/5ml V-Cillin K Eli Lilly USA penicillin phenoxymethyl- 6.2.1 tab, 250 mg V-Cillin K Eli Lilly USA penicillin phenytoin sodium 5 cap, 25, 30, Dilantin Parke-Davis USA 50,100 mg Kapseals phenytoin sodium 5 tab, 25 mg, 50 mg, Dilantin Parke-Davis USA 100 mg Infatabs phytomenadione 10.2 tab, 10 mg Konakion Roche Switzerland praziquantel 6.1.1, 6.1.3 tab, 150 mg, Biltricide Bayer Germany 600 mg prednisolone 8.3 tab, 5 mg Scherisolon Schering Colombia, Uruguay prednisolone 18.1 tab, 1 mg, 5 mg Scherisolon Schering Colombia, Uruguay prednisolone 3 tab, 5 mg Scherisolon Schering Colombia, Uruguay prednisolone 21.2 eyd, 0.5% Ultracortenol Ciba Vision (Novartis) Germany sodium phosphate procainamide HCI 12.2 tab, 250 mg, 500 mg Pronestyl Bristol-Myers Squibb USA

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INN/INNm/ Model dosage form brand company primary common List section and strength name market(s) name

procarbazine HCI 8.2 cap, 50 mg Natulan Roche Switzerland proguanil HCI 6.5.3 tab, 100 mg Paludrine Zeneca UK propranolol HCI 12.2 tab, 10, 40 mg Inderal Zeneca UK propranolol HCI 12.1 tab, 10, 40 mg Inderal Zeneca UK propranolol HCI 7.2 tab, 20 mg, 40 mg Inderal Zeneca Japan propranolol HCI 12.3 tab, 40 mg Inderal Zeneca UK pyrantel embonate 6.1.1 chtab, 250 mg Combantrin Pfizer Germany pyrantel embonate 6.1.1 osp, 50 mg/ml Combantrin Pfizer Germany pyrazinamide 6.2.4 tab, 400 mg, 500 mg Zinamide Merck Sharp & Dohme UK pyrazinamide+ 6.2.4 tab, 400 +150 + 75 mg, Rifater Hoechst Marion Italy rifampicin+isoniazid 500 +150 + 150 mg Roussel pyridostigmine 20 tab, 60 mg Mestinon Roche Switzerland bromide rifampicin 6.2.3, 6.2.4 cap, 150, 300 mg Rifadin Gruppo Lepetit Italy rifampicin 6.2.3, 6.2.4 tab, 150, 300 mg Rifadin Gruppo Lepetit Italy rifampicin + 6.2.4 tab, 150 +100 mg, Rifinah Gruppo Lepetit Italy isoniazid sulfadiazine, silver 13.2 cre, 1%/500 g Silvadene Hoechst Marion Roussel USA sulfadoxine+ 6.5.3 tab, 500 + 25 mg Fansidar Roche Switzerland pyrimethamine sulfamethoxazole+ 6.2.2 osp, 200 +40 mg Bactrim Roche Switzerland trimethoprim sulfamethoxazole+ 6.2.2 tab, 100 +20 mg Bactrim Roche Switzerland trimethoprim 400 + 80 mg sulfasalazine 17.4 tab, 500 mg Azulfidine Pharmacia-Upjohn USA tamoxifen citrate 8.3 tab, 10, 20 mg Nolvadex Zeneca UK testosterone 18.2 inj, 200 mg/1ml, Testorion Schering Germany enantate 250 mg/ml Depot Argentina China Mexico theophylline 25.1 tab, 100 mg, 125 mg, Euphylong BYK-Gulden Germany 200 mg, 250 mg, 375 mg, 500 mg timolol maleate 21.4 eyd, 0.25%, 0.5% Timoptol Merck Sharp & Dohme France Ophthalmic Solution timolol maleate 21.4 eyd, 0.25%, 0.5% Timoptol Merck Sharp & Dohme France Ocudose timolol maleate 21.4 eyd, 0.25%, 0.5% (gel) Timoptol LP Merck Sharp & Dohme France tolbutamide tab, 500 mg Rastinon Hoechst Marion Roussel Germany triclabendazole 6.1.3 tab, 250 mg Egaten Novartis Egypt tropicamide 14.1 eyd, 0.5% Mydriacyl Alcon UK verapamil HCI 12.1, 12.2 tab,40 mg,80 mg Isoptin Knoll Germany

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General Information

Medical products and the Internet The Fifty-first World Health Assembly held in May 1998 expressed its concern at the extent of uncontrolled advertising, promotion and sale of medical products through the Internet. These practices may present a hazard for public health as well as a risk to the individual patient with regard to misleading or fraudulent product information and lack of individual counselling. Such products require authorization prior to marketing and many are available only on medical prescription.

Medical Products and the Internet: a Guide to finding reliable information, reproduced below, was developed by WHO in collaboration with drug regulatory authorities, drug information experts, consumer organizations and the pharmaceutical industry. It is intended to serve as a model for adaptation by Member States needing meaningful advice for Internet users on how to obtain reliable, independent and comparable information on medical products. It is designed to be translated into national languages and modified as the local situation demands.

WHO would be grateful to receive comments on experience gained from the practical use of the guide. Please provide information by e-mail to [email protected] or write to the Department of Essential Drugs and Other Medicines (EDM), World Health Organization, 1211 Geneva 27, Switzerland.

Medical products and the should not replace such consultation (see Point 5). As you search for and evaluate information, how- Internet: a guide to finding ever, keep these considerations in mind: reliable information It may be difficult to determine the source of the Point 1: The Internet is a valuable source information you find on a web site and to verify that of information but be sure you know and source. If you are not familiar with the source of trust the source information, you may be able to find out more about it The Internet is a valuable source of health informa- from health care professionals or reliable organization on topics such as diseases, conditions, thera- tions with which you are familiar. Your own reliable pies, medical products, and health and medical sources may be able to give you help to evaluate the organizations. When used properly, it allows quick reliability and quality of the web site information. and easy access to such information from on-line medical libraries, universities, health associations There are many health and medical sites on the and government agencies. However, the quality of Internet which do provide good information that health and medical product information on the may not be easily available from other media. They Internet varies, and it is often difficult for the Internet may be designed for health professionals or for user to identify the true source of the information consumers. However, even information from reli- and to determine whether it is reliable, complete able sources may require special training in order to and up to date. evaluate it properly and to determine whether the information applies to your disease or condition. Point 2: Finding reliable health and The information provided by these web sites covers medical information on the Internet such topics as: Reliable sources of health and medical information 1. Research being conducted on a particular dis- are available on the Internet. This information can ease or a condition — including rare diseases — be helpful when you consult your health care pro- and related clinical trials. vider about your disease or condition, though it

163 General Information WHO Drug Information Vol. 13, No. 3, 1999

2. New product approvals by health authorities in cure", "exclusive product", "secret formula", "an- your country for a specific disease or condition. cient ingredient", "without risk", "anti-ageing", "improve sexual performance", and "all natural"; 3. General information about diseases or conditions, such as high blood pressure, arthritis or • Case histories from "cured" customers claiming obesity. amazing results. When you see a testimonial, ask for proof of its "typical" nature; 4. Support groups for people with certain diseases and conditions, such as acquired immunodeficiency • A list of symptoms and diseases it is claimed the syndrome (AIDS) or cancer; product cures — for example, claims that one product can cure or treat HIV/AIDS, cancer, 5. Lists of international, arthritis, Alzheimer disease, national and local organi- wrinkles, weight problems, zations that provide memory loss, and so on. support and information LOOKING AT A WEB SITE? • Advertisements that tout the for a disease or condition. CHECK THE FOLLOWING latest trendy ingredient mentioned in the news headlines. Health authorities and • Is there clear indication of the name and organizations in each contact address of the web site owner? • Claims that the product is available from only one source, for a country can provide a list • Is it clear which organization(s) contrib- limited time. of sites with links to reli- ute funding, services, or other support able sources of health and to the web site? medical information. • Testimonials from "famous" Additionally, several • If advertising or sponsorship is a source medical experts. private organizations are of funding, is this clearly stated? actively searching for • Claims of no risk or lack of any • Is this a site for consumers, health ways to ensure the quality risk information. Remember: no professionals, or some other audience? of information on the product or treatment is completely Internet. Internet users • When was the information displayed risk-free. may be interested in last updated? following or participating • Claims that a product is "scien- in these discussions and tifically proven" and "absolutely reading what others have to say on this topic. Two safe". organizations that are conducting such activities are: Health on the Net Foundation (http:// Products with the same name may contain different www.hon.ch) and Internet Healthcare Coalition ingredients in different countries. Therefore, when (http://www.ihc.net). searching for information you should look at the International Nonproprietary Name (INN) of the National authorities should identify and list addi- active ingredients and not just the product name tional organizations and reliable web sites known to (brand name, trade name). them. Product information should be as complete as Point 3: Finding reliable medical product possible, and it should include at least the elements information on the Internet outlined in the box on page 165. The Internet also offers information on medical products. As you search for and evaluate product Point 4: Be cautious about buying information, however, keep these considerations in medical products on the Internet mind: Medical products are often offered for sale on the Internet. Offering for sale and selling medical If information sounds too good to be true, it prob- products or buying medical products from another ably is. The following lists some warning signs that country via the Internet may be illegal. Therefore, medical product information may not be truthful. before buying a product, you should find out if it is legal to do so. If you are considering buying medi- • Advertisements or information that uses phrases cal products through the Internet, be cautious, such as: "scientific breakthrough", "miraculous because you may risk your health and waste your

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money. Consult your health care professional other. In such a case, your country may have before self-treatment. special legal procedures allowing you to import prescribed medicines from abroad. This could be There are many reasons why medical products done with the help of your health care professional, bought through the Internet could represent a through legitimate distribution channels. danger to you, or at the least cause inconvenience or loss of money. Ten of these reasons are dis- 2. Instructions for use may be inadequate cussed here. To be used properly and safely, medical products need to be accompanied by precise instructions. 1. Safety and efficacy assurance may be lacking There is no assurance that a product obtained via In many countries, before medical products are the Internet will have the correct instructions for approved, licensed or authorized for sale, the use, dosage and precautions. In addition, instruc- companies that develop and market them must tions may be printed in a language that you do not conduct research and demonstrate to a drug regu- know, or they may be unreliable, out of date, or latory authority that the otherwise unusable. products are safe, effective LOOKING AT PRODUCT INFORMATION? and of good quality for 3. Quality may not be A RELIABLE WEB SITE WILL PROVIDE human use. Although assured THE FOLLOWING INFORMATION: these authorized medical When you buy a medical products may be available • product name product through the through the Internet, there • active ingredient(s) appropriate channels, may also be products for • name of other ingredients known to cause such as through your sale that have not been problems to some people pharmacy, you can gener- studied and evaluated • what to use the product for ally rely on the product according to the laws and • when not to use the product (for example, in meeting manufacturing regulations of your country. pregnancy, if you suffer from allergies, if inter- requirements and you can There is no assurance of actions are possible with medicines or foods) count on its quality: in safety and effectiveness for • how to use the product other words, the product such unauthorized prod- • possible undesired effects contains the right active ucts. As an Internet user, • how to store the product ingredients and has been you may find it difficult to • manufacturer's name and contact information properly manufactured, distinguish between prod- • latest update of the information packaged, transported ucts that have met the and stored. By buying requirements of your gov- medical products through ernment and those that the Internet, you may have not. forfeit the quality assurance offered by authorized channels of medical product manufacturing, distri- Information about medical products being devel- bution and sales in your country. oped and tested in humans is available on the Internet. If you have a disease or condition for 4. Products may circumvent which there is currently no treatment or cure, you regulatory protection may have searched for information about your Medical products sold through the Internet may disease or condition and read about these new circumvent the regulatory protection provided by products on the Internet. Although new products health authorities and your government. You may are often not available for prescription, sometimes a be unable to obtain compensation from the manu- health care professional may prescribe a medica- facturer or distributor for any damage resulting from tion for you before approval, or discuss enrolling the use of these products. The identities and you in a clinical trial to study the product. It is locations of the sources of the products may be important to understand that there may be addi- disguised. This is especially common in the case of tional risks to using such a product before approval, fraudulent medical products. because the possible adverse effects (which may 5. Products may be fraudulent and be serious or life-threatening) and the effectiveness harmful to your health and proper dosage schedule may not be known. In Products promoted and offered for sale on the some cases, a prescription product may be unavail- Internet may be fraudulent if they do not meet the able in your country but approved for use in an- standards required for approval in your country and

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are not sold by licensed or authorized health or- different standards for the quality of medical prod- ganizations. Using such products to treat yourself ucts and their manufacture. Products purchased may be harmful to your health. The products may across borders might not be exactly the same provide no benefit to your disease or condition and product or quality as in your own country. you may miss an opportunity to be properly treated by health care professionals. Inefficacy of a medi- 10. Your personal information may not cal product is not only frustrating, it can also be remain confidential dangerous. Treatment with fraudulent products Many web sites require you to disclose personal may actually be harmful to your health and not just medical data. Users must be aware that there is no without benefit. assurance that this information will be kept confidential. Users who feel uncomfortable with the 6. Reimbursement may not be possible potential use of their personal data should purchase In many countries health insurance programmes their medical products through conventional, legiti- may not agree to reimburse you for medical prod- mate distribution channels. ucts bought through the Internet. Before you purchase a medical product through this channel, Point 5: See your health care professional even if the product seems legitimate to you, contact before you decide to treat yourself or change your insurance or other health coverage organiza- your medication tion to find out if the purchase would be covered Even after finding reliable, truthful health or medical and if the Internet medical product provider is information on the Internet, it is important to go to recognized by your health insurer or organization. your health care provider to discuss your disease or condition and the information you have found 7. Products may waste your resources before you take steps to treat yourself. This is By seeking medical treatment through the Internet important for several reasons: instead of through health care professionals, you could be wasting valuable resources — your time • Not all diseases and symptoms need medical and money — because the treatments may not treatment. You may be taking medicines or using help. In addition, you may spend valuable time in medical products unnecessarily and exposing treating yourself with an ineffective product when yourself to an unnecessary risk. you could have been properly treated during that time by going to a health care professional. • Many medications or other medical products may cause harm if they are used improperly. It is 8. Products bought across borders may important to be under the care of a health care not be allowed in your country professional when using such products. Countries have different laws about what medical products can be sold and shipped across national • Appropriate medication or appropriate medical borders. This means that it is possible that prod- treatment for your disease or symptoms is impor- ucts that are not approved for marketing in your tant to your health. Not every medication is country or products that have been identified as a appropriate for everyone. For example, some hazard to public health may not be allowed into individuals may be allergic to certain medications. your country if they are identified at entry. If you A health care professional can help you to deter- have already paid for the product, you may not be mine the best medicine or treatment for your able to receive it or have its cost reimbursed. In disease or condition. addition, the prescription status of medical products varies from country to country. For instance, prod- • A health care professional can provide guidance ucts that are available only on prescription in one on how best to take your medication safely. For country may be sold without prescription, or may example, the effectiveness of some medications even be unregulated, in another. may be influenced by other products, such as other medications, alcohol or certain foods. Mix- 9. Products with the same name may be ing your medication with these other products different in different countries could strengthen or weaken the effect of the Internet users need to be aware that products with medication or cause an adverse reaction. This the same name may contain different ingredients in could be dangerous to your health or, at the least, different countries. Therefore, you may be taking interfere with your timely recovery. the wrong product. In addition, countries may have

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• Some patients, such as pregnant or breast-feed- ence when using the product. By going through ing women, the elderly and children, have special your health care professional for treatment, you can concerns, needs and considerations when taking make sure that he or she will be better prepared to medication or using medical products. In particu- advise you or change the treatment if you do have lar, a number of medications are specifically an adverse reaction to a product. known to cause harm to unborn children, so that pregnant women should be sure to consult a By ordering medical products through the Internet health care professional before self-treatment. you may deprive yourself of the opportunity for personal, professional care and advice from your Any time you take medication or use a medical doctor, pharmacist or other health care profes- product it is important to inform your health care sional. professional of any side-effects you may experi-

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Biomedicines and Vaccines

DNA vaccines: integrated into the cellular genetic material and be faithfully maintained during replication. This is the improvements pending basis of the production of some recombinant therapeutic proteins. DNA insertion can occur in one of In recent years, researchers working in industry and three ways: random integration, homologous re- academia have shown that foreign protein ex- combination, or retroviral insertion. pressed by cells transfected with naked DNA can provoke a protective immune response in animals. There is relatively little data on the frequency of This immune response has shown a degree of DNA insertion in vivo and an important aspect of protection not only against viruses, bacteria, myco- preclinical safety testing is the investigation of bacteria, fungi and parasites but against T- and B- integration into chromosomes. cell lymphoma, renal carcinoma, autoimmune diseases and allergies. 2. Long-term expression may result in an undesired immunopathological reaction. Until now, there is Naked DNA vaccines appear to offer the promise of insufficient knowledge concerning the duration of long-lasting protection. They are stable and offer expression of an antigen by injected DNA. simplicity of production — underscoring their utility in developing countries. A major reason for the 3.Use of genes encoding cytokines or co-stimula- interest in DNA vaccines is the generic delivery tory molecules may pose risks. The co-administra- system on which they are based. Unlike live viral or tion of genes encoding regulatory cytokines may bacterial vaccines, which can revert to an infective have adverse consequences such as immuno- form, DNA vaccines cannot cause an infection. pathological reactions. Moreover, in the case of viral antigen, DNA vaccines use the same processes as when cells are 4. Antibodies against DNA may form and contribute invaded by infectious agents. The antigen and the towards undesired autoimmune reactions. Although response may then be more natural than in the experimental attempts to generate anti-DNA anti- case of antigens produced by animal cell produc- bodies contributing to disease have generally been tion methods (1). unsuccessful, it is not known whether unintended antibody induction would have adverse conse- Gene vaccination is also proving useful as a re- quences such as autoimmune disorders or toler- search tool and DNA vaccine technology can be ance. used to screen whole genomes of pathogenic organisms to find the best gene for a desired im- 5. The expressed antigen may have biological mune response. DNA plasmid expression libraries activity. Appropriate steps such as deletion muta- have been created for those genes contained in genesis may need to be taken to ensure lack of whole sections of a pathogen's genome. Thus, DNA toxicity. vaccines can be made to carry multiple genes encoding for a whole range of vaccination antigens. In May 1997, an International Working Group on the Standardization and Control of Nucleic Acid Questions of safety Vaccines (NAVSaC) was set up to provide a con- None the less, several safety issues are associated sensus opinion on such issues as those set out with administering plasmid DNA to humans (2) above. So far, scientific discussion has taken place which have not yet been clarified. on quality control of plasmid DNA, determination of potency, assays for detection of integration, mecha- 1. Injected DNA taken up by host cells may be nisms of action of DNA vaccines, formation of auto- integrated into chromosomes and cause an antibodies and autoimmunity, efficacy in both small insertional mutagenic event. It is known that DNA and large animals, methods of improving efficacy, taken up by mammalian cells in culture can be immunostimulatory sequences and clinical data.

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Improved efficacy References Unfortunately, until now, the level of response to recombinant vaccines has been inadequate in 1. DNA vaccines. CVI Forum, Number 18, July 1999. clinical trials in humans. Because the uptake of 2. World Health Organization. Guidelines for Assuring the plasmid DNA by host cells is inefficient, only a Quality of DNA Vaccines. Technical Report Series, No. small amount of the dose administered actually 878, 1998. ends up inside cells. Several approaches have been investigated to improve the technology. New WHO initiative 1. Researchers are now studying how to carry the microbial DNA into host cells using viruses. Promis- in vaccine safety ing results are expected from use of an RNA avian Vaccination is regarded as one of the most cost- virus which can infect human cells without causing effective public health interventions available. It is disease. It also seems able to target antigen pre- also recognized, however, that no vaccine is com- senting cells and provoke a strong immune re- pletely safe or protective in all vaccinated individu- sponse. This system has increased the potency of als due to differences in the way individual immune DNA plasmid up to 1000-fold. systems react. On rare occasions reports of side effects have been received and have influenced 2. Other plasmids are being inserted into bacteria public opinion. If such reports are not effectively such as Shigella, Salmonella and Listeria. Since dealt with, confidence in vaccination can be under- Shigella invade humans via the intestinal tract, the mined and have dramatic consequences for immu- plasmid vaccine could be administered orally nization coverage and disease incidence. It is also eliciting protective immunity to the foreign microbial essential that vaccine-associated adverse effects DNA as well as itself. should be promptly identified to encourage additional research or allow appropriate action to be 3. Alternatively, wrapping the DNA plasmid in a taken. biodegradable polymer will protect it from damage or destruction in the gastrointestinal tract when As vaccine-preventable infectious diseases decline, administered orally. the risk-benefit of vaccines will alter and the safety profile will become increasingly highlighted. Fur- 4. Animal studies are also under way on DNA thermore, recent knowledge about vaccines has led mixed with alum, which can increase the immune investigators to focus on the safety issues of vac- response to the protein encoded by the DNA. cines. In order to address such issues in an expedi- tious manner, WHO has set up a Vaccine Safety 5. Other approaches being tried are the insertion of Advisory Committee as part of its Immunization the gene for granulocyte-macrophage colony Safety Priority Project. stimulating factor into a malaria DNA plasmid vaccine. In this way the cytokine gene is spliced The Committee is a technical advisory body which into a DNA plasmid and expressed in host cells. aims to provide a reliable and independent scientific This will give a mixture of plasmids to prime the assessment of vaccine safety issues. Its members immune system to be followed some months later have been drawn from immunology, epidemiology, by a booster dose of a vaccine using a recombinant paediatrics, infectious diseases, public health and avian virus as vector for the malaria antigens. This pharmaceutical regulation and safety. The Commit- prime boost method is also being tested in candi- tee will review important safety issues which could date vaccines against HIV and cytomegalovirus affect immunization programmes and will make infection. scientific recommendations which are intended to assist WHO, national authorities and international 6. Electroporation is currently under trial in phase III organizations in formulating policies and in dealing studies in cancer patients. Application of an electri- with any issues of concern. cal field to a living cell causes a transient perme- ability in its outer membrane and DNA vaccine Reference: Vaccine safety. Weekly Epidemiological injected in conjunction with electroporation has Record, 74: 337–338 (1999). produced a 10-fold increase in the antibody response to DNA vaccine compared with controls.

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Regulatory and Safety Matters

Rotavirus vaccine and 3. Intussusception among recipients of rotavirus vaccine — United States, 1998–1999. Morbidity and Mortality intussusception Weekly Report, 48: 577–581 (1999). The manufacturer of an oral tetravalent rhesus vaccine against rotavirus infection (RRV-TV), has Zanamivir: inhaled announced withdrawal of its product, RotaShield®, following concern at the number of cases of intus- treatment for influenza susception associated with its use (1). Within less United States of America — The Food and Drug than a year, a higher than normal number of cases Administration has approved zanamivir, an inhaled of intussusception among infants who had received neuraminidase inhibitor, for the treatment of un- RRV-TV were reported. Following these reports, complicated influenza virus in adults and adoles- the Centers for Disease Control and Prevention, cents over 12 years of age. The product has been together with the manufacturer, recommended approved to treat type A and B influenza. postponement of rotavirus vaccination for infants until November 1999 to allow time to collect addi- Influenza causes significant morbidity and mortality tional data to indicate more clearly whether RRV- each year. Evidence for efficacy was provided by TV vaccine increases the risk of intussusception studies carried out in North America, the southern (2). Results of this review are awaited from the hemisphere and Europe. Effectiveness was demon- Advisory Committee on Immunization Practices. strated in patients who started treatment within two Rotavirus infections are the most common cause days of onset of symptoms. The primary endpoint of severe diarrhoea and vomiting in infants in the was defined as time to alleviation of major influ- United States of America and approximately 80% enza-like symptoms, including temperature, fever- of children develop symptoms of infection before ishness, symptoms of cough, headache, myalgia they are five years old. Worldwide, approximately and sore throat. The studies were not designed to 870 000 deaths are attributed annually to rotavirus establish safety or effectiveness in prophylactic use infection. Routine use of rotavirus vaccination was or in children. recommended for healthy infants by the United States Advisory Committee on Immunization Prac- Bronchospasm was documented in patients with tices, the American Academy of Pediatrics and the mild or moderate asthma. Any patient who de- American Academy of Family Physicians. In August velops bronchospasm should stop the drug and 1998, the Food and Drug Administration announced consult a physician or health care provider. Patients licence approval of the tetravalent rhesus rotavirus with underlying respiratory disease should have a vaccine. fast-acting bronchodilator available when being treated with zanamivir. Intussusception is a bowel obstruction in which one segment of bowel becomes enfolded within an- Reference: FDA Talk Paper, T99-34, 1999. other. The normal rate of hospitalization for intussusception among infants aged less than 12 months is around 50 per 100 000 infant-years (3). Oseltamivir approved for influenza References Switzerland — The Intercantonal Office for Medi- 1. Withdrawal of rotavirus vaccine, live, oral, tetravalent cines Control has approved oseltamivir, a neura- (Rotashield®). Center for Biologics Evaluation and Re- minidase inhibitor in pill form, designed to treat all search, 15 October 1999. common strains of influenza A and B. It will be 2. Centers for Disease Control and Prevention. CDC available on prescription only as from October 1999 recommends postponement of rotavirus vaccine for (1). infants. www.cdc.gov/oc/media, 19 July 1999.

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Data used in the evaluation showed a reduction of • An A/Moscow/10/99 (H3N2)-like virus duration of illness of 30% and a cut in severity of symptoms including fever, cough, aches and pains. • An A/Caledonia/20/99 (H1N1)-like virus Oseltamivir alleviated secondary influenza compli- • A B/Beijing/184/93-like virus (the most widely- cations such as bronchitis and sinusitis by 50% in used vaccine virus is B/Yamanashi/166/98) OR a previously healthy adults. It was well tolerated, with B/Shangdong/7/97-like virus. some patients reporting transient mild nausea or vomiting. WHO strongly recommends the use of vaccine as an effective preventive measure. About 50% to Other regulatory approvals for oseltamivir are 80% of vaccine recipients will be protected against pending worldwide. the disease when there is a good match between the vaccine and strains of influenza virus that are in References circulation. In cases where the vaccine does not fully protect against the disease, severity of illness 1. Communication to WHO from the Office Intercantonal and the frequency of serious complications are de Control de Médicaments, dated 20 October 1999. reduced. 2. Roche media release, 24 September 1999. In areas where the population has been previously infected or exposed to influenza A(H3N2), Synercid for certain vancomycin- A(H1N1), or B, one dose of influenza vaccine should be sufficient for all ages except young resistant infections children.

United States of America — The Food and Drug The specific vaccine viruses used in each country Administration has approved Synercid®, a combi- should be approved by the national control authori- nation of quinupristin and dalfopristin, for the treat- ties and national public health authorities are re- ment of infections associated with vancomycin- sponsible for recommendations regarding use of resistant Enterococcus faecium bacteraemia when the vaccines. no alternative treatment is available and for complicated skin and skin structure infections. Reference: Weekly Epidemiological Record, 74:321–325 (1999). Infections due to E. faecium occur particularly in hospitalized or immunocompromised patients and the organism is often resistant to multiple antibiot- Olanzapine: warning of neutropenia ics. Vancomycin was the last resort antibiotic until now. The drug has been granted accelerated Australia — The Adverse Drug Reactions Advisory approval. Synercid was also found to be safe and Committee has received 327 reports related to the effective for treatment of skin and soft tissue infec- antipsychotic agent, olanzapine. tions caused by methicillin-susceptible Staphylo- coccus aureus and Streptococcus pyogenes. Since marketing in 1997, the two most frequent adverse reactions have been somnolence and The most frequently reported side effects within weight gain. However, reports have also been clinical studies were muscle and joint pain, nausea, received concerning white cell disorders, convul- diarrhoea, vomiting and rash. sions and neuroleptic malignant syndrome. White cell disorders are a known effect of the related Reference: FDA Talk Paper, T99–44 1999 drug, clozapine. There have been no reports of agranulocytosis. Laboratory results available for 14 patients showed nadir neutrophil counts ranging Southern hemisphere from 0.8 to 1.9 cells x 109/L. influenza vaccine: 2000 Prescribers should be aware that white cell disor- World Health Organization — The composition of ders, seizures and neuroleptic malignant syndrome the vaccine for the year 2000 (southern hemisphere can all occur in association with olanzapine. influenza season) has been decided and communi- Reference: Australian Adverse Drug Reactions Bulletin: cated to vaccine manufacturers by WHO. The 18, Number 3, 1999. vaccine will contain the following three components:

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Over-the-counter emergency Leukotriene receptor antagonists: contraception approved suspected adverse reactions France — A preparation containing two tablets of Canada — The leukotriene receptor antagonists 75 µg levonorgestrel, Norlevo®, has been approved zafirlukast and montelukast are marketed for the for over-the-counter marketing (1). Several studies prophylaxis and chronic treatment of asthma (1, 2). have shown that levonorgestrel alone is more As of June 1999, the Canadian Adverse Drug effective and better tolerated than the Yuzpe regi- Reactions Monitoring Program has received 41 men (2). France will act as the reference member reports of suspected adverse reactions associated state under the European Community's mutual with the use of zafirlukast and 22 associated with recognition procedure. Marketing submissions are the use of montelukast. expected in other European countries. Rare cases of eosinophilic conditions have oc- This is the second product for emergency contra- curred during the use of these medications. It is ception which has been marketed in France. The unclear whether these events are related to the first, which contains ethinylestradiol 50 µg + use of the leukotriene receptor antagonists or if the levonorgestrel 250 µg, is available on prescription clinical syndrome is unmasked with the reduction or only. withdrawal of systemic corticosteroids. Although the References causes of this rare syndrome remain unclear, physicians should be aware of the possibility of 1. Extract 7982, French Official Journal, 30 May 1999. vasculitis and eosinophilic conditions presenting in 2. Pharmaceutical Journal, 261: 221 (1998). these circumstances. Additionally, because both montelukast and Flutamide: change in zafirlukast are metabolized by the cytochrome P450 enzyme system, there is a potential for drug inter- product labelling actions with numerous agents. United States of America — The manufacturer of References flutamide capsules, Eulexin®, has issued a letter warning of liver toxicity in patients taking flutamide 1. Canadian Adverse Drug Reaction Newsletter, Volume and monitoring requirements to avoid hepatic injury. 9, number 4, October 1999. Post-marketing reports for liver failure included a 2. WHO Drug Information, 13(1): 18 )1999). description of elevated serum transaminase levels, jaundice, hepatic encephalopathy and death related to acute hepatic failure. Approximately half of the Medifoxamine: hepatic injury reported cases occurred in the 3 months following France — Medifoxamine was marketed firstly in initiation of treatment. 1973 as an anxiolytic regulator of psychosomatic Serum transaminase levels should be measured symptoms and later, in 1991, for major depression. prior to initiating treatment with flutamide which is not recommended in patients whose alanine A recent review of adverse reaction reports has transaminase (ALT) values exceed twice the upper revealed the possibility of rare, but serious, hepatic limit of normal. Serum transaminases levels should injury. Since 1986, 36 cases of hepatic injury, then be measured every month for the first four including 2 cases of death and one case of liver months of treatment and periodically thereafter. transplant have been received. Following a subse- Liver function tests should be obtained at the first quent assessment of the risk-benefit ratio, the sign or symptom of liver dysfunction. In the event of Medicines Agency has decided to suspend market- jaundice or raised ALT, flutamide should be discon- ing authorization of medifoxamine. This decision is tinued immediately with close follow-up of liver further supported by the lack of efficacy in the function tests until resolution. Flutamide is not treatment of episodes of major depression. indicated for use in women. Medifoxamine is also available in Cambodia, Lao Reference: FDA Medwatch on www.fda.gov./Medwatch People's Democratic Republic, Morocco, Senegal (1999). and Viet Nam.

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Reference: Communication to WHO from the Agence du Reference: Bolletino Informazione sui Farmaci. Médicament, France dated 30 June 1999. Number 3, 1999.

Alendronate and Pioglitazone to treat type 2 diabetes gastrointestinal disorders United States of America and Japan — A new Australia — The Adverse Drugs Reactions Advi- drug in the thiazolidinedione class of drugs has sory Committee has received 331 reports of sus- been approved for the treatment of type 2 diabetes. pected adverse reactions associated with the use of Pioglitazone is for use as monotherapy in patients alendronate since marketing in 1996 (1). The most with type 2 or adult-onset diabetes who are not important effects reported were oesophagitis, adequately controlled by diet and exercise alone. oesophageal ulceration or stricture. Pioglitazone is also approved for use in combination with sulfonylureas, metformin, or insulin in Alendronic acid, the first non-hormonal treatment patients who are not adequately controlled with for osteoporosis and Paget disease, has also been these agents alone. Type 2 diabetes usually starts licensed in many other countries. In 1996, following in adulthood and is commonly associated with new information concerning gastrointestinal re- overweight. actions, instructions were reinforced by the manufacturer to emphasize that each tablet should be Pioglitazone improves resistance to insulin, which swallowed with a full glass of water at least 30 seems to be an underlying cause of type 2 diabe- minutes before food, beverage or other medication tes. Adverse events commonly reported include (2). headache, upper respiratory infections and muscle pain. Although clinical trials did not demonstrate A recent small study presented to the American drug-induced hepatotoxicity, the Food and Drug College of Gastroenterology has indicated that Administration is recommending liver enzyme gastric ulcers may be produced by the concomitant monitoring before initiation of treatment and every administration of nonsteroidal anti-inflammatory two months during the first year. drugs and alendronate. In addition, alendronate plus naproxen were poorly tolerated, with 69% of References the volunteers reporting side effects (3). 1. FDA Talk Paper, T99-33 (1999).

References 2. Pharma Japan, 1661, 30 August 1999.

1. Australian Adverse Drug Reactions Bulletin, 18(3): 11 (1999). Pimozide labelling changes

2. Circular letter from Merck & Co. Inc., dated 15 March The manufacturer of pimozide, Gate Pharmaceuti- 1996. cals, has published labelling changes for the antipsychotic, pimozide 3. Alendronate may multiply risk of gastric ulcer in naproxen-taking patients. Doctor's Guide, http:// Sudden, unexpected deaths have occurred in www.pslgroup.com/dg. patients taking greater than 10 mg doses of pimozide. One possible reason for such deaths is prolongation of the QT interval predisposing pa- Losartan and irbesartan: tients to ventricular arrhythmia. adverse reactions Accordingly, concomitant use of drugs which could impede metabolism and increase plasma concen- Italy — The Italian Pharmaceutical Committee trations could be hazardous. Inhibitors of CYP 3A (CUF) has circulated a warning letter concerning which are contraindicated with pimozide are: possible cough and angio-oedema associated with macrolide antibiotics (clarithromycin, erythromycin, use of angiotensin II antagonists. The new class of troleandomycin); azole antifungal agents (itracona- antihypertensives, losartan and irbesartan, may zole, ketoconazole); protease inhibitors (ritonavir, have a similar adverse reaction profile to angio- saquinavir); nefazodone, zileuton. As a precaution, tensin-converting enzyme (ACE) inhibitors. patients should also avoid grapefruit juice.

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Reference: Communication from Gate Pharmaceuticals, Preliminary evidence suggests that IGIV products dated September 1999. containing sucrose may present a greater risk for this complication. Hyperosmolarity of certain recon- stituted products as well as differences in stabilizer Ticlopidine and sugar choice and content may be among the fac- haematological reactions tors that have contributed to different reporting rates for renal dysfunction among the various IGIV Canada — Since marketing in 1991, the Canadian products. A disproportionate share of the cases Adverse Drug Reaction Monitoring Program has have been associated with sucrose-containing received 464 reports of adverse reactions associ- products. ated with the use of ticlopidine, a thienopyridine derivative. It is recommended that (i) patients are adequately hydrated prior to infusion; (ii) particular caution Of these, 138 concerned haematological reactions must be exercised for patients at increased risk of and included thrombocytopenic purpura, thrombo- developing acute renal failure; (iii) the recom- cytopenia, bone marrow aplasia, anaemia, pancyto- mended dose should not be exceeded; and (iv) penia, agranulocytosis and neutropenia. Such appropriate tests should be carried out before reports are consistent with the known risks. administration.

It is therefore recommended that patients be coun- Reference: Center for Biologics Evaluation and Research. selled about early warning signs of haematological http://www.fda.gov/medwatch problems including signs of infection, bleeding or neurological deficit. Aristolochia and renal failure Reference: Canadian Adverse Drug Reaction Newsletter, United Kingdom — Two reports have been re- Volume 9, number 4, October 1999. ceived of patients with end-stage renal failure associated with use of Chinese herbal medicines Immune globulin intravenous containing Aristolochia. In both cases the medicine was used for skin conditions. products: risks identified Aristolochia spp contain aristolochic acids which United States of America — The Center for are genotoxic carcinogens and are associated with Biologics Evaluation and Research has communi- interstitial nephropathy. In view of these serious cated an important drug warning concerning acute adverse effects, import, sale and supply of products renal failure associated with the administration of containing aristolochia have been prohibited. The immune globulin intravenous (human) (IGIV) prod- Medicines Control Agency is sampling and testing ucts. Such products are used for a range of condi- certain Chinese herbal medicines to gain informations including primary immune deficiencies, throm- tion on the extent of a possible problem of contami- bocytopenic purpura, Kawasaki syndrome, leukae- nation or substitution. mia and bone marrow transplant. Reference: Current Problems in Pharmacovigilance, Since 1981, 114 reports have been received of Volume 25, September 1999. acute renal dysfunction or acute renal failure associated with IGIV products. Many of the patients who died had serious underlying conditions.

174 WHO Drug Information Vol. 13, No. 3, 1999

Essential Drugs

WHO Model Formulary

As described in previous issues of this journal, work is now under way on the WHO Model Formulary and draft texts will be published regularly to obtain comments on the material proposed for publication. Observations concerning the following sections should be addressed to: Department of Essential Drugs and Other Medicines (EDM), World Health Organization, 1211 Geneva 27, Switzerland.

Antidotes and other substances endotracheal tube. Gastric lavage should not be attempted after corrosive poisoning or ingestion of used in poisonings petroleum products.

All patients who show features of poisoning should Emesis be admitted to hospital whenever possible. Patients Emesis induced by ipecacuanha is of limited value. who have taken poisons with delayed actions There is no evidence that it prevents clinically should also be admitted even if they appear well — significant absorption and its adverse effects may delayed-action poisons include acetylsalicylic acid, often complicate diagnosis. It should only be con- iron, paracetamol, tricyclic antidepressants and sidered if the patient is fully conscious and if the paraquat. poison ingested is neither corrosive nor a petroleum distillate. When it is impossible to establish with certainty the identity of the poison and the size of the dose patients must be treated symptomatically. Particular Prevention of absorption care must be given to maintenance of respiration Given by mouth, activated charcoal can bind many and blood pressure. Cardiac conduction defects poisons in the stomach thereby reducing their and arrhythmias often respond to correction of absorption. It may be effective for as long as two underlying hypoxia or acidosis. Hypothermia may hours after ingestion. It is relatively safe and is develop in patients who have been unconscious for particularly useful for the prevention of absorption some hours and they should be wrapped in blan- of poison which is toxic in small amounts such as kets to conserve body heat. Prolonged or recurrent antidepressants. convulsions may be treated with intravenous diazepam. ACTIVATED CHARCOAL Gastric lavage Powder: used as suspension in water The dangers of attempting to empty the stomach Uses: Treatment of acute poisoning. should be balanced against the toxicity of the ingested poison, as assessed by the quantity Dosage: ingested, inherent toxicity and time since ingestion. Adults: 50–100 g of activated charcoal as suspen- Gastric emptying is clearly unnecessary if the risk sion. of toxicity is small or if the patient presents too late. Emptying the stomach is probably of value if under- Children: 1 g/kg. taken within 1–2 hours after ingestion. The main risk here is inhalation of stomach contents. Gastric Severe poisoning lavage should not be undertaken in drowsy or Adults and children: Charcoal should be given in comatose patients unless there is a good cough doses of 25 g two to three times a day. reflex or the airway can be protected by a cuffed

175 Essential Drugs WHO Drug Information Vol. 13, No. 3, 1999

Contraindications: Not to be used in poisonings Precautions: Atropine increases intraocular pres- caused by corrosive substances (strong alkali or sure in patients with glaucoma. acids). Adverse effects: Anticholinergic effects such as Precautions: Unconscious patients must be intu- dry mouth, ‘flushing’, tachycardia, disturbance of bated before administration of charcoal (via a vision, urine retention, obstipation and confusion. nasogastric or gastric tube) to prevent aspiration.

Adverse effects: Constipation or diarrhoea. Aspi- DEFEROXAMINE ration may cause pneumonitis. Powder for injection, 500 mg in vial Uses: Treatment of acute iron poisoning. Iron IPECACUANHA overload, aluminium overload in patients on mainte- Syrup: containing 0.14% ipecacuanha nance haemodialysis; diagnosis of iron and alu- alkaloids calculated as emetine minium overload. Uses: Treatment of acute poisoning. Dosage and administration: 15 mg/kg over the first few hours by slow intravenous infusion. The Dosage and administration: infusion rate should be reduced after 4 to 6 hours Adults and children over 12 years: 30 ml orally, to 5 mg/kg. The total dose should not exceed followed by 100–200 ml of water. 80 mg/kg in 24 hours.

Children: 6–18 months: 10 ml; 18 months to 12 Contraindications: Known hypersensitivity to years: 15 ml followed by 100–200 ml water. deferoxamine. Patients with severe renal impairment. The same dose may be repeated in 20 to 30 minutes if vomiting has not occurred. Activated char- Adverse effects: Allergic reactions. Gastrointes- coal may be given after emesis has occurred. If the tinal discomfort. Hypotension may occur if the rate patient has not vomited within 30 minutes after the of infusion exceeds that recommended. Convul- second dose, use of activated charcoal should be sions may be exacerbated in patients with alu- considered. minium-related encephalopathy. Long-term infu- sions may predispose to adult respiratory distress Contraindications: Poisoning due to ingestion of syndrome. organic solvents (e.g. gasoline, turpentine, kero- sene and other petroleum-based products) or corrosive substances (strong alkali or acids). Un- DIMERCAPROL conscious or convulsing patients. Children less than Injection in oil: 50 mg in 2–ml ampoule 6 months of age. Uses: Treatment of acute poisoning by heavy Adverse effects: Excessive vomiting may result in metals such as arsenic, inorganic mercury, gold, loss of fluid and electrolytes or mucosal damage. bismuth and antimony. As adjunctive therapy for acute lead encephalopathy. ATROPINE Dosage and administration: 400–800 mg by deep Injection: 1 mg (sulfate ) in 1–ml ampoule intramuscular injection in divided doses (2.5–3 mg/ kg every 4 hours) on the first day. On the second and third day, 200–400 mg i.m. in 2 to 4 divided Uses: Treatment of organophosphate poisoning. doses. Thereafter, 100–200 mg i.m. in 2 divided doses. Generally, single doses should not exceed Dosage: Initially 1–2 mg as an intravenous injec- 3 mg/kg but in severe acute poisoning, single doses tion repeated according to response every 5–15 of up to 5 mg/kg may be required initially. minutes then every 15–30 minutes, increasing the dose when the cholinergic effects subside. As much Contraindications: Lead and cadmium poisoning. as 50 mg atropine may be needed during first 24 Impaired hepatic function (unless this is due to hours. arsenic poisoning). Patients with hypertension or renal impairment.

176 WHO Drug Information Vol. 13, No. 3, 1999 Essential Drugs

Precautions: Treatment should be discontinued if Adverse effects: Chest pain, dyspnoea, anxiety, acute renal failure occurs during therapy. Any tremor, dysuria, bluish skin discoloration and abnormal reaction such as hyperpyrexia should be methaemoglobinaemia may occur with high assessed before continuing therapy. doses. Haemolytic reactions are common in glucose-6-phosphate deficient patients. Adverse effects: Local pain and abscess at the site of injection. Hypertension, tachycardia, nausea, abdominal pain, salivation, lacrimation, sweating NALOXONE burning sensation in the mouth, throat and eyes, injection, 400 micrograms (hydrochloride) in headache, muscle spasms and tingling of the 1–ml ampoule extremities. Fever is common in children. Uses: Treatment of opioid overdose.

DL-METHIONINE Dosage and administration: Tablet: 250 mg Adults: 100–400 micrograms by intravenous injection repeated every two to three minutes according Uses: Treatment of paracetamol overdosage. As to the clinical response. little as 10–15 g of paracetamol may cause severe hepatocellular necrosis and, less frequently, renal Children: In emergencies, intravenous injection is tubular necrosis. preferred. 10 micrograms (0.01 mg)/kg by intravenous injection, intramuscular injection or subcuta- Dosage: Patients at risk of liver damage should be neous injection. Repeat the injection at two or three given methionine within 10 to 12 hours after the minute intervals for an additional 1–2 doses. ingestion of paracetamol. Contraindications: Known hypersensitivity to Adults and children: Initially, 2.5 g orally, followed naloxone. Physical dependence on narcotics since by 3 further doses of 2.5 g every 4 hours. naloxone will cause an acute withdrawal syndrome in dependent patients. Precautions: Care should be taken in patients with asthma. Precautions: Naloxone counteracts respiratory depression caused by opioids. Other resuscitative measures must be immediately available. This METHYLTHIONINIUM CHLORIDE includes maintenance of a clear airway, control of (METHYLENE BLUE) ventilation, cardiac massage, maintenance of an Injection: 10 mg/ml in 10-ml ampoule effective circulatory volume and vasopressor therapy. Uses: Treatment of severe methaemoglobinaemia. Adverse effects: Nausea and vomiting. Rapid Dosage and administration: 1 to 2 mg/kg by reversal of opioid action may induce withdrawal intravenous injection over a period of several symptoms in opioid-dependent patients. minutes to reduce pain at the injection site. Addi- tional doses may be given as necessary to a maxi- mum of 7 mg/kg. After administration of methylene PENICILLAMINE blue, the vein should be flushed with 50 ml normal Capsule or tablet: 250 mg saline. Uses: Treatment of heavy metal poisoning, particu- Contraindications: Severe renal impairment. larly lead. To promote excretion of copper in Wilson Known hypersensitivity. disease.

Precautions: Haemolytic anaemia can occur in Dosage: patients with glucose-6-phosphate dehydrogenase Adults: 1–2 g daily taken orally in 4 divided doses. deficiency. Blood methaemoglobin concentrations Continue treatment until urinary excretion of lead is should be monitored throughout treatment. less than 0.5 mg per day.

177 Essential Drugs WHO Drug Information Vol. 13, No. 3, 1999

Children: 20 to 25 mg/kg daily in divided doses. Adverse effects: Renal tubular necrosis. Nausea, cramps, fever, malaise, headache, myalgia, Contraindications: Penicillin-allergic patients; histamine-like responses and transient hypoten- severe thrombocytopenia or leukopenia. sion.

Precautions: Care should be taken in patients with renal impairment. SODIUM NITRITE Injection: 30 mg/ml in 10-ml ampoule Adverse effects: Nausea, fever, proteinuria, rash, bone marrow depression, renal and hepatic dys- Uses: Treatment of cyanide poisoning (together function. with sodium thiosulfate). Dosage: 300 mg by intravenous injection in 5 POTASSIUM FERRIC minutes or as an infusion. If no response occurs in HEXACYANOFERRATE 30 minutes a further dose of 150 mg may be given. Sodium thiosulfate should be given after sodium (PRUSSIAN BLUE) nitrite. Powder for oral administration Uses: Treatment of thallium poisoning. Precautions: Plasma methaemoglobin should be monitored. Care in patients with severe cardiovas- Dosage: 125 mg/kg twice daily until urinary excre- cular or cerebrovascular disease. tion of thallium falls to 0.5 mg or less, every 24 hours. Adverse effects: Hypotension, methaemoglobinaemia, headache, nausea and vomiting. Adverse effects: No adverse effects reported at the recommended dosage. SODIUM THIOSULFATE Injection: 250 mg/ml in 50–ml ampoule SODIUM CALCIUM EDETATE Uses: Treatment of cyanide poisoning (together Injection: 200 mg/ml in 5-ml ampoule with sodium nitrite). Uses: Treatment of lead poisoning Dosage: 125 mg by slow intravenous infusion Dosage and administration: 40 mg/kg twice daily repeated if necessary after 30 minutes. Sodium as an intravenous infusion in normal saline or 5% thiosulfate should be given after sodium nitrite. glucose for up to 5 days. Treatment can be repeated if necessary after 48 hours. Adverse effects: Sodium thiosulfate is relatively non-toxic. Precautions: Care should be taken in patients with renal impairment.

178 WHO Drug Information Vol. 13, No. 3, 1999

Recent Publications and Documents

Measures to combat a large proportion of the population relies heavily on traditional medicine to meet primary health care counterfeit drugs needs. There is no simple or standard solution in dealing Few plant species have been scientifically evalu- with counterfeiting of medicinal products. Each ated for their medical application, and safety and country has to develop a strategy based on its own efficacy data are only available for very few plant situation taking into account the infrastructure and extracts and active ingredients. In many countries availability of resources. Counterfeiting of medi- the market is poorly regulated and few herbal cines is a shared problem and solutions must be products are registered or controlled. Assurance of found by all the concerned parties. the safety, quality and efficacy of medicinal plants and herbal products has now become a key issue. The factors facilitating the occurrence of counterfeit drugs vary from country to country. However, It is In order to provide independent authoritative infor- known that counterfeiting affects both developed mation on the safety and efficacy of medicinal and developing countries alike and that the problem products, WHO has now published the first volume is more pronounced in those countries where of WHO Monographs on Selected Medicinal Plants medicines are less regulated and enforcement is containing monographs on the quality control and weak. traditional and clinical use of 28 medicinal plants. Guidelines for the Development of Measures to Monographs are provided for a number of phyto- Combat Counterfeit Drugs have been prepared medicines traditionally used to treat common com- within the framework of a WHO Joint Project on plaints such as diarrhoea, constipation, headache, Counterfeit Drugs which operated between 1995 loss of appetite, sleep disorders, fatigue, mild and 1997. They are the outcome of extensive respiratory disorders, and gastrointestinal and skin consultation and have been developed for use by conditions. Additional medical applications range governments, drug regulatory authorities, law from the lipid-lowering potential of garlic powder enforcement agencies, importers, distributors, preparations to the possible antiplasmodial activity professional associations, consumers and the of Fructus brucae, and the role of curcumin in pharmaceutical industry. promoting healing of peptic ulcer and reducing associated abdominal pain. The Guidelines focus on specific measures to be undertaken, including investigation of possible In preparing and publishing these monographs, counterfeiting operations, effective inspection WHO aims to encourage standardized approaches procedures, test methods for suspected counterfeit to ensuring the safety, quality and efficacy of me- products, and development of training programmes. dicinal plants and their products. The monographs were finalized following review by over 100 experts in 40 countries. Some 1400 references to the Guidelines for the Development of Measures to Combat Counterfeit Drugs. Department of Essential Drugs and literature are included. This book is an impressive Other Medicines, World Health Organization, Geneva. and complete collection of information on medicinal WHO/EDM/QSM/99.1 plants which will be of interest to a large and varied public. Monographs for medicinal plants During the past decade, traditional systems of WHO Monographs on Selected Medicinal Plants. Volume medicine have become more popular and many 1. World Health Organization, Geneva. Price Sw.fr. 92.- people in developed countries have begun to turn (Sw.fr. 64.40 developing countries). ISBN 92 4 154517 8 to alternative or complementary therapies, including the use of medicinal herbs. In developing countries,

179 Recent Publications and Documents WHO Drug Information Vol. 13, No. 3, 1999

Stability testing of drug substances Draft Guidance for Industry in the Stability Testing of Drug Substances and Drug Products is intended and drug products as a comprehensive document to provide information on all aspects of stability data generation and The purpose of stability testing is to provide evi- use. It references and incorporates substantial text dence on how the quality of a drug substance or from selected International Conference on Harmo- drug product varies with time under the influence of nization (ICH) guidelines. The guidance document a variety of environmental factors such as tempera- is being distributed for comment purposes only at ture, humidity and light. Stability testing permits the this stage. establishment of recommended storage conditions, retest periods, and shelf lives. Draft Guidance for Industry in the Stability Testing of Drug Information on the stability of drug substances Substances and Drug Products . Office of Communica- under defined storage conditions is an integral part tion, Center for Drug Evaluation and Research, Food and of the systematic approach to evaluation. Stress Drug Administration, MD 20852-1448, USA. http:// testing helps to determine the intrinsic stability www.fda.gov/cber/guidelines.htm characteristics of a molecule by establishing degra- dation pathways to identify likely products of degra- dation and to validate the stability-indicating power of the analytical procedures used.

180 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

International Nonproprietary Names for Pharmaceutical Substances (INN)

RECOMMENDED International Nonproprietary Names (Rec. INN): List 42

Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances [Off. Rec. Wld Health Org., 1955, 60, 3 (Resolution EB15.R7); 1969, 173, 10 (Resolution EB43.R9)], the following names are selected as Recommended International Nonproprietary Names. The inclusion of a name in the lists of Recommended International Nonpropri- etary Names does not imply any recommendation of the use of the substance in medicine or pharmacy. Lists of Proposed (1–73) and Recommended (1–35) International Nonproprietary Names can be found in Cumulative List No. 9, 1996. Dénominations communes internationales des Substances pharmaceutiques (DCI)

Dénominations communes internationales RECOMMENDÉES (DCI Rec): Liste 42

Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org. mond. Santé, 1955, 60, 3 (résolution EB15.R7); 1969, 173, 10 (résolution EB43.R9)] les dénominations ci-dessous sont choisises par l’Organisation mondiale de la Santé en tant que dénominations communes internationales recommandées. L’inclusion d’une dénomination dans les listes de DCI recommandées n’implique aucune recommandation en vue de l’utilisation de la substance correspondante en médecine ou en pharmacie. On trouvera d’autres listes de Dénominations communes internationales proposées (1–73) et recommandées (1–35) dans la Liste récapitulative No. 9, 1996.

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI)

Denominaciones Comunes Internacionales RECOMENDADAS (DCI Rec.): Lista 42

De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (Resolución EB15.R7); 1969, 173, 10 (Resolución EB43.R9)], se comunica por el presente anuncio que las denominaciones que a continuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas. La inclusión de una denominación en las listas de las Denominaciones Comunes Recomendadas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia. Las listas de Denominaciones Comunes Internacionales Propuestas (1–73) y Recomendadas (1–35) se encuentran reunidas en Cumulative List No. 9, 1996.

181 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

Latin, English, French, Spanish: Recommended INN Chemical name or description; Molecular formula; Graphic formula

DCI Recommandée Nom chimique ou description; Formule brute; Formule développée

DCI Recomendada Nombre químico o descripción; Fórmula empírica; Fórmula desarrollada

abaperidonum abaperidone 7-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3-(hydroxymethyl)- 4antipsychoticH-1-benzopyran-4-one abapéridone 7-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)pipéridin-1-yl]propoxy]- 3-(hydroxyméthyl)-4psychotrope H-chromén-4-one abaperidona 7-[3-[4-(6-fluoro-1,2-benzisoxazol-3-il)piperidino]propoxi]-3-(hidroximetil)- 4antipsicóticoH-1-benzopiran-4-ona

C25H25FN2O5

O N

F NOO

7781 alitretinoinum alitretinoin (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)- 2,4,6,8-nonatetraenoicantineoplastic acid alitrétinoïne acide (2E,4E,6Z,8E)-3,7-diméthyl-9-(2,6,6-triméthylcyclohex-1-ényl)nona- 2,4,6,8-tétraénoïqueantinéoplasique alitretinoína ácido (2E,4E,6Z,8E)-3,7-dimetil-9-(2,6,6-trimetil-1-ciclohexen-1-il)- 2,4,6,8-nonatetraenoicoantineoplásico

C20H28O2

CH H3C CH3 3

CH3

H3C

CO2H

182 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

anecortavum anecortave 17,21-dihydroxypregna-4,9(11)-diene-3,20-dionesteroid 21-acetate anécortave 21-acétatestéroïde de 17-hydroxy-3,20-dioxoprégna-4,9(11)-dién-21-yle anecortava 21-acetatoesteroide de 17-hidroxi-3,20-dioxopregna-4,9(11)-dien-21-ilo

C23H30O5

O O CH 3 O OH CH3 CH3 H

H O

6457 artemotilum artemotil (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-ethoxydecahydro-3,6,9-trimethyl- 3,12-epoxy-12antimalarial H-pyrano[4,3-j]-1,2-benzodioxepin artémotil (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-éthoxy-3,6,9-triméthyldécahydro- 3,12-époxypyrano[4,3-antipaludique j]-1,2-benzodioxépine artemotilo (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-etoxidecahidro-3,6,9-trimetil- 3,12-epoxi-12antipalúdico H-pirano[4,3-j]-1,2-benzodioxepina

C17H28O5

H CH H 3 O CH3 H H O H3C H H O O

OCH3

7791 arzoxifenum arzoxifene 2-(p-methoxyphenyl)-3-[p-(2-piperidinoethoxy)phenoxy]benzo[b]thiophene- 6-olantiestrogen arzoxifène 2-(4-méthoxyphényl)-3-[4-[2-(pipéridin-1-yl)éthoxy]phénoxy]benzo= [bantiœstrogène]thiophén-6-ol arzoxifeno 2-(antiestrógenop-metoxifenil)-3-[p-(2-piperidinoetoxi)fenoxi]benzo[b]tiofeno-6-ol

C28H29NO4S

O N

O H3CO

183 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

atorolimumabum atorolimumab immunoglobulin G3, anti-(human Rh(D) antigen) (human monoclonal clone P3x22914G4 γ3-chain), disulfide with human monoclonal P3x22914G4 κ immunomodulator-chain, dimer atorolimumab immunoglobuline G3, anti-(antigène Rh(D) humain) (chaîne γ3 de l'anticorps monoclonal humain P3x22914G4), dimère du disulfure avec la chaîne κ de l'anticorpsimmunomodulateur monoclonal humain P3x22914G4 atorolimumab inmunoglobulina G3, anti-(antígeno Rh(D) humano) (cadena γ3 del clon monoclonal humano P3x22914G4), dímero del disulfuro con la cadena κ del anticuerpoinmunomodulador monoclonal humano P3x22914G4

7792 avasimibum avasimibe 2,6-diisopropylphenyl[(2,4,6-triisopropylphenyl)aantihyperlipidaemic cetyl]sulfamate avasimibe [[2,4,6-tris(1-méthyléthyl)phényl]acétyl]sulfamate de 2,6-bis- (1-méthyléthyl)phényleantihyperlipidémiant avasimiba [(2,4,6-triisopropilfenil)acetil]sulfamatoantihiperlipémico de 2,6-diisopropilfenilo

C29H43NO4S

H CCH H CCH 3 3 H 3 3 N O S O OO H3C CH3 H3C

CH3 CH3 CH3

7782 bexarotenum bexarotene pantineoplastic,-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pen antidiabetic tamethyl-2-naphthyl)vinyl]benzoic acid bexarotène acide 4-[1-(3,5,5,8,8-pentaméthyl-5,6,7,8-tétrahydronaphtalén-2-yl)éthényl]= benzoïqueantinéoplasique, antidiabétique bexaroteno ácidoantineoplásico, p-[1-(5,6,7,8-tetrahidro-3,5,5,8,8-pentametil-2-naf antidiabético til)vinil]benzoico

C24H28O2

CH H3C CH3 2

CH3 CO2H H3CCH3

7764 carabersatum carabersat Nanticonvulsant-[(3R,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-4-chromanyl]-p-fluorobenzamide carabersate N-[(3R,4S)-6-acétyl-3-hydroxy-2,2-diméthyl-3,4-dihydro-2H-chromén-4-yl]- 4-fluorobenzamideanticonvulsivant carabersato Nanticonvulsivo-[(3R,4S)-6-acetil-3-hidróxi-2,2-dimetil-4-cromanil]-p-fluorobenzamida

184 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

C20H20FNO4

O NH O HO H

H CH3

H3C O H3C

7778 caspofunginum caspofungin (4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyltetradecanoyl)- 4-hydroxy-L-ornithyl-L-threonyl-trans-4-hydroxy-L-prolyl-(S)-4-hydroxy- 4-(p-hydroxyphenyl)-L-threonyl-threo-3-hydroxy-L-ornithyl-trans-3-hydroxy- → Lantifungal-proline cyclic (6 1)-peptide caspofungine N-[(2R,6S,9S,11R,12S,14aS,15S,20S,23S,25aS)-12-[(2-aminoéthyl)amino]- 20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S,2S)-1,2-dihydroxy- 2-(4-hydroxyphényl)éthyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyéthyl]- 5,8,14,19,22,25-hexaoxotétracosahydro-1H-dipyrrolo[2,1-c:2',1'-l]= [1,4,7,10,13,16]hexaazacyclohénicosén-9-yl]-10,12-diméthyltétradécamideantifongique caspofungina (4R,5S)-5-[(2-aminoetil)amino]-N2-(10,12-dimetiltetradecanoil)-4-hidroxi- L-ornitil-L-treonil-trans-4-hydroxy-L-prolil-(S)-4-hidroxi-4-(p-hidroxifenil)- → Lantifúngico-treonil-treo-3-hidroxi-L-ornitil-trans-3-hidroxi-L-prolina, péptido cíclico (6 1)

C52H88N10O15

OH H HO H OH H HH N H2N NH OH H H O NOO OH H O NO H H H HO H CH3 N NH HN H2N H HOH O H OH HNH

H3C O

CH3 CH3

185 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

celecoxibum celecoxib pcycloxygenase-2-[5-p-tolyl-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide inhibitor célécoxib 4-[5-(4-méthylphényl)-3-(trifluorométhyl)-1inhibiteur de la cyclooxygénase-2 H-pyrazol-1-yl]benzènesulfonamide celecoxib pinhibidor-[5-p-tolil-3-(trifluorometil)pirazol-1-il]bencenosulfonamida de la cicloxigenasa-2

C17H14F3N3O2S

H3C S NH2

N N

CF3

7738 corifollitropinum alfa corifollitropin alfa follicle-stimulating hormone (human α-subunit reduced), complex with follicle- stimulating hormone (human β-subunit reduced) fusion protein with β 118-145-chorionichormone gonadotropin (human -subunit) corifollitropine alfa hormone folliculostimulante modifiée formée de deux sous-unités α et β sous- unité α: gonadotropine chorionique (partie protéique réduite de la sous-unité α humaine) sous-unité β: hormone folliculostimulante (partie protéique réduite de la sous-unité β humaine)-112-139-gonadotropine chorionique (partie β protéiquehormone réduite de la sous-unité humaine) corifolitropina alfa Hormona estimulante del folículo modificada, formada por dos subunidades α y β: Subunidad α: gonadotropina coriónica (fracción proteica reducida de la subunidad α humana) Subunidad β: hormona estimulante del folículo (fracción proteica reducida de la subunidad β humana)- 112-139-gonadotropina coriónica (fracción proteica reducida de la subunidad β hormona humana)

APDVQDCPEC TLQENPFFSQ PGAPILQCMG CCFSRAYPTP LRSKKTMLVQ KNVTSESTCC* VAKSYNRVTV MGGFKVENHT* ACHCSTCYYH KS*

NSCELTNITI** AIEKEECRFC ISINTTWCAG YCYTRDLVYK DPARPKIQKT CTFKELVYET VRVPGCAHHA DSLYTYPVAT QCHCGKCDSD STDCTVRGLG PSYCSFGEMK ESSSSKAPPP* SLPSPSRLPG** PSDTPILPQ* * * glycosylation sites * sites de glycosylation * posiciónes de glicosilación

186 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

darbufelonum darbufelone 5-[(anti-inflammatoryZ)-3,5-di-tert-butyl-4-hydroxybenzylidene]-2-imino-4-thiazolidinone agent darbufélone (Z)-5-[3,5-bis(1,1-diméthyéthyl)-4-hydroxybenzylidène]-2-iminothiazolidin- 4-oneanti-inflammatoire darbufelona 5-[(antiinflamatorioZ)-3,5-di-terc-butil-4-hidroxibencilideno]-2-imino-4-tiazolidinona

C18H24N2O2S

CH3 H3C CH 3 NH HO S NH H3C

H3C CH3 O

7800 depreotidum depreotide cyclo(L-homocysteinyl-N-methyl-L-phenylalanyl-L-tyrosyl-D-tryptophyl-L-lysyl- L-valyl), (1→1')-sulfide with 3-(2-mercaptoacetamido)-L-alanyl-L-lysyl- Ldiagnostic-cysteinyl- Lagent-lysinamide dépréotide (1→1')-sulfure de cyclo[L-homocystéinyl-(N-méthyl-L-phénylalanyl)- L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl] et de [3-[(sulfanylacétyl)amino]-L-alanyl]- Lproduit-lysyl-L-cystéinyl- à usage diagnostiqueL-lysinamide depreotida (1→1')-sulfuro de ciclo[L-homocisteinil-(N-metil-L-fenilalanil)-L-tirosil-D-triptofil- Lagente-lisil-L-valilo] de diagnóstico y 3-(2-mercaptoacetamido)-L-alanil-L-lisil-L-cisteinil-L-lisinamida

C65H96N16O12S2

O S NH 3 Ala Lys Cys Lys NH H 2 N MePhe Tyr D-Trp Lys Val H O

7789 deracoxibum deracoxib p-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)pyrazol- 1-yl]benzenesulfonamidecycloxygenase-2 inhibitor déracoxib 4-[3-(difluorométhyl)-5-(3-fluoro-4-méthoxyphényl)-1H-pyrazol- 1-yl]benzènesulfonamideinhibiteur de la cyclooxygénase-2 deracoxib pinhibidor-[3-(difluorometil)-5-(3-fluoro-4-metoxifenil)pirazol-1-il]bencenosulfonamida de la cicloxigenasa-2

187 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

C17H14F3N3O3S

H3CO S NH2

F N N

7817 desloratadinum desloratadine 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta- [1,2-b]pyridine histamine-H1 receptor antagonist desloratadine 8-chloro-11-(pipéridin-4-ylidène)-6,11-dihydro-5H-benzo[5,6]cyclohepta- [1,2-b]pyridine antagoniste des récepteurs H1 de l’histamine desloratadina 8-cloro-6,11-dihidro-11-(4-piperidilideno)-5H-benzo[5,6]ciclohepta- [1,2-b]piridina antagonista de los receptores H1 de la histamina

C19H19ClN2

Cl NH

7813 desmoteplasum desmoteplase plasminogen activator (Desmodus rotundus, isoform α1 protein moiety reduced)plasminogen activator desmotéplase activateur du plasminogène (Desmodus rotondus, isoforme α1, partie protéiqueactivateur réduite) du plasminogène desmoteplasa activador del plasminógeno (isoforma α1, fracción proteica reducida de Desmodusactivador del rotundus plasminógeno)

7805 dexbudesonidum dexbudesonide (R)-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione 16,17-acetal with butyraldehydeantiasthmatic α β dexbudésonide 16antiasthmatique,17-[(1R)-butylidènebis(oxy)]-11 ,21dihydroxyprégna-1,4-diène-3,20-dione dexbudesonida 16,17-acetal butiraldehídico de (R)-11β,16α,17,21-tetrahidroxipregna- 1,4-dieno-3,20-dionaantiasmático

188 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

C25H34O6

OH O

H CH3 HO O H

CH3 H O CH3 H HH O

7797 ecopipamum ecopipam (-)-(6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl- 5dopamineH-benzo[d D1/D5]naphth[2,1- receptorb]azepin-12-ol antagonist écopipam (-)-(6aS,13bR)-11-chloro-7-méthyl-6,6a,7,8,9,13b-hexahydro- 5antagonisteH-benzo[d]naphto[2,1- des récepteursb]azépin-12-ol D1/D5 de la dopamine ecopipam (-)-(6aS,13bR)-11-cloro-6,6a,7,8,9,13b-hexahidro-7-metil-5H-benzo[d]naft= [2,1-antagonistab]azepin-12-ol de los receptores D1/D5 de la dopamina

C19H20ClNO

NCH3 H HO H

7822 emtricitabinum emtricitabine 5-fluoro-1-[(2antiviral R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine emtricitabine 4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxyméthyl)-1,3-oxathiolan-5-yl]pyrimidin- 2(1antiviralH)-one emtricitabina 5-fluoro-1-[(2antiviral R,5S)-2-(hidroximetil)-1,3-oxatiolan-5-il]citosina

C8H10FN3O3S

NH2 F N

NO H OH O

S H

189 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

enrasentanum enrasentan (1S,2R,3S)-3-[2-(2-hydroxyethoxy)-4-methoxyphenyl]- 1-[3,4-(methylenedioxy)phenyl]-5-propoxy-2-indancarboxylicendothelin receptor antagonist acid enrasentan acide (1S,2R,3S)-1-(1,3-benzodioxol-5-yl)-3-[2-(2-hydroxyéthoxy)- 4-méthoxyphényl]-5-propoxy-2,3-dihydro-1antagoniste des récepteurs de l’endothélineH-indène-2-carboxylique enrasentano ácido (1S,2R,3S)-3-[2-(2-hidroxietoxi)-4-metoxifenil]- 1-[3,4-(metilenodioxi)fenil]-5-propoxi-2-indanocarboxílicoantagonista de los receptores de la endotelina

C29H30O8

OCH3 CO2H H H O H O OH O

CH3 O

7771 eplivanserinum eplivanserin (Eserotonin)-2'-fluoro-4-hydroxychalcone receptor antagonist (Z)-O-[2-(dimethylamino)ethyl]oxime éplivansérine (E)-1-(2-fluorophényl)-3-(4-hydroxyphényl)prop-2-énone (Zantagoniste)-O-[2-(diméthylamino)éthyl]oxime de la sérotonine eplivanserina (Zantagonista)-O-[2-(dimetilamino)etil]oxima de los receptores de de la laserotonina (E)-2'-fluoro-4-hidroxicalcona

C19H21FN2O2

HO CH3 N N O CH3 F

7723 ethylcellulosum ethylcellulose cellulosepharmaceutical ethyl ether aid éthylcellulose étherauxiliaire éthylique pharmaceutique de cellulose etilcelulosa éterexcipiente etilico de celulosa

7818 etilevodopum etilevodopa (-)-3,4-dihydroxy-antiparkinsonianL-phenylalanine, ethyl ester étilévodopa (-)-(2antiparkinsonienS)-2-amino-3-(3,4-dihydroxyphényl)propanoate d’éthyle etilevodopa ésterantiparkinsoniano etílico de (-)-3,4-dihidroxi-L-fenilalanina

190 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

C11H15NO4

OCH3 HNH2 HO OH

7744 exisulindum exisulind 5-fluoro-2-methyl-1-[(antineoplastic Z)-p-(methylsulfonyl)benzylidene]indene-3-acetic acid exisulind acide 2-[5-fluoro-2-méthyl-1-[(Z)-4-(méthylsulfonyl)benzylidène]-1H-indén- 3-yl]acétiqueantinéoplasique exisulind ácidoantineoplásico 5-fluoro-2-metil-1-[(Z)-p-(metilsulfonil)bencilideno]indeno-3-acético

C20H17FO4S

CH3

CO2H

H3C S OO F

7759 fanapanelum fanapanel [[3,4-dihydro-7-morpholino-2,3-dioxo-6-(trifluoromethyl)- 1(2AMPAH)-quinoxalinyl]methyl]phosphonic receptor antagonist acid fanapanel acide [[7-(morpholin-4-yl)-2,3-dioxo-6-(trifluorométhyl)-3,4-dihydroquinoxalin- 1(2antagonisteH)-yl]méthyl]phosphonique des récepteurs de l'AMPA fanapanel ácido [[3,4-dihidro-7-morfolino-2,3-dioxo-6-(trifluorometil)- 1(2antagonistaH)-quinoxalinil]metil]fosfónico de los receptores de AMPA

C14H15F3N3O6P

O OH P O OH N N O

F3C N O H

191 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

galarubicinum galarubicin (8S,10S)-10-[(2,6-dideoxy-2-fluoro-α-L-talopyranosyl)oxy]-8-glycoloyl- 7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione 2 β 8antineoplastic,-ester with -alanine antibiotic galarubicine 3-aminopropanoate de 2-[(2S,4S)-4-[(2-fluoro-2,6-didésoxy- α-L-talopyranosyl)oxy]-2,5,12-trihydroxy-7-méthoxy-6,11-dioxo- 1,2,3,4,6,11-hexahydrotétracén-2-yl]-2-oxoéthyleantinéoplasique, antibiotique galarubicina 8S,10S)-8-(3-aminopropanoiloxiacetil)-10-[(2,6-didesoxi-2-fluoro-α-L-talopiranosil)= oxi]-7,8,9,10-tetrahidro-6,8,11-trihidroxi-1-metoxi-5,12-nafantineoplásico, antibiótico tacenodiona

C30H32FNO13

O OH O

ONH2 OH O H OCH3 O OH O O

CH3 HO OH F

7836 gantofibanum gantofiban 4-[[(5R)-3-[p-(carboxyamidino)phenyl]-2-oxo-5-oxazolidinyl]methyl]- 1-piperazineaceticfibrinogen receptor acid, antagonist 1-ethyl methyl ester gantofiban 2-[4-[[(5R)-3-[4-[(méthoxycarbonyl)carbamimidoyl]phényl]-2-oxooxazolidin- 5-yl]méthyl]pipérazin-1-yl]acétateantagoniste du récepteur du fibrinogène d’éthyle gantofibán 4-[(5R)-3-[(4-metoxicarbonilaminoiminometil)fenil]-2-oxo-5-oxazolidinilmetil]- 1-piperazinilacetatoantagonista del receptor de etilo del fibrinógeno

C21H29N5O6

H N O O N N OCH3 H NO O H3C ONH

7728 gimeracilum gimeracil 5-chloro-2,4-pyridinedioladjuvant for antineoplastic giméracil 5-chloropyridine-2,4-dioladjuvant d'antinéoplasiques gimeracilo 5-cloro-2,4-piridinadiolcoadyuvante del tratamiento con antineoplásicos

C5H4ClNO2

Cl N

HO OH

192 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

hemoglobinum glutamerum hemoglobin glutamer hemoglobin glutamer; the species specifity should be indicated in brackets behind the name, "(bovine)"; the average mass of the polymer is given as e.g.,oxygen hemoglobin carrier glutamer-250 for 250kD hémoglobine glutamère produit de la réaction du pentanedial avec l'hémoglobine; l'origine de l'hémoglobine doit être indiquée, "(bovine)"; la masse moléculaire moyenne doitporteur être d’oxygènedonnée, par exemple: hémoglobine glutamère-250 pour 250 kD hemoglobina glutámero hemoglobina polimerizada con glutaraldehído; debe indicarse entre paréntesis el origen del material, “(bovino)”; la masa del polímero medio se daportador como, depor oxígeno ej., hemoglobina glutámero-250 para 250kD

7721 hyetellosum hyetellose cellulosepharmaceutical 2-hydroxyethyl aid ether hyétellose étherauxiliaire 2-hydroxyéthylique pharmaceutique de cellulose hietelosa éterexcipiente 2-hidroxietílico de celulosa

7722 hymetellosum hymetellose cellulosepharmaceutical 2-hydroxyethyl aid methyl ether hymétellose étherauxiliaire 2-hydroxyéthylique pharmaceutique et méthylique de cellulose himetelosa éterexcipiente 2-hidroxílico metílico de celulosa

7725 hyprolosum hyprolose cellulosepharmaceutical 2-hydroxypropyl aid ether hyprolose étherauxiliaire 2-hydroxypropylique pharmaceutique de cellulose hiprolosa éterexcipiente 2-hidroxipropílico de celulosa

7735 insulinum detemirum B 6 B insulin detemir 29antidiabetic-(N -myristoyl-L-lysine)-30 -de-L-threonineinsulin (human) B 6 B insuline détémir 29antidiabétique-(N -tétradécanoyl-L-lysine)-30 -dès-L-thréonineinsuline humaine B 6 B insulina detemir 29antidiabético-(N -miristoil-L-lisina)-30 -des-L-treoninainsulina (humana)

193 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

C267H402N64O76S6

Gly Ile Val Glu Gln Cy s Cy s Thr Ser Ile Cys Ser Leu Ty r Gln Leu 10 Glu Asn Ty r Cy s Asn 20 Phe Val Asn Gln His Leu Cy s Gly Ser His Leu Val Glu Ala Leu Tyr 10 Leu Val Cys GluGly Arg Gly PhePhe ThrTyr Pro Ly s 20 N6

H3C O

77307794 leridistimum leridistim 14-L-alanine-50-L-aspartic acid-14-125-interleukin 3 (human reduced) fusion protein with peptide (synthetic) linked with 17-L-serinegranulocyte colony- stimulatingimmunomodulator factor (human reduced) léridistim protéine de fusion entre la [14-L-alanine-50-acide L-aspartique]- 14-125-interleukine 3 (humaine, réduite) et le [17-L-sérine]facteur de stimulation des colonies de granulocytes (humain,immunomodulateur réduit) leridistim proteína de fusión de la [14-L-alanina-50-ácido L-aspártico]- 14-125-interleucina-3 (humana reducida) con el [17-L-serina]factor de estimulacióninmunomodulador de las colonias de granulocitos (humano reducido)

C1550H2463N425O462S12

ANCSNMIDEI ITHLKQPPLP LLDFNNLNGE DQDILMDNNL RRPNLEAFNR AVKSLQNASA IESILKNLLP CLPLATAAPT RHPIHIKDGD WNEFRRKLTF YLKTLENAQA QQYVEGGGGS PGEPSGPIST INPSPPSKES HKSPNMATPL GPASSLPQSF LLKSLEQVRK IQGDGAALQE KLCATYKLCH PEELVLLGHS LGIPWAPLSS CPSQALQLAG CLSQLHSGLF LYQGLLQALE GISPELGPTL DTLQLDVADF ATTIWQQMEE LGMAPALQPT QGAMPAFASA FQRRAGGVLV ASHLQSFLEV SYRVLRHLAQ P

7814 leteprinimum leteprinim pnootropic-[3-(1,6-dihydro-6-oxo-9 agent H-purin-9-yl)propionamido]benzoic acid létéprinim acidenootrope 4-[[3-(6-oxo-1,6-dihydro-9H-purin-9-yl)propanoyl]amino]benzoïque leteprinim ácidonootropo p-[3-(1,6-dihidro-6-oxo-9H-purin-9-il)propionamido]benzoico

194 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

C15H13N5O4

O HN N

N CO2H N O

N H

7798 lopinavirum lopinavir (αS)-tetrahydro-N-[(αS)-α-[(2S,3S)-2-hydroxy-4-phenyl-3-[2-(2,6-xylyloxy)= α acetamido]butyl]phenethyl]-antiviral -isopropyl-2-oxo-1(2H)-pyrimidineacetamide lopinavir (2S)-N-[(1S,3S,4S)-1-benzyl-4-[[(2,6-diméthylphénoxy)acétyl]amino]- 3-hydroxy-5-phénylpentyl]-3-méthyl-2-(2-oxotétrahydropyrimidin- 1(2antiviralH)-yl)butanamide lopinavir (αS)-tetrahidro-N-[(αS)-α-[(2S,3S)-2-hidroxi-4-fenil-3-[2-(2,6-xililoxi)= α acetamido]butil]fenetil]-antiviral -isopropil-2-oxo-1(2H)-pirimidinacetamida

C37H48N4O5

CH3 H C H H O CH3 3 H N O N N H O H HOH N O H3C H

7804 lusupultidum lusupultide glycyl-L-isoleucyl-L-prolyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-valyl- L-histidyl-L-leucyl-L-lysyl-L-arginyl-L-leucyl-L-leucyl-L-isoleucyl-L-valyl-L-valyl- L-valyl-L-valyl-L-valyl-L-valyl-L-leucyl-L-isoleucyl-L-valyl-L-valyl-L-valyl- Lpulmonary-isoleucyl-L -valylglycyl-surfactant L-alanyl-L-leucyl-L-leucyl-L-isoleucylglycyl-L-leucine lusupultide glycyl-L-isoleucyl-L-prolyl-L-phénylalanyl-L-phénylalanyl-L-prolyl-L-valyl- L-histidyl-L-leucyl-L-lysyl-L-arginyl-L-leucyl-L-leucyl-L-isoleucyl-L-valyl-L-valyl- L-valyl-L-valyl-L-valyl-L-valyl-L-leucyl-L-isoleucyl-L-valyl-L-valyl-L-valyl- Lsurfactif-isoleucyl- pulmonaireL-valyl-glycyl-L-alanyl-L-leucyl-L-leucyl-L-isoleucyl-glycyl-L-leucine lusupultida glycil-L-isoleucil-L-prolil-L-fenilalanil-L-fenilalanil-L-prolil-L-valil-L-histidil-L-leucil- L-lisil-L-arginil-L-leucil-L-leucil-L-isoleucil-L-valil-L-valil-L-valil-L-valil-L-valil-L-valil- L-leucil-L-isoleucil-L-valil-L-valil-L-valil-L-isoleucil-L-valilglicil-L-alanil-L-leucil- Ltensioactivo-leucil-L-isoleucilglicil- pulmonarL-leucina

195 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

C182H310N40O35

Gly Ile Pro Phe Phe Pro Val His Leu Lys 10 Arg Leu Leu Ile Val Val Val Val Val Val 20 Leu Ile Val Val Val Ile Val Gly Ala Leu 30 Leu Ile Gly Leu

7812 maribavirum β maribavir 5,6-dichloro-2-(isopropylamino)-1-antiviral -L-ribofuranosylbenzimidazole β maribavir 5,6-dichloro-antiviral N-(1-méthyléthyl)-1-( -L-ribofuranosyl)-1H-benzimidazol-2-amine maribavir 5,6-dicloro-2-(isopropilamino)-1-β-L-ribofuranosilbenzimidazol

C15H19Cl2N3O4

O OH HO

HO H3C Cl N CH3 NH Cl N

7825 minopafantum minopafant (+)-1-ethyl-2-[[N-[[(2R)-2-methoxy-3-[[[4-octadecylcarbamoyl)oxy]piperidino]= carbonyl]oxy]propoxy]carbonyl]-platelet activating factor antagonisto-anisamido]methyl]pyridinium chloride minopafant (+)-chlorure de 1-éthyl-2-[[(2-méthoxybenzoyl)[[(2R)-2-méthoxy- 3-[[[4-[(octadécylcarbamoyl)oxy]pipéridin-1-yl]carbonyl]oxy]propoxy]= carbonyl]amino]méthyl]pyridiniumantagoniste du facteur activant les plaquettes minopafant (+)-1-etil-2-[[N-[[(2R)-2-metoxi-3-[[[4-[(octadecilcarbamoil)oxi]piperidino]= carbonil]oxi]propoxi]carbonil]-antagonista del factor de activacióno-anisamido]metil]piridinio de plaquetas

C46H73ClN4O9

CH3

H3C H3CO + N - NO O Cl

OO ON O

HOCH3 ON H

196 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

minretumomabum minretumomab immunoglobulin G1 anti-(human tumor-associated glycoprotein 72) (mouse monoclonal Mab CC-49 γ1-chain), disulfide with mouse monoclonal Mab CC-49-chain,immunomodulator dimer minrétumomab immunoglobuline G1 anti-(glycoprotéine 72 humaine associée aux tumeurs) (chaîne γ1 de l’anticorps monoclonal de souris Mab CC-49), dimère du κ disulfureimmunomodulateur avec la chaîne de l’anticorps monoclonal de souris Mab CC-49 minretumomab Inmunoglobulina G1 anti-(glicoproteína 72 humana asociada a los tumores) (cadena γ1 del anticuerpo monoclonal de ratón Mab CC-49), dímero del κ disulfuroinmunomodulador con la cadena del anticuerpo monoclonal de ratón Mab CC-49

7727 mivotilatum ∆2,α mivotilate isopropylhepatoprotectant N-(4-methyl-2-thiazolyl)-1,3-dithietane- -malonamate mivotilate 2-(1,3-dithiétan-2-ylidène)-3-[(4-méthylthiazol-2-yl)amino]-3-oxopropanoate de 1-méthyléthylehépatoprotecteur ∆2,α mivotilato Nhepatoprotector-(4-metil-2-tiazolil)-1,3-ditietano- -malonamato de isopropilo

C12H14N2O3S3

SOOCH3 H3C N N OCH3 H

7790 nelarabinum β nelarabine 2-amino-antineoplastic-D-arabinofuranosyl-6-methoxy-9H-purine β nélarabine 9-(antinéoplasique-D-arabinofuranosyl)-6-méthoxy-9H-purin-2-amine β nelarabina 2-amino-antineoplásico-D-arabinofuranosil-6-metoxi-9H-purina

C11H15N5O5

OCH3 N N

N H2N N HO O HO

197 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

nesiritidum nesiritide L-seryl-L-prolyl-L-lysyl-L-methionyl-L-valyl-L-glutaminylglycyl-L-serylglycyl- L-cysteinyl-L-phenylalanylglycyl-L-arginyl-L-lysyl-L-methionyl-L-aspartyl- L-arginyl-L-isoleucyl-L-seryl-L-seryl-L-seryl-L-serylglycyl-L-leucylglycyl- L-cysteinyl-L-lysyl-L-valyl-L-leucyl-L-arginyl-L-arginyl-L-histidine → cyclicvasodilator, (10 26)-disulfide diuretic λ nésiritide 1,32-facteurvasodilatateur, natriurétique diurétique (cerveau humain, clone hBNP57) nesiritida (10→26)-disulfuro cílico de L-seril-L-prolil-L-lisil-L-metionil-L-valil- L-glutaminilglicil-L-serilglicil-L-cisteinil-L-fenilalanilglicil-L-arginil-L-lisil- L-metionil-L-aspartil-L-arginil-L-isoleucil-L-seril-L-seril-L-seril-L-serilglicil- Lvasodilatador,-leucilglicl-L-cisteinil- diuréticoL-lisil-L-valil-L-leucil-L-arginil-L-arginil-L-histidina

C143H244N50O42S4

Ser Pro Lys Met Val Gln Gly Ser Gly Cys 10 Phe Gly Arg Lys Met Asp Arg Ile Ser Ser 20 Ser Ser Gly Leu Gly Cys Lys Val Leu Arg 30 Arg His

7787 olmesartanum olmesartan 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl- 1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclicangiotensin 2,3-carbonate II receptor antagonist olmésartan 4-(1-hydroxy-1-méthyléthyl)-2-propyl-1-[4-[2-(1H-tétrazol-5-yl)phényl]benzyl]- 1antagonisteH-imidazole-5-carboxylate du récepteur de de l’angiotensine (5-méthyl-2-oxo-1,3-dioxol-4-yl)méthyle II olmesartán 4-(1-hidroxi-1-metiletil)-2-propil-1-{[2'-(1H-tetrazol-5-il)-1,1'-bifenil-4-il]metil}- 1antagonistaH-imidazol-5-carboxilato del receptor dede angiotensina5(metil-2-oxo-1,3-dioxolen-4-il)metilo II

C29H30N6O6

H3C O O O O O NN H3C OH HN N H3C N N

CH3

oseltamivirum oseltamivir ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene- 1-carboxylateantiviral oséltamivir (3R,4R,5S)-4-(acétylamino)-5-amino-3-(1-éthylpropoxy)cyclohex-1-ène- 1-carboxylateantiviral d’éthyle oseltamivir (3R,4R,5S)-4-acetamido-5-amino-3-(1-etilpropoxi)-1-ciclohexeno- 1-carboxilatoantiviral de etilo

198 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

C16H28N2O4

H3CCH3 O O

H OCH3 HN

H3C H HNH O 2

7729 oteracilum oteracil 1,4,5,6-tetrahydro-4,6-dioxo-antineoplastic s-triazine-2-carboxylic acid otéracil acideantinéoplasique 4,6-dioxo-1,4,5,6-tétrahydro-1,3,5-triazine-2-carboxylique oteracilo ácidoantineoplásico 1,4,5,6-tetrahidro-4,6-dioxo-s-triazina-2-carboxílico

C4H3N3O4

CO2H

HN N

O N O H

7816 parecoxibum parecoxib Ncycloxygenase-2-[[p-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propionamide inhibitor parécoxib Ninhibiteur-[[4-(5-méthyl-3-phénylisoxazol-4-yl)phényl]sulfonyl]propanamide de la cyclooxygénase-2 parecoxib Ninhibidor-[[p-(5-metil-3-fenil-4-isoxazolil)fenil]sulfonil]propionamida de la cicloxigenasa-2

C19H18N2O4S

OO O

S CH3 N H

N O CH3

7828 pegacaristimum pegacaristim N-(3-hydroxypropyl)-1-163-megakaryocyte growth and development factor (human),colony stimulating monoether factor with polyethylene glycol monomethyl ether pégacaristim N-[3-[[méthylpoly(oxyéthylène)]oxy]propyl]-1-163-facteur de croissance et de développementfacteur stimulant de de mégakaryocyte colonies de mégakaryocytes (humain) pegacaristim N-(3-hidroxipropil)-1-163-factor de desarrollo y crecimiento de megacariocitos (humano),factor estimulante monoéter de con colonias el éter monometílico de polietilenglicol

199 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

SPAPPACDLR* VLSKLLRDSH VLHSRLSQCP EVHPLPTPVL LPAVDFSLGE WKTQMEETKA QDILGAVTLL LEGVMAARGQ LGPTCLSSLL GQLSGQVRLL LGALQSLLGT QLPPQGRTTA HKDPNAIFLS FQHLLRGKVR FLMLVGGSTL CVRRAPPTTA VPS * pegylation site * site de pégylation * posición de pegilación

7690 pegnartograstimum pegnartograstim N-L-methionyl-1-L-alanine-3-L-threonine-4-L-tyrosine-5-L-arginine-17-L-serine colony-stimulating factor (human clone 1034), reaction product with succinic anhydride,immunomodulator esters with polyethylene glycol monomethyl ether pégnartograstim esters entre le produit de réaction du N-L-méthionyl-[1-L-alanine- 3-L-thréonine-4-L-tyrosine-5-L-arginine-17-L-sérine] facteur de stimulation de colonie (clone humain 1034) avec l'anhydride succinique et le α-méthyl- ω immunomodulateur-hydroxypoly(oxyéthylène) pegnartograstim ésteres con el éter monometilico de polietilenglicol del producto de reacción con anhidrido succinico del N-L-metionil-1-L-alanina-3-L-treonina-4-L-tirosina- 5-inmunomoduladorL-arginina-17-L-serina-factor-estimulante de colonias (clon humano 1034)

M* APTYRASSLP QSFFLKSLEQ**VRKIQGDGAA LQEKLCATYK **

LCHPEELVLL GHSLGIPWAP LSSCPSQALQ LAGCLSQLHS GLFLYQGLLQ ALEGISPELG PTLDTLQLDV ADFATTIWQQ MEELGMAPAL QPTQGAMPAF ASAFQRRAGG VLVASHLQSF LEVSYRVLRH LAQP * pegylation site * site de pégylation * posición de pegilación

7770 ponazurilum ponazuril 1-methyl-3-[4-[p-[(trifluoromethyl)sulfonyl]phenoxy]-m-tolyl]-s-triazine- 2,4,6(1coccidiostaticH,3H,5H)-trione ponazuril 1-méthyl-3-[3-méthyl-4-[4-[(triflorométhyl)sulfonyl]phénoxy]phényl]- 1,3,5-triazine-2,4,6(1coccidiostatique H,3H,5H)-trione ponazurilo 1-metil-3-[4-[p-[(trifluorometil)sulfonil]fenoxi]-m-tolil]-s-triazina- 2,4,6(1coccidiostáticoH,3H,5H)-triona

200 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

C18H14F3N3O6S

O O

F3C S H3C N NH OO O N O

CH3

7768 rofecoxibum rofecoxib 4-[cycloxygenase-2p-(methylsulfonyl)phenyl]-3-phenyl-2(5 inhibitor H)-furanone rofécoxib 4-[4-(méthylsulfonyl)phényl]-3-phénylfuran-2(5inhibiteur de la cyclooxygénase-2 H)-one rofecoxib 4-[inhibidorp-(metilsulfonil)fenil]-3-fenil-2(5 de la cicloxigenasa-2 H)-furanona

C17H14O4S

OO S CH3

O O

7748 sarizotanum sarizotan (-)-3-[[[(antipsychoticR)-2-chromanylmethyl]amino]methyl]-5-(p-fluorophenyl)pyridine sarizotan (-)-N-[[(2R)-3,4-dihydro-2H-chromén-2-yl]méthyl][5-(4-fluorophényl)pyridin- 3-yl]méthanaminepsychotrope sarizotán (-)-3-[[[(antipsicóticoR)-2-cromanilmetil]amino]metil]-5-(p-fluorofenil)piridina

C22H21FN2O

N HH N O F

7780 satraplatinum satraplatin (OCantineoplastic-6-43)-bis(acetato)amminedichloro(cyclohexylamine)platinum satraplatine (OCantinéoplasique-6-43)-bis(acétato)amminedichloro(cyclohexanamine)platine satraplatino (OCantineoplásico-6-43)-bis(acetato)aminadicloro(ciclohexilamina)platino

C10H22Cl2N2O4Pt

H3C Cl H2 O N O Pt O Cl NH3

O CH3

201 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

semparatidum semparatide L-alanyl-L-valyl-L-seryl-L-α-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl- L-histidyl-L-α-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl- L-α-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-α-glutamyl-L-leucyl-L-leucyl- L-α-glutamyl-L-lysyl-L-leucyl-L-leucyl-L-α-glutamyl-L-lysyl-L-leucyl-L-histidyl- Lhormone-threonyl- analogueL-alaninamide semparatide L-alanyl-L-valyl-L-seryl-L-glutamyl-L-histidyl-L-glutaminy-L-leucyl-L-leucyl- L-histidyl-L-aspartyl-L-lysyl-glycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl- L-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-glutamyl-L-leucyl-L-leucyl- L-glutamyl-L-lysyl-L-leucyl-L-leucyl-L-glutamyl-L-lysyl-L-leucyl-L-histidyl- Lanalogue-thréonyl- Ld’hormone-alaninamide semparatida L-alanil-L-valil-L-seril-L-α-glutamil-L-histidil-L-glutaminil-L-leucil-L-leucil-L-histidil- L-α-aspartil-L-lisilglicil-L-lisil-L-seril-L-isoleucil-L-glutaminil-L-α-aspartil-L-leucil- L-arginil-L-arginil-L-arginil-L-α-glutamil-L-leucil-L-leucil-L-α-glutamil-L-lisil- α Lanálogo-leucil-L-leucil- de hormonaL- -glutamil-L-lisil-L-leucil-L-histidil-L-treonil-L-alaninamida

C175H300N56O51

Ala Val Ser Glu His Gln Leu Leu His Asp 10 Lys Gly Lys Ser Ile Gln Asp Leu Arg Arg 20 Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys 30 Leu His Thr Ala NH2

1489 simeticonum simeticone α-(trimethylsilyl)-ω-methylpoly[oxy(dimethylsilylene)], mixture with silicon dioxideantiflatulent siméticone mélange de α-(triméthylsilyl)-ω-méthylpoly[oxy(diméthylsilylène)] et de dioxydeantiflatulent de silicium α ω simeticona antiflatulento-(trimetilsilil)- -metilpoli[oxi(dimetilsilileno)], mezcla con dióxido de silicio

7834 sitamaquinum sitamaquine 8-[[6-(diethylamino)hexyl]amino]-6-methoxy-4-methylquinolineantiprotozoal sitamaquine N,Nantiprotozoaire-diéthyl-N’-(6-méthoxy-4-méthylquinoléin-8-yl)hexane-1,6-diamine sitamaquina 8-[[6-(dietilamino)hexil]amino]-6-metoxi-4-metilquinolinaantiprotozoario

C21H33N3O

CH3

3C NH NH N

H3CO

CH3

7832

202 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

solimastatum solimastat (2S,3R)-3-[[(1S)-2,2-dimethyl-1-(2-pyridylcarbamoyl)propyl]carbamoyl]- 2-methoxy-5-methylhexanohydroxamicmatrix metalloproteinase inhibitor acid solimastat (2R,3S)-N1-[(1S)-2,2-diméthyl-1-[(pyridin-2-yl)carbamoyl]propyl]-N4-hydroxy- 3-méthoxy-2-(2-méthylpropyl)butanediamideinhibiteur de la métalloprotéinase de la matrice solimastat ácido (2S,3R)-3-[[(1S)-2,2-dimetil-1-(2-piridilcarbamoil)propil]carbamoil]- 2-metoxi-5-metilhexanohidroxámicoinhibidor de la metaloproteinasa de matriz

C20H32N4O5

CH3 H3C O H O H HO N N N N H H H OH O CH3 CH3 H3C CH3

7799 sonepiprazolum sonepiprazole (-)-antipsychoticp-[4-[2-[(S)-1-isochromanyl]ethyl]-1-piperazinyl]benzenesulfonamide sonépiprazole (-)-4-[4-[2-[(1S)-3,4-dihydro-1H-isochromén-1-yl]éthyl]pipérazin- 1-yl]benzènesulfonamidepsychotrope sonepiprazol (-)-antipsicóticop-[4-[2-[(S)-1-isocromanil]etil]-1-piperazinil]bencenosulfonamida

C21H27N3O3S

N H N

H2N S OO

7830 tabimorelinum tabimorelin (R)-α-[(E)-5-amino-N,5-dimethyl-2-hexenamido]-N-methyl- α Ngrowth-[(R)- hormone-(methylcarbamoyl)phenethyl]-2-naphthalenepropionamide release stimulating peptide tabimoréline (E)-5-amino-N-[(1R)-2-[[(1R)-1-benzyl-2-(méthylamino)-2-oxoéthyl]= éthylamino]-1-(naphtalén-2-ylméthyl)-2-oxoéthyl]-peptide stimulant la libération de l’hormone de croissanceN,5-diméthylhex-2-énamide tabimorelina (R)-α-[(E)-5-amino-N,5-dimetil-2-hexenamido]-N-metil- α Npéptido-[(R)- -(metilcarbamoil)fenetil]-2-naftalenopropionamidestimulante de la liberación de la hormona del crecimiento

203 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

C32H40N4O3

O CH O H3C NH2 H 3 N CH3 H3CNN H H CH3 O

7835 tafenoquinum tafenoquine (±)-8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl- α,α,α 5-[(antimalarial-trifluoro-m-tolyl)oxy]quinoline tafénoquine (4RS)-N4-[2,6-diméthoxy-4-méthyl-5-[3-(trifluorométhyl)phénoxy]quinoléin- 8-yl]pentane-1,4-diamineantipaludique tafenoquina (±)-8-[(4-amino-1-metilbutil)amino]-2,6-dimetoxi-4-metil-5-[(α,α,α-trifluoro- mantipalúdico-tolil)oxi]quinolina

C24H28F3N3O3

H CH3 H2N NH

N OCH3 and enantiomer H CO et énantiomère 3 y enantiómero O CH3

CF3

7820 talampanelum talampanel (R)-7-acetyl-5-(p-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo= [4,5-AMPAh][2,3]benzodiazepine receptor antagonist talampanel (8R)-7-acétyl-5-(4-aminophényl)-8-méthyl-8,9-dihydro-7H-1,3-dioxolo= [4,5-antagonisteh][2,3]benzodiazépine des récepteurs de l'AMPA talampanel (R)-7-acetil-5-(p-aminofenil)-8,9-dihidro-8-metil-7H-1,3-dioxolo= [4,5-antagonistah][2,3]benzodiazepina del receptor AMPA

204 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

C19H19N3O3

H2N

O N CH3 N O O H CH3

7803 telithromycinum telithromycin (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyloctahydro-11-methoxy- 3a,7,9,11,13,15-hexamethyl-1-[4-[4-(3-pyridyl)imidazol-1-yl]butyl]- 10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]- 2antibioticH-oxacyclotetradecino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tetrone télithromycine (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-10-[[3-(diméthylamino)- 3,4,6-tridésoxy-β-D-xylo-hexopyranosyl]oxy]-4-éthyl-11-méthoxy- 3a,7,9,11,13,15-hexaméthyl-1-[4-[4-(pyridin-3-yl)-1H-imidazol-1-yl]butyl]= octahydro-2antibiotiqueH-oxacyclotétradécino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tétrone telitromicina (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-etiloctahidro-11-metoxi- 3a,7,9,11,13,15-hexametil-1-[4-[4-(3-piridil)imidazol-1-il]butil]- 10-[ [3,4,6-tridesoxy-3-(dimetilamino)-β-D-xilo-hexopiranosil]oxi]- 2antibióticoH-oxaciclotetradecino[4,3-d]oxazol-2,6,8,14(1H,7H,9H)-tetrona

C43H65N5O10

O H H H3C N CH3 N H C O 3 CH3 N H C H O 3 N CH 3 H H O O O O CH H 3 CH N(CH ) 3 3 2 O O

HCH3 OH

7739 tenatoprazolum tenatoprazole (±)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]- 1antiulcerH-imidazo[4,5- agentb]pyridine ténatoprazole 5-méthoxy-2-[(RS)-[(4-méthoxy-3,5-diméthylpyridin-2-yl)méthyl]sulfinyl]- 1antiulcéreuxH-imidazo[4,5-b]pyridine tenatoprazol (±)-5-metoxi-2-[[(4-metoxi-3,5-dimetil-2-piridil)metil]sulfinil]- 1antiulcerosoH-imidazo[4,5-b]piridina

205 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

C16H18N4O3S

H3CO NH CH 3 and enantiomer N OCH et énantiomère N 3 S y enantiómero O N CH3

7761 teriflunomidum α α α teriflunomide (Zantirheumatic)-2-cyano- , , -trifluoro-3-hydroxy-p-crotonotoluidide tériflunomide (Zantirhumatismal)-2-cyano-3-hydroxy-N-[4-(trifluorométhyl)phényl]but-2-énamide α α α teriflunomida (Zantirreumático)-2-ciano- , , -trifluoro-3-hidroxi-p-crotonotoluidida

C12H9F3N2O2

CF3 OH O

H3C N H CN

7807 timcodarum timcodar (S)-N-benzyl-p-chloro-α-[N-methyl-2-(3,4,5-trimethoxyphenyl)glyoxylamido]- Nmultidrug-[3-(4-pyridyl)-1-[2-(4-pyridyl)ethyl]propyl]hydrocinnamamide resistance inhibitor, antineoplastic timcodar (2S)-N-benzyl-3-(4-chlorophényl)-2-[méthyl[2-oxo- 2-(3,4,5-triméthoxyphényl)acétyl]amino]-N-[3-(pyridin-4-yl)-1-[2-(pyridin- 4-yl)éthyl]propyl]propanamideinhibiteur de la multirésistence aux médicaments, antinéoplasique timcodar (S)-N-bencil-p-cloro-α-[N-metil-2-(3,4,5-trimetoxifenil)glioxilamido]= Ninhibidor-[3-(4-piridil)-1-[2-(4-piridil)etil]propil]hidrocinamamida de la resistancia a multiples fármacos, antineoplástico

C43H45ClN4O6

OCH3

H3CO O H N N H3CO N

O CH3 O

206 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

tipranavirum tipranavir 3'-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-phenethyl-6-propyl-2H-pyran- 3-yl]propyl]-5-(trifluoromethyl)-2-pyridinesulfonanilideantiviral tipranavir N-[3-[(1R)-1-[(6R)-4-hydroxy-2-oxo-6-(2-phényléthyl)-6-propyl-5,6-dihydro- 2antiviralH-pyran-3-yl]propyl]phényl]-5-(trifluorométhyl)pyridine-2-sulfonamide tipranavir 3'-[(1R)-1-[(6R)-5,6-dihidro-4-hidroxi-2-oxo-6-fenetil-6-propil-2H-piran- 3-il]propil]-5-(trifluorometil)-2-piridinasulfonanilidaantiviral

C31H33F3N2O5S

HO OO SN O CH3 N H H O F3C H3C

7765 tonabersatum tonabersat N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-4-chromanyl]-3-chloro- 4-fluorobenzamideanticonvulsant tonabersate N-[(3S,4S)-6-acétyl-3-hydroxy-2,2-diméthyl-3,4-dihydro-2H-chromén-4-yl]- 3-chloro-4-fluorobenzamideanticonvulsivant tonabersato N-[(3S,4S)-6-acetil-3-hidroxi-2,2-dimetil-4-cromanil]-3-cloro- 4-fluorobenzamidaanticonvulsivo

C20H19ClFNO4

F Cl

O NH O H H

HO CH3

H3C O H3C

7827 tositumomabum tositumomab immunoglobulin G2a anti-(human antigen CD 20) (mouse monoclonal clone γ λ B1R1 2a-chain), disulfide with mouse monoclonal clone B1R1 x-chain, dimerimmunomodulator tositumomab immunoglobuline G2a anti-(antigène CD 20 humain) (chaîne γ2a de λ l’anticorps monoclonal de souris B1R1), dimère du disulfure avec la chaîne x deimmunomodulateur l’anticorps monoclonal de souris B1R1 tositumomab Inmunoglobulina G2a anti-(antígeno CD 20 humano) (cadena γ2a del λ anticuerpo monoclonal de ratón B1R1),dímero del disulfuro con la cadena x delinmunomodulador anticuerpo monoclonal de ratón B1R1 207 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

travoprostum travoprost isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy- α,α,α− 4-[(prostaglandintrifluoro-m-tolyl)oxy]-1-butenyl]cyclopentyl]-5-heptenoate travoprost (5Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E)-(3R)-3-hydroxy- 4-[3-(trifluorométhyl)phénoxy]but-1-ényl]cyclopentyl]hept-5-énoate de 1-méthyléthyleprostaglandine travoprost (Z)-7-[(1R,2R,3R,5S)-3,5-dihidroxi-2-[(1E,3R)-3-hidroxi-4-[(α,α,α-trifluoro- mprostaglandina-tolil)oxi]-1-butenil]ciclopentil]-5-heptenoato de isopropilo

C26H35F3O6

OH H H OCH3

O CH3 O H H OH HOH

CF3

7815 valdecoxibum valdecoxib pcycloxygenase-2-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide inhibitor valdécoxib 4-(5-méthyl-3-phénylisoxazol-4-yl)benzènesulfonamideinhibiteur de la cyclooxygénase-2 valdecoxib pinhibidor-(5-metil-3-fenil-4-isoxazolil)bencenosulfonamida de la cicloxigenasa-2

C16H14N2O3S

OO S NH2

N O CH3

7810 vangatalcitum vangatalcite dialuminumantacid tetramagnesium carbonate dodecahydroxide trihydrate vangatalcite carbonate et dodécahydroxyde de dialuminium et de tétramagnésium trihydratéantiacide vangatalcita dodecahidróxidoantiácido carbonato de dialuminio y tetramagnesio trihidrato

Al2Mg4(OH)12CO3, 3 H2O

208 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

vepalimomabum vepalimomab immunoglobulin M (mouse monoclonal 1B2 µ-chain anti-human vascular adhesion protein VAP-1), disulfide with mouse monoclonal 1B2 light chain, dimerimmunomodulator vépalimomab immunoglobuline M anti-(protéine d’adhésion vasculaire humaine VAP-1) (chaîne µ de l’anticorps monoclonal de souris 1B2), dimère du disulfure avec laimmunomodulateur chaîne légère de l’anticorps monoclonal de souris 1B2 vepalimomab inmunoglobulina M (cadena µ del anticuerpo monoclonal de ratón 1B2 dirigido contra la proteína humana de adhesión vascular VAP-1), dímero del disulfuro coninmunomodulador la cadena ligera del anticuerpo monoclonal de ratón 1B2

7497 volpristinum volpristin (3R,4R,5E,10E,12E,14S,26aR)-8,9,14,15,24,25,26,26a-octahydro- 14-hydroxy-3-isopropyl-4,12-dimethyl-3H-21,18-nitrilo-1H,22H-pyrrolo= [2,1-antibacterialc][1,8,4,19]dioxadiazacyclotetracosine-1,7,16,22(4H,17H)-tetrone volpristine (5E,10E,12E)-(3R,4R,14S,26aR)-14-hydroxy-4,12-diméthyl-3-(1-méthyléthyl)- 3,4,8,9,14,15,24,25,26,26a-décahydro-7H-21,18-nitrilo-1H,22H-pyrrolo= [2,1-antibactérienc][1,8,4,19]dioxadiazacyclotétracosène-1,7,16,22(17H)-tétrone volpristina (3R,4R,5E,10E,12E,14S,26aR)-8,9,14,15,24,25,26,26a-octahidro-14-hidroxi- 3-isopropil-4,12-dimetil-3H-21,18-nitrilo-1H,22H-pirrolo= [2,1-antibacterianoc][1,8,4,19]dioxadiazaciclotetracosina-1,7,16,22(4H,17H)-tetrona

C28H37N3O7

O H CH N O 3 N O H O H CH3 O CH3 H CH3 HO N H O

209 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

AMENDMENTS TO PREVIOUS LISTS MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES MODIFICACIONES A LAS LISTAS ANTERIORES

Recommended International Nonproprietary Names (Rec. INN): List 29 (WHO Drug Information, Vol. 3, No. 3, 1989) p. 4 dexmedetomidinum dexmedetomidine replace the chemical name and the graphic formula by the following: (+)-(S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

H N

N H3C HCH CH3 3

Dénominations communes internationales recommendées (DCI Rec.): Liste 29 (Informations Pharmaceutiques OMS, Vol. 3, No. 3, 1989) p. 4 dexmedetomidinum dexmédétomidine remplacer le nom chimique et la formule developpée par: (+)-(S)-4-[1-(2,3-diméthylphényl)éthyl]-1H-imidazole

H N

N H3C HCH CH3 3

Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 29 (Información Farmacéutica OMS, Vol. 3, No. 3, 1989) p. 4 dexmedetomidinum dexmedetomidina sustitúyanse el nombre quimico y la fórmula desarrollada por: (+)-(S)-4-[1-(2,3-dimetilfenil)etil]-1H-imidazol

H N

N H3C HCH CH3 3

210 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

Recommended International Nonproprietary Names (Rec. INN): List 36 Dénominations communes internationales recommedées (DCI Rec.): Liste 36 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 36 (WHO Drug Information, Vol. 10, No. 3, 1996) p. 153 odulimomabum odulimomab replace the description by the following: immunoglobulin G1, anti-(human CD11 (antigen) α-chain) (mouse monoclonal 25.3 γ1-chain), disulfide with mouse monoclonal 25.3 light chain, dimer

odulimomab remplacer la description par la suivante: immunoglobuline G1, anti-(chaîne α de l'antigène CD11 humain) (chaîne γ1 de l'anticorps monoclonal de souris 25.3), dimère du disulfure avec la chaîne légère de l’anticorps monoclonal de souris 25.3

odulimomab sustitúyase la descripción por la siguiente: inmunoglobulina G1, anti-(cadena α del antígeno CD11 humano) (cadena γ1 del anticuerpo monoclonal de ratón 25.3), dímero del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón 25.3

Recommended International Nonproprietary Names (Rec. INN): List 37 Dénominations communes internationales recommedées (DCI Rec.): Liste 37 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 37 (WHO Drug Information, Vol. 11, No. 1, 1997) p. 35 bectumomabum bectumomab replace the description by the following: immunoglobulin G2a, anti-(human CD22 (antigen)) Fab' fragment (mouse monoclonal IMMU-LL23 γ2a-chain), disulfide with mouse monoclonal IMMU- LL2 light chain

bectumomab remplacer la description par la suivante: immunoglobuline G2a, anti-(antigène CD22 humain) fragment Fab' (chaîne γ2a de l'anticorps monoclonal de souris IMMU-LL2), disulfure avec la chaîne légère de l’anticorps monoclonal de souris IMMU-LL2

bectumomab sustitúyase la descripción por la siguiente: inmunoglobulina G2a, anti-(antígeno CD22 humano) fragmento Fab' (cadena γ2a del anticuerpo monoclonal de ratón IMMU-LL2), disulfuro con la cadena ligera del anticuerpo monoclonal de ratón IMMU-LL2

211 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

p. 48 sulesomabum sulesomab replace the description by the following: immunoglobulin G1, anti-(human NCA-90 granulocyte cell antigen) Fab' fragment (mouse monoclonal IMMU-MN3 γ1-chain), disulfide with mouse monoclonal IMMU-MN3 light chain

sulésomab remplacer la description par la suivante: immunoglobuline G1, anti-(antigène cellulaire NCA-90 de granulocyte humain) fragment Fab’ (chaîne γ1 de l’anticorps monoclonal de souris IMMU-MN3), disulfure avec la chaîne légère de l’anticorps monoclonal de souris IMMU-MN3

sulesomab sustitúyase la descripción por la siguiente: inmunoglobulina G1, anti-(antígeno NCA-90 de células de granulocito humano) fragmento Fab' (cadena γ1 del anticuerpo monoclonal de ratón IMMU-MN3), disulfuro con la cadena ligera del anticuerpo monoclonal de ratón IMMU-MN3

p. 49 technetium (99mTc) pintumomabum technetium (99mTc) pintumomab replace the description by the following: immunoglobulin G1, anti-(human adenocarcinoma antigen) (mouse monoclonal 170 γ1-chain), disulfide with mouse monoclonal 170 κ-chain, dimer, technetium [99mTc] salt

technétium (99mTc) pintumomab remplacer la description par la suivante: sel de [99mTc]technétium de l’immunoglobuline G1, anti-(antigène associé aux adénocarcinomes humains) (chaîne γ1 de l’anticorps monoclonal de souris 170), dimère du disulfure avec la chaîne κ de l’anticorps monoclonal de souris 170

tecnecio (99mTc) pintumomab sustitúyase la descripción por la siguiente: sal de [99mTc]tecnecio del inmunoglobulina G1, anti-(antígeno asociado a los adenocarcinomas humanos) fragmento Fab' (cadena γ1 del anticuerpo monoclonal de ratón 170), dímero del disulfuro con la cadena κ del anticuerpo monoclonal de ratón 170

Recommended International Nonproprietary Names (Rec. INN): List 38 Dénominations communes internationales recommedées (DCI Rec.): Liste 38 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 38 (WHO Drug Information, Vol. 11, No. 3, 1997) p. 161 basiliximabum basiliximab replace the description by the following: immunoglobulin G1, anti-(human interleukin 2 receptor) (human-mouse monoclonal CHI621 γ1-chain), disulfide with human-mouse monoclonal CHI621 light chain, dimer

212 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

basiliximab remplacer la description par la suivante: immunoglobuline G1, anti-(récepteur de l'interleukine 2 humain) (chaîne γ1 de l'anticorps monoclonal chimérique homme-souris CHI621), dimère du disulfure avec la chaîne légère de l’anticorps monoclonal chimérique homme-souris CHI621

basiliximab sustitúyase la descripción por la siguiente: inmunoglobulina G1, anti-(receptor de interleukina 2 humano) (cadena γ1 del anticuerpo monoclonal hombre-ratón CHI621), dímero del disulfuro con la cadena ligera del anticuerpo monoclonal quimérico hombre-ratón CHI621

p. 174 nerelimomabum nerelimomab replace the description by the following: immunoglobulin G1, anti-(human tumor necrosis factor α) (mouse monoclonal BAYX1351 γ1-chain), disulfide with mouse monoclonal BAYX1351 light chain, dimer

nérélimomab remplacer la description par la suivante: immunoglobuline G1, anti-(facteur de nécrose tumorale α humain) (chaîne γ1 de l'anticorps monoclonal de souris BAYX1351), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris BAYX1351

nerelimomab sustitúyase el nombre quimico por: inmunoglobulina G1, anti-(factor de necrosis tumoral α humano) (cadena γ1 del anticuerpo monoclonal de ratón BAYX1351), dímero del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón BAYX1351 p. 178 technetium (99mTc) nofetumomabum merpentanum technetium (99mTc) nofetumomab replace the description by the following: merpentan immunoglobulin G2b, anti-(human tumor) Fab fragment (mouse monoclonal NR-LU-10 γ2b-chain), disulfide with mouse monoclonal NR-LU-10 κ-chain, oxo[[N,N'-[1-(3-oxopropyl)-1,2-ethanediyl]bis[2-mercaptoacetamidato]]= (4-)-N,N',S,S']technetate(1-)-[99mTc] conjugate

technétium (99mTc) nofétumomab remplacer la description par la suivante: merpentan immunoglobuline G2b, anti-(tumeur humaine) fragment Fab (chaîne γ2b de l’anticorps monoclonal de souris NR-LU-10), disulfure avec la chaîne κ de l’anticorps monoclonal de souris NR-LU-10, conjuguée avec l’oxo= [[N,N’-[1-(3-oxopropyl)éthylène]bis[2-sulfanylacétamidato]]= (4-)-N,N’,S,S’][99mTc]technétate(1-)

tecnecio (99mTc) nofetumomab sustitúyase el nombre quimico por: merpentán inmunoglobulina G2b, anti-(tumor humano) fragmento Fab (cadena γ2b del anticuerpo monoclonal de ratón NR-LU-10), disulfuro con la cadena κ del anticuerpo monoclonal de ratón NR-LU-10, conjugado con el oxo[[N,N'-[1-(3-oxopropil)etano-1,2-diil]bis[2-sulfanilacetamidato]]= (4-)-N,N',S,S'][99mTc]tecnetato(1-)

213 RECOMMENDED INN: List 42 WHO Drug Information, Vol. 13, No. 3, 1999

Proposed International Nonproprietary Names (Rec. INN): List 39 Dénominations communes internationales proposées (DCI Rec.): Liste 39 Denominaciones Comunes Internacionales Propuestas (DCI Rec.): Lista 39 (WHO Drug Information, Vol. 12, No. 1, 1998) p. 43 cedelizumabum cedelizumab replace the description by the following: immunoglobulin G4, anti-(human CD4 (antigen)) (human-mouse monoclonal OKTcdr4a complementary determining region-grafted γ4-chain), disulfide with human-mouse monoclonal OKTcdr4a complementary determining region- grafted κ-chain, dimer

cédélizumab remplacer la description par la suivante: immunoglobuline G4, anti-(antigène CD4 humain) (chaîne γ4 de l’anticorps monoclonal de souris OKTcdr4a humanisé), dimère du disulfure avec la chaîne κ de l’anticorps monoclonal de souris OKTcdr4a humanisé

cedelizumab sustitúyase la descripción por la siguiente: inmunoglobulina G4, anti-(antígeno CD4 humano) (cadena γ4 del anticuerpo monoclonal humanizado de ratón OKTcdr4a), dímero del disulfuro con la cadena κ del anticuerpo monoclonal humanizado de ratón OKTcdr4a

p. 148 igovomabum

igovomab replace the description by the following:

immunoglobulin G1, anti-(human CA 125 (carbohydrate antigen)) F(ab')2 γ1 fragment (mouse monoclonal OC125F(AB')2 -chain), disulfide with mouse

monoclonal OC125F(AB')2 light chain, dimer igovomab remplacer la description par la suivante: immunoglobuline G1, anti-(antigène osidique CA 125 humain) fragment γ F(ab’)2 (chaîne 1 de l’anticorps monoclonal de souris OC125F(AB’)2), dimère du disulfure avec la chaîne légère de l’anticorps monoclonal de souris

OC125F(AB’)2 igovomab sustitúyase la descripción por la siguiente: inmunoglobulina G1, anti-[(antígeno hidrato de carbono) CA 125 humano] γ (fragmento F(ab')2 (cadena 1 del anticuerpo monoclonal de ratón

OC125F(AB')2), dímero del disulfuro con la cadena ligera del anticuerpo

monoclonal de ratón OC125F(AB')2

214 WHO Drug Information, Vol. 13, No. 3, 1999 RECOMMENDED INN: List 42

Proposed International Nonproprietary Names (Rec. INN): List 40 Dénominations communes internationales proposées (DCI Rec.): Liste 40 Denominaciones Comunes Internacionales Propuestas (DCI Rec.): Lista 40 (WHO Drug Information, Vol. 12, No. 2, 1998) p. 181 fidarestatum fidarestat replace the graphic formula by the following: fidarestat remplacer la formule developpée par: fidarestat sustitúyase la fórmula desarrollada por:

O HN NH O F H H2N O O

Procedure and Guiding Principles / Procédure et Directives / Procedimientos y principios generales

The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceuti- cal Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharma- ceutical Substances will be reproduced in uneven numbers of proposed INN lists only.

Les textes de la Procédure à suivre en vue de choix de dénominations communes internationales recommandées pour les substances pharmaceutiques et des Directives générales pour la formation de dénominations communes internatio-nales applicables aux substances pharmaceutiques ont été publiés avec la liste 81 des DCI proposées et seront, à nouveau, publiés avec la prochaine liste des DCI proposées.

El texto de los Procedimientos de selección de denominaciones comunes internacionales recomendadas para las sus-tancias farmacéuticas y de los Principios generales de orientación para formar denominaciones comunes internacio-nales para sustancias farmacéuticas aparece solamente en los números impares de las listas de DCI propuestas.

215