Perspectives

Pharmacovigilance and tuberculosis: applying the lessons of thioacetazone Dennis Falzon,a Geraldine Hill,b Shanthi N Pal,c Wimon Suwankesawongd & Ernesto Jaramilloa

Following its introduction in the late quencies for a particular medicine is Fig. 1. Reported cutaneous 1940s, thioacetazone was widely-used impossible with spontaneous reporting, a as an anti-tuberculosis medicine in the as there is no way to obtain a denomina- hypersensitivity reactions associated with thioacetazone, following decades.1 Reports of cutane- tor – an accurate estimate of the number Thailand, 1984–1993 ous hypersensitivity reactions related of people exposed to the drug. Moreover, to its use emerged in the literature soon incomplete reports mean that it is diffi- after its introduction and by the early cult to establish a relationship between 20 d 18 1970s the association between the medi- the suspected medicine and the adverse te 16 cine and the adverse drug reaction was drug reaction. 2 14 well established. Despite the increased Currently the WHO Programme 12 recognition of this risk, thioacetazone for International Drug Monitoring – a tions repor 10 remained in use mainly in low-income worldwide pharmacovigilance network 8 3 countries because of its low cost. – receives individual case safety reports 6 In the late 1980s and early 1990s, from the national drug safety authorities 4

reports appeared from Africa describing of 118 countries. Spontaneous reports Number of reac 2 an increased risk of severe cutaneous of adverse drug reactions, submitted 0 reactions associated with the use of by participating countries are gathered 1984– 1986– 1988– 1990– 1992– 1985 1987 1989 1991 1993 thioacetazone in persons with human in the database VigiBase™, which is Years immunodeficiency virus (HIV) infec- maintained by the WHO Collaborating tion.4,5 At that time, HIV infection had Centre, the Uppsala Monitoring Centre a Bullous eruption (n = 1); Erythema multiforme already reached epidemic proportions in Sweden.9 VigiBase™ has accumulated (n = 2); Exfoliative dermatitis (n = 14); Stevens- Johnson syndrome (n = 19); Toxic epidermal in many African countries. Among well over nine million individual case necrolysis (n = 1). children and adults with HIV infection safety reports since the late 1960s, over Data source: VigiBase™9 and tuberculosis, high fatality was ob- half of which have been received in served in those who developed Stevens- the last five years. This reflects an im- by other countries during this time but Johnson syndrome or toxic epidermal proved regulatory environment, greater no other country reported as large an necrolysis when treated with regimens awareness of the need for drug safety increase as Thailand. containing thioacetazone.4,5 In 1991, monitoring, and the expansion of the The lessons learnt from the thio- the World Health Organization (WHO) WHO Programme for International acetazone episode remain pertinent recommended replacing thioacetazone Drug Monitoring. VigiBase™ currently today; medicines that have been in use with ethambutol in patients with known accrues about 800 000 individual case for a long time need to be monitored or suspected HIV infection.6 Thioacet- safety reports each year.10 for safety when used for new indica- azone is no longer included in WHO’s We searched VigiBase™ for adverse tions or in a population with different recommended first line treatment for drug reactions related to thioacetazone co-morbidity profiles. The spontaneous tuberculosis and is now reserved for and found an increase in reports of skin reports from Thailand show the useful- uncommon situations in which treat- conditions, some of them reported as ness of databases for pharmacovigilance, ment options have been compromised severe, in Thailand during the 1980s and despite the limitations of these reports. by resistance to other anti-tuberculosis early 1990s (Fig. 1). These reports are The treatment of drug-resistant medicines in HIV-negative individuals.7 consistent with – and even predate – the tuberculosis is now poised to undergo For more than 50 years, WHO publications from Africa. While there changes. More patients in more coun- has been encouraging countries to re- is no information about whether these tries will be receiving treatment in the inforce their pharmacovigilance – the conditions were occurring in people coming years and important modifica- surveillance of adverse drug reactions with HIV infection, it is notable that the tions in the regimen composition and – at national level.8 Nonetheless, under- timing of the reporting peak coincides duration will be increasingly introduced. reporting is a major problem, both in with the evolution of the HIV epidemic Current treatment regimens for these developed and developing countries. in Thailand.11 Isolated reports of cuta- patients are long and complex and their Computing adverse drug reaction fre- neous hypersensitivity were reported toxicity when used in certain patient

a Global TB Programme, World Health Organization, avenue Appia 20, 1211 Geneva 27, Switzerland. b Uppsala Monitoring Centre, Uppsala, Sweden. c Essential Medicines and Health Products, World Health Organization, Geneva, Switzerland. d National Pharmacovigilance Centre, Bangkok, Thailand. Correspondence to Dennis Falzon (email: [email protected]). (Submitted: 10 June 2014 – Revised version received: 29 August 2014 – Accepted: 8 September 2014 – Published online: 7 October 2014 )

918 Bull World Health Organ 2014;92:918–919 | doi: http://dx.doi.org/10.2471/BLT.14.142570 Perspectives Dennis Falzon et al. Pharmacovigilance in tuberculosis programmes subgroups may not be completely pro- developments in tuberculosis treat- that enable the proper monitoring of pa- filed.7,12 Several of these patients will also ment are compelling reasons to inte- tients, including laboratory diagnostics be treated for other co-morbidities, in- grate pharmacovigilance with other and the collection and analysis of data cluding HIV infection, at the same time. routine monitoring and operational will be necessary. Health-care workers The introduction of new drugs and the research components of tuberculosis need to acquire new skills to undertake repurposing of medicines beyond their programmes. The different pharmaco- sound pharmacovigilance. primary indication are expected to be- vigilance methods that can be used in Among the leading donors sup- come more widespread as tuberculosis such programmes have been detailed porting tuberculosis control efforts, programmes strive to improve outcomes by WHO.16,17 However, these methods the Global Fund to Fight AIDS, Tuber- for their patients. Two new medicines do not detract from the importance of culosis and Malaria has been a long- – bedaquiline and delamanid – have practitioners reporting potential harms standing proponent for strengthening recently been approved by the United in the medical literature. pharmacovigilance within treatment States’ Food and Drug Administration Active surveillance techniques such programmes.18 Nonetheless, actual and/or the European Medicines Agency, as Cohort Event Monitoring are now investment by national tuberculosis for use in multidrug-resistant tuber- recommended by WHO to use when programmes in pharmacovigilance has culosis patients.13,14 Other drugs that new drugs and regimens are intro- fallen short.19 It is therefore important have not yet completed phase 3 clinical duced.7 Instructions on how to opera- that in any funding proposal for novel trials for tuberculosis are already being tionalize pharmacovigilance in tubercu- or repurposed tuberculosis medicines included in treatment regimens. In ad- losis programmes are being worked out and/or for the introduction of new dition, more medicines are expected to with countries and technical partners tuberculosis regimens, tuberculosis be released shortly.12 The clinical use of to ensure that adverse drug reactions programmes and technical partners in- these new medicines will likely generate are detected faster and managed early. corporate activities that reinforce phar- adverse reactions or drug interactions Integration of pharmacovigilance in the macovigilance. These activities need to that are yet unknown. programmes will require an effective be realistically budgeted for to be able Until now, pharmacovigilance has collaboration between the tuberculosis to increase patient safety and to avoid had a low priority among the activities control programme and the drug safety future incidents like the thioacetazone of national tuberculosis programmes authority at country level. It will also episode. ■ and it is not yet an integral part of the require active participation in the WHO framework used to assess tuberculo- Programme for International Drug Competing interests: None declared. sis programme performance.15 The Monitoring. Investment in technologies

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