Introduction: Comprehensive safety data assembled from clinical trials are communicated to Regulatory Authorities but rarely appear in de- tail in publicly available literature (often focusing preferentially on efficacy). This may cause disconnection between labeling and daily clinical perception and creates uneasiness amongst clinicians (who may feel they are shown only the tips of potentially important safety issues).
Aim: Our aim was to test a new approach consisting of presenting the randomized controlled clinical trials safety database of a widely used drug in a form accessible to clinicians while maintaining scientific in- tegrity.
Methods: Moxifloxacin, a fluoroquinolone antibiotic, was selected based on (i) its large clinical use (140 millions prescriptions to date [PO, IV/PO, IV]) and (ii) questions raised about its safety (general suspicion about the whole fluoroquinolone class; possible adverse clinical out- comes of QTc prolongation; specific actions taken by EMA following occurrence of rare but serious cases of hepatotoxicity and skin reac- tions). The table shows the analyzed populations (all actively con- trolled trials). Crude incidences (with filters to highlight the most meaningful differences) and relative risk estimates (Mantel–Haenszel analysis stratified by study) for AE, ADR, SAE, SADR, treatment discontinuation due to an AE or ADR, and fatal outcomes related to an AE or ADR were calculated (overall and by study design, indica- tion, comparator(s), and risk groups).
Results: The study took about 2 years to complete due to the need for extensive analysis of original data, compilations, construction and assessment of the filters, and integrity checks. It required involving 2 employees of the manufacturer (with their supporting staff), 1 in- dependent author, and a writing bureau. It essentially showed that the safety of moxifloxacin was comparable to that of comparator(s) (that were all standard therapy[ies]) at the time each trial was designed.
Results of the study have now been accepted for publication as an original research paper (less than 6000 words) in an on-line journal with supporting exhibits and supplementary material.
Conclusions: Clinicians currently assess risk based on information in the label of a drug and spontaneous reports. The approach des- cribed here (i) is costly in terms of manpower effort, (ii) provides in- formation on patients enrolled in clinical trials only, and (iii) cannot detect very rare side effects. However, it allows clinicians making direct comparisons of the risks of one drug vs its accepted comparators for its main indications based on data compiled over a long time period.
Reference
1. Tulkens P, Arvis P, Kruesmann F. Moxifloxacin Safety: an Analysis of 14 Years of Clinical Data. Drugs in Research and Development. In press
P026. Drug-Induced Hypersensitivity Reactions in Hospitalized Patients
M. Ponte,1F. Cseh,2G. Keller3and G. Di Girolamo3 1 Hospital Argerich; 2 University of Salvador, Buenos Aires, Argentina; 3 Second Chair, Pharmacology, University of Buenos Aires, Argentina
Background: Drug-induced hypersensitivity syndromes including cu- taneous adverse drug reactions (ADR) are some of the most prevalent induced ADR. These reactions are unfreqently serious, but because of its high prevalence they are one of the most common causes of drug - related admission. Some of them, like DRESS, can be very serious and life threatening. The aim of this study was to determine the prevalence, types and seriousness of these entities in a tertiary care hospital.
Methods: The study was performed by the pharmacovigilance system of a public tertiary care hospital (Hospital Argerich) in Buenos Aires, Argentina. The period included was between June 2008 and April 2012. All hospitalization rooms were evaluated, and Naranjo score was applied to asses the causality of a drug in a medical adverse event.
Certain and probable reactions were included.
Results: We detected 2463 ADRs in this period, 163 (0.62%; 95% CI 2.8–10.43) were hypersensitivity reactions. 130 (78.31%; 95% CI 17.09–48.85%) were non serious cutaneous ADRs, 16 (9.82%; 95%
CI 5.25–14.38) were considered serious cutaneous drug reactions and 17 (10.24%; 95% CI 7.54–12.93%) were other serious hypersensitivity reactions. The drugs that most commonly cause serious cutaneous ADRs were antiepileptic drugs 5 (31.25% 95% CI 8.54–53.96) cases, antibiotics 6 (37.5% 95% CI 13.78–61.22) cases, and there was 1 case of nonsteroidal anti-inflammatory drugs, 1 case of filgrastim, 1 case of allopurinol, 1 case of tenofovir and 1 case of dexamethasone. Other hypersensitivity reactions were 8 cases of angiooedema, 2 anaphylactic shock and a case of transfution related lung injury (TRALI).
Discussion: We found a relative low incidence of cutaneous drug re- actions according to other international bibliography and there has been a similarity considering the drugs involved. A high percentage of these ADRs were serious including a fatal case.
References
1. Rotunda A, Hirsch RJ, Scheinfeld N, et al. Severe cutaneous reactions associated with the use of human immunodeficiency virus medications. Acta Derm Venereol 2003; 83 (1): 1-9
2. Rzany B, Correia O, Kelly JP, et al. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first week of antiepileptic therapy:
a casa-control study. The Lancet 1999; 353 (9171): 2190-4
P027. Causality Methods in Cosmetovigilance:
Comparison of Colipa and PLM versus Global Introspection
P.G.M.A. Zweers,1N.J. Gilmour,2P.A. Hepburn,2R.F. Gerritsen1 and E.P. Van Puijenbroek1
1 Netherlands Pharmacovigilance Centre Lareb
‘s-Hertogenbosch, the Netherlands; 2 Unilever Safety
& Environmental Assurance Centre, Colworth, UK
Background: The European Cosmetics Regulation requires a post- marketing system for detection of undesirable effects on human health of cosmetic products. Colipa, the European cosmetic, toiletry and perfumery association, provided guidelines for causality assessment of these effects. In addition, another causality method originally designed for causality rating in Post Launch Monitoring (PLM) of novel foods has been employed to assess causality of cosmetic products.
Table I. Population analysed (number of patients [moxifloxacin/compara- tor(s)] from actively controlled trials [phase II – phase IV studies - 1995-2010]) Study design Double blind:
11299/11p70
Open label:
3682/3953
Route of admin. PO: 10613/10685 IV/PO: 3431/3415 IV: 937/923
Risk groups PO IV PO
Age= or >65 2451/2403 1373/1334 170/191
Diabetes m. 777/717 923/917 80/72
Renal impair. 1283/1229 888/863 203/218
Hepatic imp. 146/163 183/196 46/46
Cardiac disor. 1476/1404 1167/1136 106/104
BMI= or <18 318/365 116/115 45/53
Abstracts 889
Adisª 2012 Springer International Publishing AG. All rights reserved. Drug Saf 2012; 35 (10)
Objective/Aim: In this study these two causality schemes for consumer cosmetic products were validated against clinical assessment, using the method of global introspection (GI), based on the method of the World Health Organisation (WHO)
Methods: Information upon the nature of undesirable effect(s) by use of cosmetic products was obtained directly from the consumer by use of a questionnaire. A total number of 100 reported cases were ran- domly selected, which were spread among different product categories.
For all cases, causality assessments were independently performed by three experienced assessors in pharmacovigilance. Spearman correla- tion coefficients for the comparison of the outcome of the GI method versus the Colipa and PLM schemes were calculated using SPSS 16.0.
Results: The overall Spearman correlation coefficient was 0.74 for comparison of Colipa versus GI, whereas this was 0.50 for PLM versus GI. The sensitivity was 0.95 for both the Colipa and PLM method, specificity was 0.84 for Colipa and 0.40 for PLM.
Discussion: Although the PLM method originally was designed for the causality rating novel food products, over the years experience had been also been gained with topically applied products. The main dif- ference between Colipa and PLM, which would account for the dif- ference in concordance, is the course of the reaction which is not taken into account in PLM. Both Colipa and PLM do not allow for a short latency – seconds to minutes- between reaction and suspected product to be taken into account. Moreover, both methods, being presented as an algorithm, are based on strict answers as yes/ no/ unknown, whereas the GI method is less rigid and more closely resembles clinical ob- servations. This explains some of the remaining differences in causality outcomes between Colipa or PLM and GI.
Conclusion: From these results it can be concluded the performance of the Colipa causality method yielded better correlation to GI than PLM causality method. The factor identified from comparison of these two schemes as having greatest impact was the course of the reaction.
References
1. Afssaps, 2009. Imputabilite des effets indesirables lies aux produit cosmetiques. (online: www.afssaps.fr)
2. Colipa, 2008. Colipa Guidelines on the Management and reporting of Undesirable Event Reports in the context of EU Cosmetovigilance. (online:
http://www.likochema.lt/docs/naujienos/COSVIG_Guidelines_updated.pdf) 3. Council of Europe, 2009. Cosmetic Regulation 1223/2009. (online: http://
eur-lex.europa.eu/)
4. van Puijenbroek EP, Hepburn PA, Herd TM, et al. Post Launch Monitoring of food products: what can be learned from pharmacovigilance.
Regul Toxicol Pharmacol 2007; 47: 213-20
5. Bons B, Audebert F, Bitaudeau C, et al.; Members of the Colipa Cosmetovigilance Task Force. Assessment of undesirable events in cosmetic market surveillance: background, description and use of a causality assessment method in cosmetovigilance. Regul Toxicol Pharmacol 2010; 58: 349-53
P028. VaccineVigilance: Safety Profile of Influenza Vaccine - Guillain Barre´ Syndrome
B.B.D. Nardi
Universidade de Sa˜ o Paulo, Brazil
Background: Influenza viruses are among the most important patho- gens affecting humans, since they can cause severe asymptomatic infection, including death. For these reasons, major medical societies recommend vaccination for all people from six months old. An im- portant aspect to be considered in the implementation of vaccination programs is the proper orientation to allow the public understanding
of the characteristics of the vaccine, its benefits, limitations and possi- ble adverse events following immunization (AEFI).
Objective: To review, in the indexed literature, articles which present a possible association of influenza vaccines, including vaccines against influenza A (H1N1)/2009 and seasonally used in national vaccination campaigns, in particular about the development of Guillain Barre Sy- drome (GBS).
Materials and Methods: The methodology used in this paper is to re- view and analysis of articles in Portuguese and English and relate to suspected adverse events after influenza vaccine (seasonal and/or pandemic). The databases used are the Web of Science, PubMed and Scielo. Were also searched conference abstracts on the subject.
Results: There were 15 studies that met the inclusion criteria: 12 studies for review and three epidemiological studies. There are few epidemio- logical studies regarding GBS.
Conclusion: The studies collected showed that the frequency of occur- rence of GBS after vaccination does not exceed the occurrence of other etiologies, both are considered seasonal or pandemic influenza vaccine A/H1N1 2009.
Considering the 2009 H1N1 influenza vaccine, the frequency of serious adverse events temporally related to the vaccine was similar to the estimates presented in the literature. The occurrence of GBS was not higher than expected incidence in the general population. Still, it was found that the safety profile of the vaccine is compatible with other influenza vaccines in use worldwide.
While these data indicate that the positive safety profile of influenza vaccines, it is necessary to improve the system for capturing and re- porting of adverse events in the world, there may be underreporting of events reported since it is not mandatory for health professionals in some countries. Moreover, there is a need to improve the quality and timeliness of investigations AEFI because many events are reported incompletely and in most cases the follow-up for investigation of cases is difficult. The use of influenza vaccine continues to be an important factor to control influenza virus infection in the world.
References
1. BRASIL. Ministe´rio da Sau´de. Secretaria de Vigilaˆncia em Sau´de.
Ageˆncia Nacional em Vigilaˆncia Sanita´ria. Protocolo de vigilaˆncia epide- miolo´gica de eventos adversos po´s-vacinac¸a˜o. Estrate´gia de vacinac¸a˜o contra o vı´rus influenza pandeˆmica (H1N1) - Brası´lia: Ministe´rio da Sau´de, 2010. 60 pa´ginas
2. Portal Sau´de. Ministe´rio da Sau´de. Brasil. 2010. http://portal.saude.gov.
br/portal/aplicacoes/noticias/default.cfm?pg=dspDetalheNoticia&id_area=
124&CO_NOTICIA=11562 (accessed 28/07/2010) Table I.
Review Studies Black S, et al. Lancet. 2009
Dias-Tosta E, et al. Arq Neuropsiquiatr. 2002 Jun; 60 (2-B): 367-73.
Gatta´s VL, et al. Conf Intern em Epid EPI. CVE. Sa˜o Paulo, November/2010.
Grumach AS, et al. Conf Intern em Epid EPI. CVE. Sa˜o Paulo, November/2010.
Landaverde JM, et al. J Infect Dis. 2010 Epidemiological Studies
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