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BACKGROUND: In Italy HPV vaccination with the quadrivalent vaccine (Gardasil®) is offered actively and free of charge to girls aged 12 since 2007. A nine-valent vaccine (Gardasil 9®) received the European market authorization in 2015 to protect, with only 2 doses, against around 90% of all HPV positive cancers, over 80% of high-grade precancerous lesions and 90% of genital warts caused by HPV types 6/11. METHODS: A dynamic transmission model simulating the natural history of HPV-infections was calibrated to the Italian setting and used to estimate costs and QALYs associated with vaccination strategies. The analyses compared two strategies with the nine-valent vaccine (cervical cancer screening and vaccination in girls only or vaccination in boys and girls) to four alternative strategies (cervical cancer screening and vaccination with quadrialent vaccine in girls only, in both boys and girls, with bivalent vaccine in girls and screening strategy only). The National Health Service perspective was considered. CONCLUSION: The switch to the nine-valent vaccine in Italy can further reduce the burden associated to cervical cancer and HPV-related diseases and is highly cost-effective. RESULTS: Compared to the current vaccination program with quadrivalent vaccine, the nine-valent vaccine in a programme including girls and boys shows further reductions of 17% in the incidence of cervical cancer, 35 and 14% in anal cancer for males and females, as well as over a million cases of genital warts avoided after 100 years. The new technology is associated with an ICER of 10,463 per QALY gained in universal vaccination, decreasing to 4483 when considering the vaccine switch for girls-only.
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BACKGROUND: Herpes zoster (HZ) or "shingles" is common in persons aged 50 years or over. HZ is characterised by a painful dermatological rash which typically resolves in approximately one month. Persistent pain for months or years after rash onset, however, is a common complication of HZ; referred to as post-herpetic neuralgia (PHN). Both HZ and PHN have a significant impact on patients' lives, with considerable implications for healthcare systems and wider society. The aim of the present review is to provide comprehensive documentation and critical appraisal of published data concerning the humanistic, economic and societal burden of HZ in Europe. METHODS: Systematic literature searches were conducted in Medline, EMBASE, PsycINFO, EconLit, HEED and CRD databases. Searches were conducted in July 2014 and restricted to articles published in the past 20 years. Articles were selected for full review by two independent researchers in accordance with predefined eligibility criteria. RESULTS: From a review of 1619 abstracts, 53 eligible articles, were identified which reported data concerning healthcare resource use (n = 38), direct costs (n = 20), indirect costs (n = 16), total costs (n = 10) and impact on health-related quality of life (HRQoL) (n = 21). Findings highlight that PHN is associated with greater impairments in HRQoL and higher costs of management than HZ. For both HZ and PHN, pain severity is a significant predictor of impact on individuals, healthcare systems and society. While the incidence of HZ and PHN increase with age, age does not appear to be a key driver of overall costs for HZ and PHN. Specifically, while direct costs (e.g. GP, specialists, medications, hospitalisations) tend to be higher for older patients, indirect costs (e.g. work time missed) are higher for younger patients. CONCLUSIONS: Available evidence highlights that HZ and PHN result in significant humanistic and economic burden for patients, healthcare systems and wider societies. A tendency to focus upon healthcare resource use and the direct costs of management at the expense of other impacts (e.g. informal caregivers and formal social care) may result in an underestimation of the true burden of HZ and PHN.
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Efeitos Psicossociais da Doença , Herpes Zoster/economia , Herpes Zoster/epidemiologia , Adulto , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-IdadeRESUMO
The COVID-19 pandemic's dramatic impact has been a vivid reminder that vaccines-especially in the context of infectious respiratory viruses-provide enormous societal value, well beyond the healthcare system perspective which anchors most Health Technology Assessment (HTA) and National Immunization Technical Advisory Group (NITAG) evaluation frameworks. Furthermore, the development of modified ribonucleic acid-based (mRNA-based) and nanoparticle vaccine technologies has brought into focus several new value drivers previously absent from the discourse on vaccines as public health interventions such as increased vaccine adaptation capabilities, the improved ability to develop combination vaccines, and more efficient vaccine manufacturing and production processes. We review these novel value dimensions and discuss how they might be measured and incorporated within existing value frameworks using existing methods. To realize the full potential of next-generation vaccine platforms and ensure their widespread availability across populations and health systems, it is important that value frameworks utilized by HTAs and NITAGs properly reflect the full range of benefits for population health and well-being and cost efficiencies that these new vaccines platforms provide.
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OBJECTIVES: Fluoroquinolones are widely used in geriatric patients, but elderly patients are known to be at increased risk of decline in renal function. As fluoroquinolones usually exhibit a dominant renal elimination pathway, reduced dosage regimens are often used in geriatric patients. Our objective was to assess the capability to reach a pharmacokinetic-pharmacodynamic target of efficacy with such reduced dosage regimens of ofloxacin, levofloxacin and ciprofloxacin in elderly patients. METHODS: Using Monte Carlo simulations, 1000 simulated elderly patients were created, based on published pharmacokinetic and pharmacodynamic data, and measured demographic data. Three usually proposed drug regimens taking renal function into account were evaluated using compartmental models. The probability of reaching an fAUC/MIC >100 was calculated for each regimen. RESULTS: For MICs <1 mg/L, all simulated patients reach the efficacy target. However, with higher values of MIC, the proposed regimens were inefficient for patients with moderate or severe renal impairment: 3.4% and 30.2% of patients with moderate renal impairment reached the efficacy target for ciprofloxacin and ofloxacin, respectively, for an MIC of 2 mg/L. For ciprofloxacin, more than 80% of patients with severe renal impairment were unable to reach the target fAUC/MIC with an MIC as low as 1 mg/L, whereas for levofloxacin, all simulated patients reached the efficacy target until an MIC of 4 mg/L. CONCLUSIONS: This suggests that the proposed dosage reduction does not allow the same exposure to be achieved in elderly patients with renal impairment, eventually leading to treatment failure or development of resistant strains.
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Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Plasma/químicaRESUMO
BACKGROUND: In France, each year, influenza viruses are responsible for seasonal epidemics leading to 2-6 million cases. Influenza can cause severe disease that may lead to hospitalization or death. As severe disease may be due to the virus itself or to disease complications, estimating the burden of severe influenza is complex. The present study aimed at estimating the epidemiological and economic burden of severe influenza in France during eight consecutive influenza seasons (2010-2018). METHODS: Influenza-related hospitalization and mortality data and patient characteristics were taken from the French hospital information database, PMSI. An ecological approach using cyclic regression models integrating the incidence of influenza syndrome from the Sentinelles network supplemented the PMSI data analysis in estimating excess hospitalization and mortality (CépiDc-2010-2015) and medical costs. RESULTS: Each season, the average number of influenza-related hospitalizations was 18,979 (range: 8627-44,024), with an average length of stay of 8 days. The average number of respiratory hospitalizations indirectly related with influenza (i.e., influenza associated) was 31,490 (95% confidence interval [CI]: 24,542-39,012), with an average cost of 141 million (range: 54-217); 70% of these hospitalizations and 77% of their costs concerned individuals ≥65 years of age (65+). More than 90% of excess mortality was in 65+ subjects. CONCLUSIONS: The combination of two complementary approaches allowed estimation of both influenza-related and associated hospitalizations and deaths and their burden in France, showing the substantial impact of complications. The present study highlighted the major public health burden of influenza and its severe complications, especially in 65+ subjects.
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Influenza Humana , Efeitos Psicossociais da Doença , Hospitalização , Humanos , Incidência , Influenza Humana/complicações , Influenza Humana/epidemiologia , Estações do AnoRESUMO
BACKGROUND: Maintaining a high vaccination coverage rate (VCR) throughout the lifetime and complying with the National Immunization Program are essential to optimize the protection of the population. The study objectives were to evaluate the evolution of the VCRs and the compliance with the vaccination visits for the diphtheria, tetanus, poliomyelitis and pertussis boosters in France since the changes implemented in the 2013 National Immunization Program. METHODS: Cumulative booster VCRs were estimated at all vaccination visits, from 2013 to 2017, among persons eligible for a booster vaccination from a 1/97th random sample of French claims data. Broader age groups around the recommended ages by the vaccination schedule (6, 11-13, 25, 45, 65, 75, 85, 95y) were used: all persons aged 5 to 8, 10 to 15, 21 to 29, 41 to 49, 61 to 69, 71 to 79, 81 to 89 and 91 to 99. RESULTS: Over the study period, the diphtheria-tetanus-poliomyelitis booster VCRs increased, reaching in 2017: 73.3% at 8 years old, 75.6% at 15 years old, 46.6% at 29 years old, 38.4% at 49 years old, 36.3% at 69 years old, 30.8% at 79 years old, 22.1% at 89 years old and 11.0% at 99 years old. The pertussis VCRs were also increasing at all vaccination visits, in particular at the vaccination visits at 6 and 11-13 years old (from 16.4% to 63.8% and from 50.3% to 61.2%, respectively). Delayed vaccinations were observed at all vaccination visits. CONCLUSION: VCRs for Diphtheria, Tetanus, Poliomyelitis and Pertussis booster vaccination increased from 2013 to 2017 while remaining suboptimal across all ages and lower in the adult populations. The analysis also shows that the introduction in 2013 of a pertussis vaccination at 6 years of age was relatively well-established in 2017 while other changes in recommendations were slowly or partially implemented.
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Vacinas contra Difteria, Tétano e Coqueluche Acelular , Difteria , Poliomielite , Tétano , Coqueluche , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos , Criança , Pré-Escolar , Difteria/prevenção & controle , França , Humanos , Imunização Secundária , Pessoa de Meia-Idade , Poliomielite/prevenção & controle , Tétano/prevenção & controle , Vacinação , Cobertura Vacinal , Coqueluche/prevenção & controleRESUMO
Until 2018, cervical cancer screening in France was an unorganized individual screening, with the exception of some pilot programs in some territories. We aimed to assess, before the implementation of organized cervical cancer screening and human papillomavirus (HPV) nonavalent vaccine introduction in the vaccination schedule in 2018, (i) the individual cervical cancer screening coverage, (ii) the management of squamous intraepithelial lesions (SIL) and (iii) the related costs. We used the Système National des Données de Santé (SNDS) (Echantillon Généraliste de Bénéficiaires [EGB] and Programme de Médicalisation des systèmes d'information [PMSI]) to assess the cervical screening coverage rate in France between January 1st, 2012 and December 31st, 2014, and to describe diagnostic investigations and therapeutic management of SIL in 2013. After extrapolation to the general population, a total of 10,847,814 women underwent at least one smear test over the 3-year study period, corresponding to a coverage rate of 52.4% of the women aged 25 to 64 included. In 2013, 126,095 women underwent HPV test, 327,444 women underwent colposcopy, and 9,653 underwent endocervical curettage; 31,863 had conization and 12,162 had laser ablation. Besides, 34,067 women experienced hospital stays related to management of SIL; 25,368 (74.5%) had high-grade lesions (HSIL) and 7,388 (21.7%) low-grade lesions (LSIL). Conization was the most frequent in-hospital therapeutic procedure: 89.5% (22,704) of women with an in-hospital procedure for HSIL and 64.7% (4,781) for LSIL. Mean cost of smear test, colposcopy and HPV tests were around 50. Total cost for hospital stays in 2013 was estimated at M41, or a mean cost of 1,211 per woman; 76% were due to stays with HSIL. This study highlights the low coverage rate of individual cervical cancer screening and a high burden related to SIL management.
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Detecção Precoce de Câncer/métodos , Programas de Rastreamento/métodos , Lesões Intraepiteliais Escamosas/diagnóstico , Lesões Intraepiteliais Escamosas/terapia , Neoplasias do Colo do Útero/diagnóstico , Adulto , Idoso , Colo do Útero/patologia , Colo do Útero/virologia , Colposcopia/economia , Conização , Estudos Transversais , Detecção Precoce de Câncer/economia , Feminino , França/epidemiologia , Custos de Cuidados de Saúde , Humanos , Programas de Rastreamento/economia , Pessoa de Meia-Idade , Infecções por Papillomavirus/virologia , Lesões Intraepiteliais Escamosas/economia , Lesões Intraepiteliais Escamosas/epidemiologia , Neoplasias do Colo do Útero/economia , Neoplasias do Colo do Útero/epidemiologia , Esfregaço Vaginal/economia , Esfregaço Vaginal/métodos , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/economia , Displasia do Colo do Útero/epidemiologia , Displasia do Colo do Útero/virologiaRESUMO
Human papillomaviruses (HPV) infection is now known to be responsible for almost all cervical cancers, and for a substantial fraction of Head and Neck cancers (HNCs). However, comprehensive epidemiological and economic data is lacking in France, especially for rarer potentially HPV-related cancers, which include anal, vulvar and vaginal cancers. Using the national comprehensive database of French public and private hospital information (PMSI), we assessed prevalence and incidence of patients with in-hospital diagnosis for potentially HPV-related cancers in 2013, and estimated costs related to their management over a 3-year period after diagnosis in France. Concerning female genital cancers, 7,597, 1,491 and 748 women were hospitalized for cervical, vulvar and vaginal cancer in 2013, respectively, with 3,120, 522 and 323 of them being new cases. A total of 4,153 patients were hospitalized for anal cancer in 2013, including 1,661 new cases. For HNCs, 8,794 and 14,730 patients were hospitalized for oral and oropharyngeal cancer in 2013, respectively; 3,619 and 6,808 were new cases. Within the 3 years after cancer diagnosis, the average cost of hospital care per patient varied from 28 K for anal cancer to 41 K for oral cancer. Most expenditures were related to hospital care, before outpatient care and disability allowance; they were concentrated in the first year of care. The total economic burden associated with HPV-potentially related cancers was about 511 M for the French National Health Insurance over a 3 years period (2011 to 2013), ranging from 8 M for vaginal cancer to 222 M for oropharyngeal cancer. This study reported the most up-to-date epidemiological and economic data on potentially HPV-related cancers in France. These results may be used to evaluate the potential impact of new preventive strategies, namely the generalized organized screening of cervical cancer and the nine-valent HPV vaccine, indicated in the prevention of cervical, vaginal, vulvar and anal cancers.
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Neoplasias dos Genitais Femininos/economia , Neoplasias dos Genitais Femininos/virologia , Neoplasias de Cabeça e Pescoço/economia , Neoplasias de Cabeça e Pescoço/virologia , Infecções por Papillomavirus/epidemiologia , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Efeitos Psicossociais da Doença , Feminino , França/epidemiologia , Neoplasias dos Genitais Femininos/epidemiologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Custos de Cuidados de Saúde , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Seguro Saúde , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/economia , Prevalência , Adulto JovemRESUMO
INTRODUCTION: Since 2007, HPV vaccination programs have been implemented in Europe. Significant real-life impact has already been reported in countries where the programs have been successfully implemented. In France, HPV vaccination coverage rate (VCR) is currently one of the lowest in Europe. This represents a missed opportunity for individuals who will not be protected. The study aimed to estimate the consequences of the sub-optimal VCR. METHODS: A dynamic transmission model was calibrated to the French setting. Outcomes resulting from the vaccination of girls with quadrivalent HPV vaccine according to two theoretical VCR: 17% and 70%, reflecting the range of VCRs in Western Europe, were evaluated. RESULTS: Over 100 years, with the current low VCR, an additional 85,000 cancers, 28,000 deaths and more than 5 million avertable disease events overall would occur compared with a 70% VCR. At steady state, the 17% VCR was estimated to be associated with an additional 1700 cancers, 600 deaths and 66,000 avertable disease events each year, compared with a 'standard' EU VCR. CONCLUSION: The loss of chance associated with sub-optimal VCR is substantial for the French population and could amount to the occurrence of hundreds of avoidable deaths and thousands of disease events annually.
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INTRODUCTION: Since 2007, the German Standing Vaccination Committee recommends HPV vaccination for girls aged 12-17 with a 2- (Cervarix®) or 4-valent (Gardasil®) vaccine. A 9-valent vaccine (Gardasil 9®) recently received a European market authorization in 2015. METHODS: A dynamic transmission model was calibrated to the German setting and used to estimate costs and QALYs associated with vaccination strategies. RESULTS: Compared to the current vaccination program, the 9-valent vaccine extended to boys shows further reductions of 24% in the incidence of cervical cancer, 30% and 14% in anal cancer for males and females, as well as over a million cases of genital warts avoided after 100 years. The new strategy is associated with an ICER of 22,987 per QALY gained, decreasing to 329 when considering the vaccine switch for girls-only. CONCLUSION: Universal vaccination with the 9-valent vaccine can yield significant health benefits when compared to the current program.
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Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Vacinação/métodos , Adolescente , Neoplasias do Ânus/prevenção & controle , Neoplasias do Ânus/virologia , Criança , Análise Custo-Benefício , Feminino , Alemanha , Humanos , Programas de Imunização , Masculino , Infecções por Papillomavirus/economia , Vacinas contra Papillomavirus/economia , Saúde Pública/economia , Anos de Vida Ajustados por Qualidade de Vida , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/virologia , Vacinação/economiaRESUMO
Influenza B strains represent on average 23% of all circulating strains in Europe and when there is a vaccine mismatch on B strains, additional influenza-related hospitalizations and deaths as well as substantial additional costs are observed. The objective was to estimate the public health and economic impact of seasonal influenza vaccination with quadrivalent influenza vaccines (QIV) compared to trivalent influenza vaccines (TIV) in Europe (EU). Based on data from 5 EU countries (France, Germany, Italy, Spain and UK) during 10 influenza seasons from 2002 to 2013, epidemiological and associated economic outcomes were estimated for each season for the actual scenario where the TIV was used, and for a hypothetical scenario where QIV could have been used instead. By using QIV, this study estimated that for the 5 EU countries, an additional 1.03 million (327.9/100,000 inhabitants) influenza cases, 453,000 (143.9/100,000) general practitioners consultations, 672,000 (213.1/100,000) workdays lost, 24,000 (7.7/100,000) hospitalizations and 10,000 (3.1/100,000) deaths could have been avoided compared to the use of TIV over the 10-seasons-period. This study estimates that QIV can be of economic value since from a societal perspective 15 million Euros would have been saved on general practitioners consultations (14 million Euros from third-party payer perspective), 77 million on hospitalizations (74 million Euros from third-party payer perspective) and 150 million Euros on workdays lost, across the 5 EU countries. In conclusion, the present study estimates that, compared to TIV, QIV may result in a substantial decrease in epidemiological burden and in influenza-related costs.
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Efeitos Psicossociais da Doença , Análise Custo-Benefício , Vacinas contra Influenza/economia , Vacinas contra Influenza/imunologia , Influenza Humana/economia , Influenza Humana/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Humanos , Lactente , Vacinas contra Influenza/administração & dosagem , Influenza Humana/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Background Population aging brings up a number of health issues, one of which is an increased incidence of herpes zoster (HZ) and its complication, post-herpetic neuralgia (PHN). Zostavax vaccine has recently become available to prevent HZ and PHN. This study evaluates the cost-effectiveness of vaccination against HZ in Spain considering a vaccination of the population aged 50 years and older and comparing this to the current situation where no vaccination is being administered. Methods An existing, validated, and published economic model was adapted to Spain using relevant local input parameters and costs from 2013. Results Vaccinating 30% of the Spanish population aged 50 years and older resulted in 16,577/QALY gained, 2025/HZ case avoided, and 5594/PHN case avoided under the third-party payer perspective. From a societal perspective, the ICERs increased by 6%, due to the higher price of the vaccine. The number needed to vaccinate to prevent one case was 20 for HZ, and 63 for PHN3. Sensitivity analyses showed that the model was most sensitive to the HZ and PHN epidemiological data, the health state utilities values, and vaccine price used. Conclusion Considering an acceptable range of cost-effectiveness of 30,000-50,000 per QALY gained, vaccination of the 50+ population in Spain against HZ with a new vaccine, Zostavax, is cost-effective and makes good use of the valuable healthcare budget.
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Vacina contra Herpes Zoster/administração & dosagem , Vacina contra Herpes Zoster/economia , Herpes Zoster/prevenção & controle , Neuralgia Pós-Herpética/prevenção & controle , Fatores Etários , Idoso , Efeitos Psicossociais da Doença , Análise Custo-Benefício , Humanos , Incidência , Reembolso de Seguro de Saúde , Pessoa de Meia-Idade , Modelos Econométricos , Anos de Vida Ajustados por Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , EspanhaRESUMO
Herpes zoster (HZ; shingles) is a common viral disease that affects the nerves and surrounding skin causing a painful dermatomal rash and leading to debilitating complications such as, mainly, post-herpetic neuralgia (PHN). Currently, there is no effective treatment for HZ and PHN. The objective of this study was to assess the cost-effectiveness of a HZ vaccination program in Germany. An existing Markov Model was adapted to the German healthcare setting to compare a vaccination policy to no vaccination on a lifetime time-horizon, considering 2 scenarios: vaccinating people starting at the age of 50 or at the age of 60 years, from the perspective of the statutory health insurance (SHI) and the societal perspective. According to the perspective, vaccinating 20% of the 60+ German population resulted in 162,713 to 186,732 HZ and 31,657 to 35,793 PHN cases avoided. Corresponding incremental cost-effectiveness ratios (ICER) were 39,306 /QALY from the SHI perspective and 37,417 /QALY from a societal perspective. Results for the 50+ German population ranged from 336,468 to 394,575 HZ and from 48,637 to 56,087 PHN cases avoided from the societal perspective. Corresponding ICER were 39,782 /QALY from a SHI perspective and 32,848 /QALY from a societal perspective. Sensitivity analyses showed that results are mainly impacted by discount rates, utility values and use of alternative epidemiological data.The model indicated that a HZ vaccination policy in Germany leads to significant public health benefits and could be a cost-effective intervention. The results were robust and consistent with local and international existing literature.
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Análise Custo-Benefício/métodos , Herpes Zoster/prevenção & controle , Neuralgia Pós-Herpética/prevenção & controle , Vacinação/economia , Idoso , Idoso de 80 Anos ou mais , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Population pharmacokinetics and simulation techniques currently play an important role in new drug development. This paper illustrates the potential value of those methods in postmarketing safety assessment, using buflomedil in elderly patients as an example. We retrospectively assessed the risk of buflomedil overdosing associated with the latest dosing recommendations of the French Drug Agency (AFSSAPS). First, buflomedil concentrations measured in 24 elderly patients were analysed with a nonparametric population approach. Then, the pharmacokinetic model was used to perform a 1000-patient Monte Carlo simulation for the two recommended buflomedil dosage regimens. The maximum concentrations calculated after 10 days of therapy were compared with levels observed in reported cases of toxicity to assess the probability of overdosing. A three-compartment model best fit concentration data. Population predictions showed little bias (-0.14 mg/L) and good precision (8.73 mg(2) /L(2)). Overall results of the simulation study showed that the application of the two recommended dosage regimens of buflomedil was associated with overdosing (C(max) > 10 mg/L) and potential toxicity in 2.9% of geriatric patients. In patients with mild renal impairment, who may receive the higher-dosage regimen by therapeutic error, the probability of overdosing was 6.2%. Despite specific dosing recommendations in case of renal impairment, this study shows that the use of buflomedil could be associated with significant risk of overdosing in geriatric patients. Such results might have enhanced decision-making when buflomedil safety was reassessed by AFSSAPS in 2006. The retrospective case of buflomedil illustrates how these methods may be valuable in postmarketing safety evaluation of potentially toxic drugs.