Comparative analysis of the use and control of thalidomide in Brazil and different countries: is it possible to say there is safety?

INTRODUCTION: One of the biggest drug disasters in history has not prevented thalidomide from being used to treat various clinical conditions. Currently, Brazil has a worrying scenario: high consumption of the drug and, cases of pregnant women using thalidomide, even after adopting restrictive legislation. AREAS COVERED: This review of the literature and legislation sought to comparatively analyze the monitoring of thalidomide use in Brazil and other countries that use this drug. Finally, we discuss the differences between the countries. EXPERT OPINION: This analysis allows us to think beyond the safe use of thalidomide, but the safety provided by any type of monitoring system. It seems that out-patients that use unsafe drugs are exposed to some degree of risk. To improve safety, more extensive improvements are needed than monitoring systems related to the use of thalidomide. Its safe use depends on a drastic reduction in the incidence of leprosy and Erythema Nodosum Leprosum in the world; investment in research and development of safe and effective therapeutic alternatives to thalidomide; improvement of health systems and their health surveillance systems, particularly in primary health care; awareness of health professionals and patients for greater responsibility in the use of medicines, especially thalidomide.

Controle e utilização da talidomida: adequados à ampliação do uso e mitigação do risco de teratogenicidade no Brasil? / Thalidomide control and use: are these appropriate to extend the use and mitigate the risk of teratogenicity in Brazil?

Resumo Estudo de utilização de medicamento que descreve o controle da talidomida no Brasil e sua utilização em Minas Gerais. Questionário online foi enviado às unidades federativas do Brasil para coleta de dados de distribuição, dispensação, cadastro de usuários e eventos adversos da talidomida. Dados de distribuição (2011-2018) e dispensação (2015-2018) de Minas Gerais foram obtidos pelo sistema de gerenciamento da assistência farmacêutica. Análise de variância e teste de Tukey foram empregados para comparações dos dados. Das 16 unidades federativas participantes, 100% e 50% utilizavam sistema eletrônico para distribuição e dispensação, respectivamente, e cerca de 43% cadastravam usuários. Sistemas de notificação de eventos adversos eram escassos. Houve redução de 44% na distribuição em Minas Gerais no período. A dispensação manteve-se constante (média 0,0004 DDD/1000 hab./dia) e ocorreu principalmente para eritema nodoso hansênico e mieloma múltiplo. O uso off-label (2,2%) foi crescente. A maioria dos usuários era do sexo masculino (idade média 56 anos). Das mulheres, 30% estavam em idade fértil. A vigilância da talidomida é um desafio em saúde pública. Apesar da ampliação do uso e obrigatoriedade de controle, não há padronização em nível nacional e a notificação de eventos adversos é incipiente.

Abstract Drug utilization research to describe the control of thalidomide in Brazil and its use in Minas Gerais state. An online questionnaire was sent to the Brazilian federative units to collect data concerning distribution, dispensation, user registration, and thalidomide adverse events. Distribution (2011-2018) and dispensing (2015-2018) data in Minas Gerais were obtained through the pharmaceutical care management system. Analysis of variance and Tukey test were used for data comparisons. Of the 16 participating federative units, 100% and 50% used electronic distribution and dispensing systems, respectively, and about 43% registered users. Adverse event reporting systems were scarce. A 44% reduction was observed in the distribution in Minas Gerais for the period. Dispensing remained constant (mean 0.0004 DDD/1,000 inhabitants/day) and occurred mainly for erythema nodosum leprosum and multiple myeloma. Off-label use (2.2%) was increasing. Most users were male (mean age 56 years) and thirty percent of women were of childbearing age. Thalidomide surveillance is a public health challenge. Despite the increased use and mandatory control, there is no national standardization, and adverse event reporting is incipient.

Adverse events in patients with leprosy on treatment with thalidomide

Abstract INTRODUCTION: Thalidomide, used to treat erythema nodosum leprosum (ENL), is associated with severe adverse events (AEs) and is highly teratogenic. METHODS: A cross-sectional study was conducted on thalidomide-treated patients with ENL. AEs and selected variables were investigated through interviews and assessment of medical records. Odds ratios with 95% confidence intervals were estimated via logistic regression. RESULTS: Peripheral neuropathy symptoms and deep vein thrombosis (DVT) were the most common AEs reported. Although women of reproductive age used contraceptives, <50% of patients reported using condoms. Polypharmacy was associated with all endpoints, except DVT. CONCLUSIONS: Pharmacovigilance is crucial to prevent harmful thalidomide-associated AEs.

The impact of thalidomide use in birth defects in Brazil.

Although the thalidomide tragedy occurred more than 50 years ago, the medication is still being used worldwide for different reasons, and several aspects regarding its teratogenicity remain unsolved. Despite the strict regulation implemented, new cases of thalidomide embryopathy (TE) are still being registered in Brazil. Furthermore, the molecular processes that lead to malformations when the embryo is exposed to thalidomide have not yet been fully identified. In this article, we perform a critical analysis of thalidomide's history in Brazil, highlighting aspects of the occurrence of TE over the decades. Finally, we present the main perspectives and challenges for ongoing surveillance and prevention of TE in Brazil. The effective control of dispensing thalidomide, especially in areas where leprosy is endemic, is one of the most important and challenging points. Furthermore, the emergence of thalidomide analogues is fast approaching, and their availability would pose additional concerns. The understanding of the molecular mechanisms and targets of thalidomide in both experimental and human models is essential for generating new insights into teratogenic mechanisms, so that safer thalidomide analogues can be developed.

Occurrence and clinical management of moderate-to-severe adverse events during drug-resistant tuberculosis treatment: a retrospective cohort study.

OBJECTIVES: To determine the incidence of symptomatic moderate-to-severe adverse events during treatment of drug-resistant tuberculosis, and to compare their risk and outcomes by patients' human immunodeficiency virus (HIV) co-infection status. METHODS: We conducted a retrospective cohort analysis of patients treated for drug-resistant tuberculosis between January 2008 and February 2010. Routinely, clinicians monitored and managed patients' response to treatment until its completion. Any symptomatic adverse event observed by the clinician or reported by the patient was recorded in the standard patient treatment booklet of the National Tuberculosis and Leprosy Programme. There were 18 symptomatic adverse events routinely monitored. Depending on the nature of the medical intervention needed, each was graded as mild, moderate or severe. Data were extracted from the patient treatment booklet using a structured form, then descriptive, bivariate and Cox proportional hazard analysis performed, stratified by patients' HIV infection status. Statistical associations were done at the 5% level of significance and reported with 95% confidence intervals. RESULTS: Fifty seven (57) patients with drug-resistant tuberculosis were identified, 31 (53%) of whom were HIV co-infected. The cumulative incidence of moderate-to-severe adverse events was 46 events in 100 patients. HIV co-infected patients experienced more moderate-to-severe adverse events compared with the HIV uninfected patients (median 3 versus 1 events, p = 0.01). They had a four-fold increase in the cumulative hazard of moderate-to-severe adverse events compared with the HIV uninfected patients (HR = 4.0, 95% CI 1.5 - 10.5). Moderate-to-severe adverse events were the main determinant of a clinician's decision to reduce the dose or to stop the suspected offending medicine (RR = 3.8, 95% 1.2-11.8). CONCLUSIONS: Moderate-to-severe adverse events are common during drug-resistant tuberculosis therapy. They are more likely to occur and to persist in HIV co-infected patients than in HIV uninfected patients. Clinicians should employ various strategies for preventing drug-induced patient discomfort and harm, such as reducing the dose or stopping the suspected offending medicine. Managers of tuberculosis control programmes should strengthen pharmacovigilance systems. We recommend a more powered study for conclusive risk-factor analysis.

Estudio de utilización y empleo de farmacovigilancia intensiva de la talidomida por médicos especialistas del área Metropolitana y Edo. Miranda de la República Bolivariana de Venezuela. Año 2009-2010 / Study of the use and use of intensive pharmacovigilance of thalidomide by medical specialists in the Metropolitan area and Edo. Miranda of the Bolivarian Republic of Venezuela. Year 2009-2010

Introducción. La talidomida (TA) es un fármaco conocido por los efectos secundarios que generaba, en los años 50, en el feto cuando se administraba a mujeres embarazadas más que por sus efectos terapéuticos reconocidos. En la actualidad, se sabe que la TA tiene propiedades inmunomoduladoras y antiangiogénicas, propiedad que la podría hacer útil en el tratamiento de ciertas enfermedades, tales como: complicaciones patológicas debido a la infección por el virus de la inmunodeficiencia humana (VIH), la lepra, enfermedades autoinmunes, neoplasias hematológicas, tumores sólidos, entre otras. Objetivo: Describir los usos clínicos, condiciones de prescripción y empleo de la Farmacovigilancia Intensiva (FI) del fármaco TA por dieciocho (18) médicos especialistas adscriptos a instituciones públicas y privadas del Edo. Miranda y el Distrito Capital. Metodología: La investigación realizada es de diseño no experimental, con un tipo de investigación de campo de carácter cualitativa, y cuyo nivel de estudio es exploratorio. Muestra: Dieciocho (18) médicos especialistas que prescriben el fármaco TA incluidos en la base de datos del Banco de Drogas Antineoplásicas (BADAN). Técnica de Recolección de datos: Aplicación de un guión de entrevista formalizada validada por expertos. Resultados: De los dieciocho (18) especialistas consultados, catorce (77,7%) prescriben TA para el tratamiento de Mieloma Múltiple. Más del 40% incluyen el uso de TA con esteroide. La dosis empleada de TA oscila entre 100-400 mg/dia. Existe el conocimiento de los riesgos de exposición de parte del médico al paciente pero sólo el 50% afirma emplear el Consentimiento Informado. Además, sólo el 44,4 % emplea un sistema de FI para TA. Discusión: El uso del fármaco se realiza fuera de las indicaciones aprobadas en el prospecto. En la RBV, la comercialización de TA se concibe como medicamento de servicio. TA tiene acceso restringido por BADAN y el IVSS. El CENAVIF (INH "RR") no contempla un programa de FI para TA. Conclusiones: Las propiedades antiangiogénicas e inmunomoduladoras de TA son un potencial terapéutico en patologías hematológicas, oncológicas, dermatológicas e inmunológicas. La prescripción de la TA en Venezuela, no está apegada a un programa de FI establecido por la autoridad sanitaria, que defina puntualmente las condiciones o restricciones respecto al uso seguro y eficaz del fármaco en cuestión.

Introduction. Thalidomide (TA) is a drug known for its secondary that it generated, in the 50s, in the fetus when it was administered to women pregnant rather than for its recognized therapeutic effects. Currently, it is known that TA has immunomodulatory and antiangiogenic properties, property that could make it useful in the treatment of certain diseases, such as: Pathological complications due to infection by the virus human immunodeficiency (HIV), leprosy, autoimmune diseases, neoplasms hematological, solid tumors, among others. Objective: To describe the clinical uses, conditions of prescription and use of Intensive Pharmacovigilance (IF) of the TA drug by eighteen (18) medical specialists attached to institutions public and private of the Edo. Miranda and the Capital District. Methodology: The The research carried out is of non-experimental design, with a type of research of qualitative field, and whose level of study is exploratory. Sample: Eighteen (18) medical specialists who prescribe the TA drug included in the database of the Bank of Antineoplastic Drugs (BADAN). technique of Data collection: Application of a formalized interview script validated by experts. Results: Of the eighteen (18) specialists consulted, fourteen (77.7%) prescribe AT for the treatment of Multiple Myeloma. More than 40% include the use of steroid TA. The dose of TA used ranges between 100-400 mg/day There is knowledge of the risks of exposure on the part of the doctor to the patient but only 50% affirm to use the Informed Consent. Besides, only 44.4% use an IF system for AT. Discussion: The use of the drug is performed outside the approved indications in the package insert. In the RBV, the marketing of AT is conceived as a service drug. TA has access restricted by BADAN and the IVSS. CENAVIF (INH "RR") does not contemplate a FI program for AT. Conclusions: The antiangiogenic properties and TA immunomodulators are a therapeutic potential in hematological pathologies, oncological, dermatological and immunological. The AT prescription in Venezuela is not attached to an FI program established by the authority health, which defines exactly the conditions or restrictions regarding the use safe and effective of the drug in question.