Informe técnico N. 001/22 - Hanseníase: orientações para a prescrição e dispensação do medicamento talidomida / Technical report N. 001/22 - Leprosy: guidelines for prescribing and dispensing thalidomide drug

A Talidomida é um medicamento de uso controlado, cuja utilização exige uma série de medidas relacionadas à produção, prescrição e dispensação pelos seus efeitos teratogênicos comprovados ­ Resolução n° 11 de 22 de março de 2011

Thalidomide is a drug for controlled use, whose use requires a series of measures related to production, prescription and dispensing for their teratogenic effects proven - Resolution No. 11 of March 22, 2011

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.

Reacción acneiforme como efecto adverso del apremilast / Acneiform reaction as an adverse effect of apremilast

El apremilast es un fármaco inhibidor de la fosfodiesterasa-4 que modula, a nivel intracelular, la expresión de citoquinas involucradas en la patogenia inflamatoria de la psoriasis. Su uso está indicado en la psoriasis en placas moderada y severa, con buenos resultados clínicos. Los principales efectos adversos son gastrointestinales y, en menos del 2% de los pacientes, dermatológicos, con exantema y foliculitis. Se presenta el caso de un paciente de 42 años que, luego de tomar el apremilast, desarrolló lesiones faciales que correspondieron clínica e histopatológicamente a una reacción acneiforme, con evolución favorable y resolución total del cuadro posterior a la suspensión del medicamento.

Apremilast is a phosphodiesterase-4 inhibitor that modulates the intracellular expression of cytokines, which are involved in the pathogenesis of psoriasis. Apremilast is indicated in moderate to severe plaque psoriasis, and it has shown good clinical results. The main adverse effects occur at a gastrointestinal level, and in less than 2% at the dermatologic level with exanthema and folliculitis. We present a 42-year-old patient that developed facial lesions after taking apremilast. The facial lesions were clinically and histopathologically correspond to an acneiform eruption. The patient evolved favorably and fully recovered after suspending apremilast.

"Descansar e dormir sem riscos": o Jornal do Médico (Portugal) e o desastre da talidomida, 1960-1962 / "Risk-free rest and sleep: " Jornal do Médico (Portugal) and the thalidomide disaster, 1960-1962

Resumo O artigo analisa como o periódico Jornal do Médico, editado na cidade do Porto, em Portugal, divulgou o desastre da talidomida. A pesquisa percorreu as páginas da fonte desde o início de 1960 até o final de 1962. Aqui, objetivam-se apontar e discutir duas questões interligadas: a morosidade em publicar matérias sobre os efeitos deletérios do medicamento, vendido no país sob a denominação Softenon®, e a construção discursiva da isenção da responsabilidade do médico no fenômeno da iatrogenia medicamentosa.

Abstract This article analyzes the way the Porto-based journal Jornal do Médico reported on the thalidomide disaster. The pages of the publication are researched from the beginning of 1960 to the end of 1962 with the aim of identifying and discussing two interconnected questions: the delay in publishing news on the harmful effects of the drug, which was sold in the country under the brand name Softenon®, and the discursive construction of a lack of accountability on the part of physicians for the phenomenon of medication iatrogenesis.

The tale of lenalidomide clinical superiority over thalidomide and regulatory and cost-effectiveness issues / A narrativa de que a lenalidomida é clinicamente superior à talidomida, e questões regulatórias e de custo-efetividade

Abstract In April 2017, the National Sanitary Surveillance Agency (ANVISA-Brazil) approved lenalidomide (LEN) for multiple myeloma (MM) and myelodysplastic syndrome. ANVISA had rejected the first application in 2010, and denied a request for reconsideration in 2012. The reason for rejection was the lack of comparative effectiveness studies proving that LEN was more effective than thalidomide (THAL), a strictly controlled drug regulated by Federal law 10.651/2003 and dispensed to patients (at no costs) through public health system units and hospitals. ANVISA unexplained retreat on the LEN approval for marketing was an unquestionable triumph of the lobbying that ensued the denial, at the forefront of which were politicians, Congress members, patient organizations and medical societies. Two randomized (phase III) trials and three observational (case-control and population-based cohort) compared the effectiveness of THAL- versus LEN-based therapies in MM. Overall, these studies showed no difference in efficacy between LEN- and THAL-based therapies. LEN caused less neuropathy, and more severe hematologic adverse effects. It is much costlier than THAL, and substitution of THAL by LEN shall raise considerably public healthcare costs in Brazil.

Resumo A Agência Nacional de Vigilância Sanitária (ANVISA) aprovou em abril de 2017 a lenalidomida (LEN) para o mieloma múltiplo (MM) e síndrome mielodisplásica. A ANVISA havia negado o registro em 2010, e indeferido um recurso apresentado em 2012. O motivo do indeferimento foi a falta de estudos comparativos de efetividade demonstrando que LEN era mais eficaz do que a talidomida (TAL), um medicamento rigorosamente controlado pela lei federal 10.651/2003 e dispensado gratuitamente a pacientes através de unidades de saúde e hospitais públicos. O recuo não explicado da ANVISA em relação ao registro da LEN foi um inquestionável triunfo do lobby que sucedeu a recusa inicial do registro, a frente do qual estavam políticos, membros do Congresso, associações de pacientes e sociedades médicas. Dois ensaios randomizados (fase III) e três estudos observacionais (caso-controle e coorte de base populacional) compararam a efetividade de terapias para o MM com TAL- e com LEN. Em conjunto, esses estudos mostraram que não havia diferenças quanto a eficácia de tratamentos com LEN- e aqueles com TAL. A LEN causou menos neuropatias, e efeitos adversos hematológicos mais graves. Ela é muito mais cara do que a TAL, e a substituição da TAL pela LEN aumentará muito os custos da assistência pública à saúde no Brasil.

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.

Anti-phospholipid syndrome in seven leprosy patients with thrombotic events on corticosteroid and/or thalidomide regimen: insights on genetic and laboratory profiles

Abstract INTRODUCTION Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and ß2-glycoprotein-I (ß2GPI) Val247Leu polymorphism were assessed. RESULTS Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented ß2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS Corticosteroid or thalidomide adverse effects and aPL and ß2GPI polymorphisms may cause TBE in patients with MB leprosy.

Pharmacovigilance of patients with multiple myeloma being treated with bortezomib and/or thalidomide

In order to evaluate the main adverse effects of drug protocols using bortezomib and/or thalidomide for the treatment of multiple myeloma, we conducted a prospective study. Data were collected through interviews, clinical observation, and from hospital records. A total of 59 patients were included. There was a predominance of females, 36 (61%) vs 23 (39%) males, and of whites, 49 (83.1%) vs 10 (16.9%) blacks. Age ranged from 40 to 94 years, with a median of 65 years (SD=11.6). Regarding staging at diagnosis, 27 (45.7%) patients were in stage III-A, with 12 (20.3%) patients having serum creatinine ≥2 mg/dL. The main adverse effects in the bortezomib treatment group (n=40) were: neutropenia (42.5%), diarrhea (47.5%), and peripheral neuropathy in 60% of cases, with no difference between the iv (n=26) and sc (n=14) administration routes (P=0.343). In the group treated with thalidomide (n=19), 31.6% had neutropenia, 47.4% constipation, and 68.4% peripheral neuropathy. Neutropenia was associated with the use of alkylating agents (P=0.038). Of the 3 patients who received bortezomib in combination with thalidomide, only 1 presented peripheral neuropathy (33.3%). Peripheral neuropathy was the main adverse effect of the protocols that used bortezomib or thalidomide, with a higher risk of neutropenia in those using alkylating agents. Improving the identification of adverse effects is critical in multiple myeloma patient care, as the patient shows improvements during treatment, and requires a rational and safe use of medicines.

História da talidomida no Brasil a partir da mídia impressa (1959-1962) / History of thalidomide in Brazil based on the print media (1959-1962)

O artigo discute algumas questões relacionadas à droga talidomida, a partir de notícias da mídia impressa. As fontes utilizadas na pesquisa foram jornais editados na cidade do Rio de Janeiro entre 1959 e 1962. O estudo destaca o contexto histórico brasileiro que antecede a chegada da talidomida no Brasil, com ênfase em alguns aspectos relativos à indústria farmacêutica no cenário da década de 1950; traz algumas informações sobre o Instituto Pinheiros Produtos Terapêuticos S/A, o principal laboratório que produziu e comercializou a droga no país; demonstra como os jornais veicularam as primeiras propagandas incentivando a prescrição do medicamento e acompanha as notícias sobre os malefícios da talidomida; aponta quais ações foram tomadas para a retirada da droga do mercado brasileiro, uma vez que ela era amplamente comercializada no país naquele momento; conclui que a mídia impressa deu destaque moderado para a tragédia, que a talidomida circulou largamente pelo território nacional e sugere que a primeira geração de bebês vítimas da talidomida deve ser maior do que normalmente se supõe.

The article reviews and discusses the events surrounding the thalidomide tragedy based on news from the print media. Newspapers published in the city of Rio de Janeiro, RJ, Brazil, from 1959 to 1962 were investigated. The analysis highlights the historical context that predates the arrival of the drug in Brazil, with emphasis on some aspects of the pharmaceutical industry in the country. It provides information on the Instituto Pinheiros Produtos Terapêuticos, the main laboratory that produced and marketed the drug in the country, and demonstrates how newspapers presented the first news about the dangers of thalidomide. Furthermore, it indicates what actions were taken to withdraw the drug from the Brazilian market, as the drug was widely marketed in the country at that time. It concludes that the print media reported the event without urgency and without featuring it on the front pages of the newspapers. The article concludes that thalidomide ended up circulating widely throughout Brazil and suggests that the first generation of thalidomide babies must be greater than is commonly supposed.

The prognostic impact of inflammatory factors in patients with multiple myeloma treated with thalidomide in Korea

BACKGROUND/AIMS: The purpose of this study was to determine the correlations between inflammatory factors-including absolute lymphocyte count, lactate dehydrogenase, beta2-microglobulin, albumin, C-reactive protein, and ferritin-and the prognosis for survival in patients with multiple myeloma (MM) treated with induction chemotherapy containing thalidomide and who underwent autologous stem cell transplantation (ASCT). METHODS: Data from patients at 13 university hospitals in South Korea were collected retrospectively between December 2005 and May 2013. RESULTS: The median age of the 232 patients was 57 years (range, 33 to 77) and the male to female ratio was 1.09:1. In the multivariate analysis, fewer than two combined abnormal inflammatory factors was the only independent prognostic factor for superior progression-free survival (relative risk [RR], 0.618; 95% confidence interval [CI], 0.409 to 0.933; p = 0.022), and platelet count > 100 x 109/L and fewer than two combined abnormal inflammatory factors were independent prognostic factors for superior overall survival (RR, 4.739; 95% CI, 1.897 to 11.839; p = 0.001 and RR, 0.263; 95% CI, 0.113 to 0.612; p = 0.002, respectively). CONCLUSIONS: Patients with two or more than two combined inflammatory factors who were treated with thalidomide induction chemotherapy and who underwent ASCT showed significantly shorter survival compared to those with fewer than two combined inflammatory factors. These results could be helpful for predicting prognosis in patients with MM.

Efectividad y seguridad de bortezomib y lenalidomida comparados con regímenes que no los contienen para pacientes con mieloma múltiple / Effectiveness and safety of bortezomib and lenalidomide compared to regimens that do not contain them for patients with multiple myeloma

Introducción: el mieloma múltiple (MM) es un desorden neoplásico de células plasmáticas que representa aproximadamente el 1% de las enfermedades neoplásicas y el 10% de las neoplasias hematológicas; la edad promedio de diagnóstico es de 70 años. Se clasifica como asintomático y sintomático, de acuerdo con el compromiso de órganos o tejidos, el cual se caracteriza por elevación del calcio sérico, insuficiencia renal, anemia y enfermedad ósea. La introducción del trasplante de progenitores hematopoyéticos (TPH) y la disponibilidad de nuevos medicamentos, ha modificado el tratamiento y mejorado su pronóstico. Objetivo: evaluar los beneficios y riesgos del uso de bortezomib y lenalidomida para el tratamiento de pacientes con mieloma múltiple. Metodología: se realizó una búsqueda de evidencia en las bases de datos: MEDLINE, EMBASE, la Librería Cochrane y LILACS. Dos evaluadores de manera independiente, tamizaron las referencias obtenidas, resolviendo las discrepancias por consenso. La calidad de los estudios seleccionados fue evaluada empleando la herramienta AMSTAR. Resultados: se identificaron 29 referencias, de las cuales se incluyeron 3 revisiones sistemáticas de alta calidad. Se presentan los datos de efectividad y seguridad de comparaciones entre regímenes que contienen bortezomib o lenalidomida con aquellos que no contienen estos agentes, en términos de parámetros de respuesta específica, supervivencia libre de progresión (SLP), supervivencia global (SG) y eventos adversos. Conclusiones: Tanto bortezomib como lenalidomida son alternativas terapéuticas efectivas para el tratamiento de inducción en pacientes con mieloma múltiple. Los eventos adversos más comúnmente relacionados con el uso de estos medicamentos son el herpes zoster y la neuropatía periférica para bortezomib, y trombosis venosa profunda para lenalidomida. (AU)

Polineuropatia sensitiva induzida por talidomida e estudo eletrofisiológico do nervo sural como forma de screening diagnóstico: relato de caso / Thalidomide-induced sensory polyneuropathy and electrophysiological study of the sural nerve as a screening diagnosis: a case report

Polineuropatia é uma condição clínica freqüente com sintomatologia debilitante e o tratamento depende fundamentalmente da etiologia. Inúmeras são as causas possíveis deste tipo de distúrbio e o diagnóstico etiológico nem sempre é fácil. Neste relato de caso descrevemos um caso de um paciente com mieloma múltiplo que evoluiu com polineuropatia puramente sensitiva, comprovadapor estudo eletrofisiológico, induzida por talidomida.

Polyneuropathy is a common clinical condition with debilitating symptoms whose treatment dependson etiology. There are numerous possible causes of this type of disorder and the etiologicaldiagnosis is not always easy. In this case report we describe a case of a patient with multiple myeloma who developed purely sensory polyneuropathy, confirmed by electrophysiological study, induced by thalidomide.

Talidomida usada por pacientes com eritema nodoso hansênico / Thalidomide used by patients with erythema nodosum leprosum

INTRODUÇÃO: A talidomida é um fármaco utilizado atualmente no tratamento do eritema nodoso hansênico no Brasil. MÉTODOS: Estudo prospectivo para acompanhar a evolução clínica, registrar os eventos adversos e determinar as concentrações plasmáticas de talidomida em dose diária de 100mg/dia, em 20 pacientes com manifestações clínicas de eritema nodoso hansênico, divididos em dois grupos: após ou em curso da poliquimioterapia para hanseníase. RESULTADOS: Não foram observadas diferenças significativas nos grupos no decorrer do estudo, tanto na evolução clínica favorável dos pacientes, de 70 por cento e 90 por cento, quanto nos eventos adversos registrados que foram tontura e sonolência. Os teores plasmáticos de talidomida em D7 e D14 foram de 0,82±0,4μg/mL e 0,79±0,3μg/mL no grupo 1 e de 0,82±0,4 e 1,55±1,0 no grupo 2, respectivamente. CONCLUSÕES: Na amostra estudada, a poliquimioterapia não interferiu na evolução clínica, na incidência dos efeitos adversos e nos níveis plasmáticos de talidomida.

INTRODUCTION: Thalidomide is a drug currently used in Brazil for treating erythema nodosum leprosum. METHODS: This was a prospective study to follow up clinical evolution, record adverse events and determine plasma thalidomide levels from a dose of 100 mg/day, among 20 patients with clinical manifestations of erythema nodosum leprosum, divided into two groups: during or after leprosy multidrug therapy. RESULTS: No significant differences between the groups were seen during the study, either in relation to favorable clinical evolution among the patients (70 percent and 90 percent), or in relation to the adverse events recorded, which were dizziness and somnolence. The plasma thalidomide levels on D7 and D14 were 0.82 ± 0.4μg/ml and 0.79 ± 0.3 μg/ml in group 1 and 0.82 ± 0.4 and 1.55 ± 1.0 in group 2, respectively. CONCLUSIONS: In this sample, the multidrug therapy had no effect on the clinical evolution, incidence of adverse events and plasma thalidomide levels.

Thalidomide Induced Nonspecific Interstitial Pneumonia in Patient with Relapsed Multiple Myeloma

A 63-year-old female diagnosed with relapsed multiple myeloma visited our hospital complaining of a persistent cough. Since July 2006, she had been taking 100 mg thalidomide daily and gradually developed shortness of breath and a persistent dry cough. A chest X-ray and computed tomography showed ground glass opacities in both lungs. An open lung biopsy of the right middle lobe under general anesthesia revealed chronic peribronchial inflammation, mild interstitial fibrosis, and intra-alveolar macrophage infiltration, with some hemosiderin features, compatible with non-specific interstitial pneumonia (NSIP). After discontinuing the thalidomide, the patient's symptoms did not deteriorate, although the radiographs did not improve. The patient is alive and well with regular outpatient follow-up without progression of the NSIP.

Nonspecific Interstitial Pneumonitis after Bortezomib and Thalidomide Treatment in a Multiple Myeloma Patient

Bortezomib, an inhibitor of 26S proteosome, is recently approved treatment option for multiple myeloma. Thalidomide, a drug with immunomodulating and antiangiogenic effects, has also shown promise as an effective treatment in multiple myeloma. Pulmonary complications are believed to be rare, especially interstitial lung disease. Here, we describe a patient with dyspnea and diffuse pulmonary infiltrates while receiving bortezomib and thalidomide in combination with dexamethasone for treatment-naive multiple myeloma. Bronchoalveolar lavage demonstrated a significant decrease in the ratio of CD4 : CD8 T lymphocytes (CD4/8 ratio, 0.54). Extensive workup for other causes, including infections, was negative. A lung biopsy under video-assisted thorascopic surgery revealed a diagnosis of nonspecific interstitial pneumonitis. The symptoms and imaging study findings improved after initiating steroid treatment. Physicians should be aware of this potential complication in patients receiving the novel molecular-targeted antineoplastic agents, bortezomib and thalidomide, who present with dyspnea and new pulmonary infiltrates and fail to improve despite treatment with broad-spectrum antibiotics.