Prevalence and Appropriateness of Antipsychotic Prescribing in an Italian Prison: Is Everything Always Really Overprescribed?

PURPOSE/BACKGROUND: Although the prevalence of mental disorders in prisoners is known to be higher than in the general population, less is known about the antipsychotic (AP) prescribing rate in jail. The aim of this research was to investigate prevalence and appropriateness of AP prescription in an Italian prison to expand our understanding on this crucial area of clinical-forensic practice. METHODS/PROCEDURES: A cross-sectional (census day) design was used among male adults in the Parma Penitentiary Institutes (PPI). Sociodemographic, clinical and prescription data were collected from the PPI electronic clinical database management system. The AP prescribing appropriateness was examined in accordance with the therapeutic indications included in the Italian National Formulary. A descriptive statistical analysis was performed. FINDINGS/RESULTS: A total of 98 (14.1%) of 696 PPI prisoners were taking AP medications. Moreover, 90 (91.8%) of the 98 PPI participants were also taking other psychotropic medications concurrently. Quetiapine and olanzapine were the most common prescribed APs. Antipsychotic medications were most likely to be prescribed for off-label indications (74.4%). Less than one fifth of all AP prescriptions were for psychotic disorders. IMPLICATIONS/CONCLUSIONS: Antipsychotic medications are widely used in prison, often together with other psychotropic drugs. Considering their common adverse effects, it is crucial to longitudinally monitor their potential risk of metabolic, cardiovascular, and extrapyramidal symptoms and signs, as well as their early risk of mortality. Given the high prevalence of AP off-label prescription, the rationale for AP prescribing should be clearly documented and regularly reviewed within the prison by mental health professionals.

Medicamentos off-label e não licenciados no âmbito pediátrico: uma revisão descritiva dos últimos dez anos / Off-label and unlicensed drugs in the pediatric field: a descriptive review of the last ten years

A falta de medicamentos contendo bulas prevendo o tratamento de pacientes pediátricos representa um problema frequentemente observado em hospitais, principalmente nos setores de unidade de terapia intensiva (UTI) pediátrica e neonatais. Sabe-se que, para que um tratamento seja considerado seguro e eficaz, uma série de estudos clínicos são necessários, no entanto, relata-se um baixo número dessas pesquisas envolvendo crianças, principalmente devido a questões éticas que dificultam a condução das mesmas. Assim, poucos são os medicamentos que provam ser adequados para o tratamento desses pacientes, tornando necessário recorrer ao uso de medicamentos off-label e não licenciados. Os medicamentos são classificados como off-label quando seu uso se dá de maneira que difere de suas especificações aprovadas, por sua vez, produtos não licenciados são classificados desta forma por não possuírem aprovação para sua comercialização no país ou não possuírem comprovação de segurança e eficácia. O preparo de protocolos de estudo organizados, relato de informações aos pais e à criança de maneira clara e objetiva, aproximação entre pesquisadores e pais para o estabelecimento de uma relação de confiança e a condução das pesquisas em momentos de disponibilidade da família demonstram-se estratégias importantes para facilitar a realização dos ensaios clínicos.

The lack of medicines containing drug information leaflets considering the treatment of pediatric patients is a problem frequently observed in hospitals, especially in the pediatric and neonatal intensive care unit (ICU) sectors. It is known that, for a treatment to be considered safe and effective, a series of clinical studies are necessary; however, a low number of these studies involving children are reported, mainly due to ethical issues that make conducting them difficult. Thus, few drugs prove to be suitable for treating these patients, making it necessary to resort to using off-label and unlicensed drugs. Drugs are classified as off-label when their use differs from their approved specifications, in turn, unlicensed products are classified in this way due to not having approval for marketing in the country or do not have proof of safety and efficacy. Preparation of organized study protocols, reporting information to parents and the child in a clear and objective way, bringing researchers and parents closer to establish a relationship of trust and conducting research at moments when the family is available are important strategies to facilitate conducting clinical trials.

Off-label drugs in palliative care: a Group Delphi treatment recommendation process.

OBJECTIVES: The use of drugs beyond their marketing authorisation, that is, off-label use, is common practice in palliative care with over 70% of off-label use having little or no scientific support. The lack of evidence makes recommendations for off-label use essential, in order to increase the safety of drug therapy and thus patient safety. The aim of this study was to develop a guide for preparing and consenting drug-specific recommendations for off-label use in palliative care. METHODS: Group Delphi Study with three rounds and a prior online survey to identify topics of dissent. Participants represented professional groups working in palliative care involved in direct patient care and/or drug management and various care settings. Furthermore, representatives of relevant professional associations, experts with academic, non-clinical background and experts with international expertise were invited. RESULTS: 18/20 invited professionals participated in the prior online-survey. 15 experts participated in the Group Delphi process. Six domains, including identification of drugs, drug uses, assessment of evidence, formulation, consensus and updating of recommendations were generated and respective statements were included in the Group Delphi process. The consensus process resulted in 28 statements forming the guide for recommendations. CONCLUSIONS: The resultant systematic approach for preparing and consenting drug-specific recommendations for off-label use will allow the development of recommendations with transparent and reproducible monographs. This will help to increase treatment quality and patient safety as well as security of decision-making in palliative care. The developed guide is part of a larger project aiming to provide therapy recommendations for areas that have little or no scientific evidence.

Reduced doses of dabrafenib and trametinib combination therapy for BRAF V600E-mutant non-small cell lung cancer prevent rhabdomyolysis and maintain tumor shrinkage: a case report.

BACKGROUND: A BRAF V600E mutation is found as driver oncogene in patients with non-small cell lung cancer. Although combined treatment with dabrafenib and trametinib is highly effective, the efficacy of reduced doses of the drugs in combination therapy has not yet been reported. CASE PRESENTATION: A Japanese man in his mid-sixties was diagnosed with unresectable lung adenocarcinoma and was unresponsive to cytotoxic chemotherapy and immune checkpoint inhibitors. The BRAF V600E mutation was detected by next generation sequencing, and the patient was subjected to treatment with dabrafenib and trametinib in combination. Although the treatment reduced the tumor size, he experienced myalgia and muscle weakness with elevated serum creatine kinase and was diagnosed with rhabdomyolysis induced by dabrafenib and trametinib. After the patient recovered from rhabdomyolysis, the treatment doses of dabrafenib and trametinib were reduced, which prevented further rhabdomyolysis and maintained tumor shrinkage. CONCLUSION: The reduction of the doses of dabrafenib and trametinib was effective in the treatment of BRAF V600E-mutant NSCLC, and also prevented the incidence of rhabdomyolysis.

Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals.

BACKGROUND: A previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak. METHODS: In order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). RESULTS: Of the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available. CONCLUSION: Off-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies.

Off-Label Use of Sirolimus and Everolimus in a Pediatric Center: A Case Series and Review of the Literature.

BACKGROUND: It has been 15 years since sirolimus, an mTOR inhibitor, received Food and Drug Administration approval to prevent acute rejection in kidney transplantation, and 8 years since its analog everolimus acquired the same status. Since then, these drugs have become more and more utilized and their immunosuppressive and antiproliferative properties have been tested in a great variety of clinical conditions, often achieving excellent results. Despite such positive evidence, the on-label indications for these rapalogs are still very restrictive, especially in children. AIMS: The aims of this study were to describe our center's experience with sirolimus and everolimus in managing rare pediatric conditions for which mTOR inhibitors have been reported as a therapeutic option, although without conclusive approval from regulatory agencies, and to evaluate safety and tolerability of the treatment at the prescribed doses. METHODS: All the subjects who received off-label sirolimus or everolimus at the Pediatric Department of the IRCCS Burlo Garofolo in the last 13 years were included. For each disease found in our case series, we reviewed the current scientific literature. RESULTS: Off-label treatment with rapalogs was prescribed in 16 children (11 males, 5 females, median age of 9.5 years, range 1-16 years). Seven had immunologic disorders: four autoimmune lymphoproliferative syndrome (ALPS), one multicentric Castleman disease (mCD), one activated PI3K delta kinase syndrome (APDS), and one immunodysregulation with polyendocrinopathy enteropathy X-linked (IPEX). Eight had proliferative disorders or vascular anomalies: one cystic lymphangioma, two Bannayan-Riley-Ruvalcaba syndrome (BRRS), one blue rubber bleb nevus syndrome (BRBNS), two tuberous sclerosis complex (TSC), and one low-flow mixed arterial and venous malformation. One case had congenital hyperinsulinism (CHI). The average dosage administered was 1 mg/m2 for sirolimus and 7 mg/m2 for everolimus. We experienced a good measurable clinical improvement in 14 patients. Nobody experienced serious adverse events (SAEs). The therapy was interrupted in two cases, for lack of efficacy and poor tolerance in one case and for occurrence of bacterial pneumonia in the other one. A review of the literature identified 101 published reports that met our inclusion criteria. CONCLUSIONS: Although use of mTOR inhibitors has been considered to be complicated, our experience shows that, using low dosages, it is possible to obtain relevant clinical improvements, with a good profile of safety and tolerability.

Outdated Prescription Drug Labeling: How FDA-Approved Prescribing Information Lags Behind Real-World Clinical Practice.

BACKGROUND: Prescription drug labeling is an authoritative source of information that guides the safe and effective use of approved medications. In many instances, however, labeling may fail to be updated as new information about drug efficacy emerges in the postmarket setting. When labeling becomes outdated, it loses its value for prescribers and undermines a core part of the FDA's mission to communicate accurate and reliable information to patients and physicians. METHODS: We compared the number of drug uses indicated on product labels to the number of uses contained in a leading drug compendium for 43 cancer drugs approved between 1999 and 2011. We defined a "well-accepted off-label use" of a drug as one that was not approved by the FDA and received a category 1 or 2A evidence grade. RESULTS: Of the 43 drugs reviewed in this study, 34 (79%) had at least one well-accepted off-label use. In total, 253 off-label uses were identified; 91% were well accepted, and 65% were in cancer types not previously represented on labeling. Off-patent drugs had more well-accepted off-label uses than brand-name drugs, on average (mean 13.7 vs 3.8, P = .018). CONCLUSIONS: The labeling for many cancer drugs, particularly for older drugs, is outdated. Although FDA-approved labeling can never be fully aligned with real-world clinical practice, steps should be taken to better align the two when high-quality data exist. Such steps, if taken, will assist patients and prescribers in discerning which uses of drugs are supported by the highest quality evidence.

Suitability of new drugs registered in Brazil from 2003 to 2013 for pediatric age groups / Adequação às faixas etárias pediátricas de medicamentos novos registrados no Brasil de 2003 a 2013

ABSTRACT Objective To analyze suitability of new drugs registered in Brazil from 2003 to 2013 for pediatric age groups. Methods A descriptive study of drugs with pediatric indication included in a retrospective cohort of new drugs registered in Brazil. The evaluation of drug suitability for the pediatric age group was performed using the following criteria: suitability of dosage form and capacity to deliver the recommended dose. The drugs were considered adequate for the pediatric age groups when they met both criteria. The statistical analysis included calculation of frequencies and proportions. Results Suitability due to the drug capacity to deliver the recommended dose was greater than 80% across all age groups. Regarding suitability of the dosage form, we identified that the older the age group, the greater suitability for pediatric use. Concerning the drugs presented in solid dosage form, we showed that half were classified as inadequate for one or more pediatric age groups to whom they were indicated. The adequacy of drugs to the pediatric age group was 64.3% for preschool children, 66.7% for full-term newborns, 66.7% for premature newborns, and over 70% for other age groups. Conclusion Drugs for children aged under 6 years were less often adequate, considering the dosage form and capacity to provide the recommended dose. The availability and proportional suitability of medicines for pediatric use are greater for older age groups, according to age groups the drug is registered for.

RESUMO Objetivo Analisar a adequação às faixas etárias pediátricas dos medicamentos novos registrados no Brasil no período de 2003 a 2013. Métodos Estudo descritivo dos medicamentos com indicação pediátrica incluídos em uma coorte retrospectiva de medicamentos novos registrados no Brasil. A avaliação da adequação do medicamento à faixa etária pediátrica foi realizada empregando os seguintes critérios: adequação da forma farmacêutica e capacidade de fornecer a dose recomendada. Os medicamentos foram considerados adequados às faixas etárias pediátricas quando preencheram os dois critérios. A análise estatística compreendeu cálculo de frequências e proporções. Resultados A adequação devido à capacidade do medicamento fornecer a dose recomendada foi superior a 80% em todas as faixas etárias. Em relação à adequação da forma farmacêutica, identificou-se que quanto maior a faixa etária, maior a proporção de adequação para uso pediátrico. Em relação aos medicamentos que se apresentavam em formas farmacêuticas sólidas, evidenciou-se que metade foi classificada como inadequada para uma ou mais faixas etárias pediátricas para as quais estavam indicados. A adequação dos medicamentos à faixa etária pediátrica foi 64,3% para pré-escolares, 66,7% para recém-nascidos a termo, 66,7% para recém-nascidos prematuros e superior a 70% para as demais faixas etárias. Conclusão Os medicamentos destinados às crianças menores de 6 anos apresentaram menor frequência de adequação, considerando a forma farmacêutica e a capacidade de fornecer a dose recomendada. A disponibilidade e a proporção de adequação dos medicamentos para uso pediátrico aumentam com a elevação da faixa etária para a qual o medicamento é registrado.

Use of unlicensed and off-label drugs in neonates in a Brazilian university hospital

ABSTRACT This study was designed to investigate the use of off-label and unlicensed drugs in a Neonatal Care Unit (NCU) and to compare the frequency of use of off-label drugs according to the drug regulatory agencies in Brazil (Agência Nacional de Vigilância Sanitária-ANVISA) and the United States Food and Drug Administration (FDA). A prospective observational study was carried out in the NCU. Prescriptions were classified as off-label and unlicensed using both ANVISA and FDA criteria. A total of 157 newborns and 1187 prescriptions were analyzed. The most prescribed drug was fentanyl (9.3%), followed by multivitamin (8.4%) and gentamicin (7.9%). According to ANVISA criteria, there were 665 (56.0%) off-label prescriptions and 86 (7.2%) unlicensed prescriptions and 95.5% of newborns received at least one drug off-label. By contrast, according to FDA criteria, there were 592 (49.9%) off-label prescriptions and 84 (7.1%) unlicensed prescriptions, and 72.0% of newborns received at least one drug off-label. The off-label use of drugs registered by ANVISA differed significantly from that of drugs registered by the FDA. There was a high frequency of off-label and unlicensed drug use in the investigated NCU, and there was an inverse relationship between off-label and unlicensed usage and the gestational age of the newborns.

Off-label prescription of drugs at hospital.

OBJECTIVES: To develop a procedure for management of off-label medications, and to analyze the treatments, indications, and hospital units which will request them more frequently, as well as which variables will have an impact on the authorization decision, and its economic impact. METHODS: A procedure was designed where clinicians would complete request forms and the Hospital Unit would prepare reports assessing their efficacy, safety, convenience, and cost. The request forms for the past five years were analyzed. RESULTS: A total of 834 applications were received, and 88.1% of these were accepted. The authorization rates were higher for Paediatric Units (95.7% vs. 86.6%; p<0.05). The reasons for considering prescriptions as off-label were: different indication (73.2%), different combination (10.2%), different line of treatment (8.6%) and different age (8%). A 73.4% of requests were for antineoplastic drugs, and the most frequently prescribed were rituximab (120) and bevacizumab (103). The quality of evidence supporting the prescriptions was moderate-low, though no direct relationship with the likelihood of approval was demonstrated (p = 0.413). The cost of the approved medications was 8,567,537 €, and the theoretical savings for those drugs rejected was of 2,268,642 €. There was a statistically significant decrease in the authorization rate (p < 0.05, Student's t test) when spending increased. CONCLUSIONS: The responsibility for assessing off-label prescriptions has fallen on the Pharmacy Unit. It has not been demonstrated that the quality of evidence represents a decisive variable for approval of treatment; on the other hand, age and cost have demonstrated a significant impact.

Objetivos: Desarrollar un proceso de gestión de medicamentos en condiciones fuera de ficha técnica y analizar los tratamientos, indicaciones y unidades clínicas que los solicitan, qué variables influyen en la decisión de autorización y su impacto económico. Métodos: Se diseñó un procedimiento según el cual los clínicos cumplimentarían las solicitudes, el Servicio de Farmacia redactaría los informes valorando su eficacia, seguridad, conveniencia y coste, y la dirección médica tomaría la decisión de aceptar o no su uso. Se analizaron las solicitudes de los últimos cinco años. Resultados: Se recibieron 834 solicitudes, autorizándose el 88,1%. Las tasas de autorización fueron mayores para los Servicios Pediátricos (95,7% frente a 86,6%; p < 0,05). Las razones por las que las prescripciones se consideraron fuera de ficha técnica fueron: diferente indicación (73,2%), combinación diferente (10,2%), línea diferente (8,6%) y edad diferente (8%). El 73,4% de las solicitudes fueron de antineoplásicos, siendo rituximab (120) y bevacizumab (103) los más prescritos. La calidad de la evidencia que avalaba las prescripciones fue moderada-baja, aunque sin demostrar relación directa con la probabilidad de aprobación (p = 0,413). El coste de los medicamentos aprobados fue de 8.567.537 € y el ahorro teórico de los denegados 2.268.642 €. El porcentaje de autorización disminuyó según aumentó el gasto de manera estadísticamente significativa (p < 0,05, test t de Student). Conclusiones: La responsabilidad de evaluación de las prescripciones fuera de ficha técnica ha recaído en los Servicios de Farmacia. La calidad de la evidencia no ha demostrado ser una variable decisiva para la aprobación de los tratamientos. En cambio, la edad y el coste sí que han demostrado influir significativamente.

[Off-label use of oncology drugs: national survey results]. / Uso de medicamentos fuera de ficha la técnica en oncohematología: resultado de una encuesta nacional.

PURPOSE: identify by means of a survey the off-label treatments more often used in the oncohaematology area, as well as to know the established procedures and criteria used to authorise those treatments. METHODS: a four-section survey was designed: 1) demographic data and hospital activity, 2) Off-label treatments protocol, 3) Approval criteria and 4) Off-label oncology treatments conducted during the last year. RESULTS: in 42.1% of the hospitals it's needed an authorisation before dispensing in more tan 80% of the treatments. The most influential factor in the approval-dispensation system is the available evidence. The consent of the hospital management with previous Pharmacy department's report was the most common authorisation procedure. 55.3% of the hospitals settled specific patient criteria to help the decision-making altogether with the available safety and efficacy data of the drug for the requested indication. In most centers a lower level of evidence is accepted if there are no therapeutic alternatives as well as in tumors of low prevalence. Most of the centers have not clearly established a criterion of effectiveness to consider a benefit as clinically relevant, nor the cost-effectiveness threshold for approving a FFT. CONCLUSIONS: there is a great variability in the off-label treatments use and also in the criteria used for its approval.

Objetivo: identificar mediante una encuesta los tratamientos fuera de la ficha tecnica (FFT) que mas frecuentemente se utilizan en el area de oncohematologia. Conocer los procedimientos y criterios que se han establecido para autorizar estos tratamientos. Método: se diseno una encuesta con cuatro secciones: 1) datos demograficos y de actividad del hospital, 2) procedimiento de utilizacion de medicamentos FFT, 3) criterios de aprobacion y 4) tratamientos oncologicos FFT tramitados durante el ano anterior. Resultados: en el 42,1% de los centros la proporcion en la que es necesaria autorizacion previa a la dispensacion es mayor del 80%. El factor mas importante que influye en el circuito de autorizacion-dispensacion de estos farmacos es la evidencia disponible. El procedimiento de autorizacion mas habitual es la autorizacion de la direccion del hospital previo informe del servicio de farmacia. En un 55,3% de los hospitales se han establecido criterios especificos del paciente que ayudan a la toma de decisiones, junto con los aspectos de eficacia y seguridad de los farmacos en la indicacion solicitada. En la mayoria de los centros se acepta un menor nivel de evidencia en el caso de que no existan alternativas terapeuticas, asi como en los tumores de baja prevalencia. La mayor parte de los centros no tienen claramente establecido un criterio de eficacia para considerar un beneficio como clinicamente relevante, y tampoco el umbral coste-eficacia para aprobar un FFT. Conclusiones: existe una gran variabilidad en el procedimiento de utilizacion de los FFT y en los criterios que se utilizan para su aprobacion.

[Criteria for good prescribing practice in children]. / Inhaltliche Kriterien für eine gute Verordnung bei Kindern.

Paediatric prescribing is complex. A whole range of aspects needs to be considered to achieve an efficacious and safe drug therapy for children. Legal requirements for prescribing are clearly insufficient for this purpose. Children are immature individuals under constant growth and development. Consequently, based on age and cognitive abilities of the child individual drugs and dosing regimens have to be chosen. Frequent off-label use and a lack of age-appropriate formulation worsen the situation. Additionally, not all dosage forms are similarly adequate in different age groups. Taste significantly influences patient adherence. Dose calculations based on body weight are prone to errors, putting a point on the wrong place or mixing up measuring units easily result in ten-fold dosing errors. Computer-based tools to enhance prescribing are promising but, however, not yet widely implemented in paediatrics because of missing evidence-based data sources and the hugely complex process. Communication between clinicians and pharmacists as well as with the patient remains very important.

Critical evaluation of the off-label indication and of the risks associated to the use of multi-dose vials on the treatment of age-related macular degeneration

Age-related macular degeneration (AMD) is an ocular inflammatory diseases treated mainly by means of a bevacizumab (Avastin®) or ranibizumab (Lucentis®) intravitreal injection. Among these drugs, only ranibizumab has a specific therapeutic indication for AMD. Considering that, the off-label use on ophthalmic therapy seems to become a rule when it should be an exception. Furthermore, bevacizumab presentation consists of multi-dose vials although it does not contain preservatives in its formula. The current literature review aimed at assessing the risks for the patient related to the use of off-label indication and multi-dose vials on AMD treatment. Considering this, the proposal related to the Brazilian Public Consultation no.10, dated September 12, 2012, which proposes the Clinical Protocol and Therapeutic Guidelines for AMD treatment, was evaluated. This systematic review allowed to conclude that the bevacizumab off-label indication results in increased risks for the patient when compared to the product with specific therapeutic indication for AMD treatment (ranibizumab), especially referring to the significant raise in the adverse events. The risks for the patient related to the multi-dose vial use, referring to the microbiological stability and dose precision, were also made clear.

A degeneração macular relacionada à idade (DMRI) é uma doença ocular inflamatória tratada principalmente por injeção intravítrea de bevacizumabe (Avastin®) ou de ranibizumabe (Lucentis®). Entre os medicamentos citados, apenas o ranibizumabe tem indicação terapêutica específica para uso oftálmico. Considerando essa realidade, o uso off-label na terapia oftálmica parece constituir regra quando deveria ser exceção. Ademais, a apresentação do bevacizumabe consiste em frascos de múltipla-dose, embora esse medicamento não contenha conservante em sua fórmula. A presente revisão da literatura avaliou os riscos ao paciente relativos ao uso indicado off-label e de frascos de múltipla-dose no tratamento de DMRI. Nesse sentido, avaliou-se a proposta relativa à Consulta Pública Brasileira nº 10, de 12 de setembro de 2012, que propõe o Protocolo Clínico e Diretrizes Terapêuticas para o tratamento de DMRI. O levantamento sistemático de trabalhos científicos e de informações relevantes de banco de dados eletrônicos permitiu concluir que a indicação off-label do bevacizumabe acarreta riscos maiores ao paciente, quando comparado ao produto com indicação terapêutica específica para o tratamento de DMRI (ranibizumabe), especialmente quanto ao aumento significativo de eventos adversos. Evidenciaram-se, também, os riscos ao paciente relativos ao uso de frascos de múltipla-dose, quanto à estabilidade microbiológica e à precisão da dose.