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.

Curative effect and safety of the new generation of anti-vascular endothelial growth factor drugs in neovascular eye diseases / 中华实验眼科杂志

Retinal neovascularization,a common pathological process of a variety of eye diseases,is a major cause of blindness.Vascular endothelial growth factor (VEGF) has been believed to be the most important therapeutic target of neovascular eye diseases.In the era of anti-VEGF for retinal diseases,several drugs aiming at the single molecular target VEGF-A have achieved considerable success in decreasing neovascularization and relieving the symptoms.In the past two years,novel anti-VEGF drugs aiming at multiple molecular targets including VEGF-A,VEGF-B and PlGF have surged into clinic service.Represented by aflibercept (VEGF Trap-Eye,Eylea) and conbercept (KH902),multiple targets anti-VEGF drugs relieve the clinical symptoms in patients resistant to single target anti-VEGF drugs.In addition,because similar curative effects are achieved with longer injection interval,risk of complications related to the intraocular injection procedure is reduced.However,it is reported that the additional inhibited targets are associated with maintaining the normal functions of blood vessels and neurons.Therefore,although there are still no severe adverse effects for these new developed drugs,further long-term observation is mandatory to evaluate their safety.In this review,we summarized the characteristics of aflibercept and conbercept,a new generation of anti-VEGF drugs,from the aspects of basic research,pharmacokinetics,efficacy,safety and the existing problems.