Nitisinone
Fuentes regulatorias consultadas
Indicaciones aprobadas
- Tratamiento de pacientes adultos y pediátricos con tirosinemia hereditaria tipo 1, junto con una dieta restrictiva de tirosina y fenilalanina.
- Tratamiento de pacientes adultos con alcaptonuria.
Contraindicaciones
Absolutas
- Hipersensibilidad al principio activo o a alguno de los excipientes; no amamantar durante el tratamiento.
Advertencias clínicas
- Advertencia mayor · Mantener la restricción de tirosina y fenilalanina; si la tirosina plasmática supera 500 micromol/L, intensificar la dieta y no reducir ni suspender la nitisinona solo para disminuirla. — AEMPS CIMA, Orfadin, ficha técnica 04303003, sección 4.4
- Advertencia mayor · Realizar exploración oftalmológica con lámpara de hendidura antes de iniciar y después regularmente; valorar de inmediato síntomas visuales o tirosina plasmática elevada. — AEMPS CIMA, Orfadin, ficha técnica 04303003, sección 4.4
- Advertencia mayor · Monitorizar succinilacetona urinaria, función hepática y alfa-fetoproteína durante el tratamiento de la tirosinemia hereditaria tipo 1. — AEMPS CIMA, Orfadin, ficha técnica 04303003, secciones 4.2 y 4.4
Interacciones medicamentosas
- ModeradaTolbutamida y otros sustratos predominantes de CYP2C9
Mecanismo: La nitisinona es un inhibidor moderado de CYP2C9 y aumentó 2,3 veces el AUC de tolbutamida en el estudio citado en la ficha técnica.
Recomendación: Revisar los medicamentos metabolizados principalmente por CYP2C9 y valorar ajuste o monitorización según su ficha técnica.
https://cima.aemps.es/cima/dochtml/ft/04303003/FT_04303003.html
- ModeradaInhibidores e inductores de CYP3A4
Mecanismo: La nitisinona se metaboliza in vitro por CYP3A4; los inhibidores o inductores de esta enzima pueden modificar su exposición.
Recomendación: Revisar la medicación concomitante que inhiba o induzca CYP3A4 y valorar un ajuste de la dosis de nitisinona conforme a la ficha técnica.
https://cima.aemps.es/cima/dochtml/ft/04303003/FT_04303003.html
Eventos adversos
Comunes (≥1%)
Conjuntivitis · Opacidad corneal · Queratitis · Fotofobia · Dolor ocular
Raros pero graves
Leucopenia · Trombocitopenia · Granulocitopenia
Embarazo y lactancia
No debe utilizarse durante el embarazo salvo que la situación clínica requiera nitisinona. No se debe amamantar durante el tratamiento.
Bibliografía reciente (PubMed)
Alkaptonuria (AKU) is an ultra-rare inherited inborn error of metabolism that afflicts the tyrosine metabolic pathway, resulting in the accumulation of homogentisic acid (HGA) in the circulation, and significant excretion in urine. Clinical manifestations, typically observed from the third decade of life, are lifelong and significantly affect the quality of life. This review provides a comprehensive overview of the natural history of AKU, including clinical, biochemical and genetic perspectives. An update on the major advances on studies in murine models and human subjects, providing mechanistic insight into the molecular and biochemical processes that underlie pathophysiology and its response to treatment are presented. The impact of treatment with nitisinone is also presented with a specific emphasis on hypertyrosinemia, as uncertainty on this topic remains. Future perspectives are explored, such as novel approaches to treat hypertyrosinemia including the use of binding agents and amino acid transporter inhibitors, as well as advanced potentially curative gene and cell therapy initiatives.
Alkaptonuria is a rare inherited disorder for which there was no disease-modifying treatment. In order to develop a successful approved therapy of AKU multiple barriers had to be overcome. These included activities before the conduct of the study including deciding on the drug therapy, the dose of the drug to be used, clarify the nature of the disease, develop outcome measures likely to yield a positive outcome, have a strategy to ensure appropriate patient participation through identification, build a consortium of investigators, obtain regulatory approval for proposed investigation plan and secure funding. Significant barriers were overcome during the conduct of the multicentre study to ensure harmonisation. Mechanisms were put in place to recruit and retain patients in the study. Barriers to patient access following completion of the study and regulatory approval were resolved.
Alkaptonuria is an extremely rare disorder of tyrosine metabolism caused by an autosomal recessive enzymatic deficiency of homogentisic acid (HGA) oxidase, causing its accumulation in collagenous structures, especially in hyaline cartilage. It is characterized by a triad of homogentisic aciduria, bluish-black discoloration of connective tissues (ochronosis) and arthropathy of the spine and large weight-bearing joints. Several clinical manifestations were described including coronary and valvular calcification, aortic stenosis, limited chest expansion, and renal, urethral and prostate calculi as well as ocular and cutaneous pigmentation. Skeletal affection usually presents as spondylotic changes of the spine. The knee is the most common peripheral joint to be involved. Enthesopathy or tendon ruptures may occur, and reduced bone density is not unusual. A low-protein diet and ascorbic acid may reduce HGA levels. Nitisinone can safely and effectively reduce HGA production and urinary excretion. In severe ochronotic arthropathy, joint arthroplasty can offer reliable pain relief and excellent functional outcomes. Cementless fixation is successful in young patients.