Nitisinone
Sources réglementaires consultées
Indications approuvées
- Traitement des patients adultes et pédiatriques atteints de tyrosinémie héréditaire de type 1, associé à un régime restreint en tyrosine et en phénylalanine.
- Traitement des patients adultes atteints d'alcaptonurie.
Contre-indications
Absolues
- Hypersensibilité à la substance active ou à l'un des excipients ; l'allaitement ne doit pas avoir lieu pendant le traitement.
Mises en garde cliniques
- Mise en garde majeure · Maintenir la restriction en tyrosine et en phénylalanine ; si la tyrosine plasmatique dépasse 500 micromol/L, renforcer le régime et ne pas réduire ni arrêter la nitisinone dans le seul but de la diminuer. — AEMPS CIMA, Orfadin, ficha técnica 04303003, sección 4.4
- Mise en garde majeure · Réaliser un examen ophtalmologique à la lampe à fente avant le début puis régulièrement ; évaluer rapidement les symptômes visuels ou une tyrosine plasmatique élevée. — AEMPS CIMA, Orfadin, ficha técnica 04303003, sección 4.4
- Mise en garde majeure · Surveiller la succinylacétone urinaire, la fonction hépatique et l'alpha-foetoprotéine pendant le traitement de la tyrosinémie héréditaire de type 1. — AEMPS CIMA, Orfadin, ficha técnica 04303003, secciones 4.2 y 4.4
Interactions médicamenteuses
- ModéréeTolbutamide et autres substrats principaux du CYP2C9
Mécanisme: La nitisinone est un inhibiteur modéré du CYP2C9 et a augmenté de 2,3 fois l'AUC du tolbutamide dans l'étude citée dans l'information produit.
Recommandation: Examiner les médicaments principalement métabolisés par le CYP2C9 et envisager un ajustement ou une surveillance selon leur information produit.
https://cima.aemps.es/cima/dochtml/ft/04303003/FT_04303003.html
- ModéréeInhibiteurs et inducteurs du CYP3A4
Mécanisme: La nitisinone est métabolisée in vitro par le CYP3A4 ; les inhibiteurs ou inducteurs de cette enzyme peuvent modifier son exposition.
Recommandation: Examiner les médicaments concomitants qui inhibent ou induisent le CYP3A4 et envisager un ajustement de la dose de nitisinone conformément à l'information produit.
https://cima.aemps.es/cima/dochtml/ft/04303003/FT_04303003.html
Effets indésirables
Communs (≥1%)
Conjonctivite · Opacité cornéenne · Kératite · Photophobie · Douleur oculaire
Rares mais graves
Leucopénie · Thrombopénie · Granulocytopénie
Grossesse et allaitement
Il ne doit pas être utilisé pendant la grossesse sauf si la situation clinique nécessite la nitisinone. L'allaitement ne doit pas avoir lieu pendant le traitement.
Bibliographie récente (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.