Nitisinone
Regulatory sources consulted
Approved indications
- Treatment of adult and paediatric patients with hereditary tyrosinaemia type 1, together with a tyrosine- and phenylalanine-restricted diet.
- Treatment of adult patients with alkaptonuria.
Contraindications
Absolute
- Hypersensitivity to the active substance or any excipient; breastfeeding must not occur during treatment.
Clinical warnings
- Major warning · Maintain tyrosine and phenylalanine restriction; if plasma tyrosine exceeds 500 micromol/L, intensify the diet and do not reduce or stop nitisinone solely to lower it. — AEMPS CIMA, Orfadin, ficha técnica 04303003, sección 4.4
- Major warning · Perform slit-lamp eye examination before starting and regularly thereafter; promptly assess visual symptoms or elevated plasma tyrosine. — AEMPS CIMA, Orfadin, ficha técnica 04303003, sección 4.4
- Major warning · Monitor urinary succinylacetone, liver function and alpha-fetoprotein during treatment of hereditary tyrosinaemia type 1. — AEMPS CIMA, Orfadin, ficha técnica 04303003, secciones 4.2 y 4.4
Drug interactions
- ModerateTolbutamide and other predominant CYP2C9 substrates
Mechanism: Nitisinone is a moderate CYP2C9 inhibitor and increased tolbutamide AUC 2.3-fold in the study cited in the product information.
Recommendation: Review medicines mainly metabolised by CYP2C9 and consider adjustment or monitoring according to their product information.
https://cima.aemps.es/cima/dochtml/ft/04303003/FT_04303003.html
- ModerateCYP3A4 inhibitors and inducers
Mechanism: Nitisinone is metabolised in vitro by CYP3A4; inhibitors or inducers of this enzyme may alter its exposure.
Recommendation: Review concomitant medicines that inhibit or induce CYP3A4 and consider a nitisinone dose adjustment according to the product information.
https://cima.aemps.es/cima/dochtml/ft/04303003/FT_04303003.html
Adverse events
Common (≥1%)
Conjunctivitis · Corneal opacity · Keratitis · Photophobia · Eye pain
Rare but serious
Leukopenia · Thrombocytopenia · Granulocytopenia
Pregnancy and lactation
It should not be used during pregnancy unless the clinical condition requires nitisinone. Breastfeeding must not occur during treatment.
Recent literature (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.