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Cover of Clinical Review Report: Nitisinone (Nitisinone Tablets)

Clinical Review Report: Nitisinone (Nitisinone Tablets)

(Cycle Pharmaceuticals Ltd.)

Indication: For the treatment of patients with hereditary tyrosinemia type 1 in combination with dietary restriction of tyrosine and phenylalanine

CADTH Common Drug Review

Hereditary tyrosinemia type 1 (HT-1) is a rare, autosomal recessive disorder of amino acid metabolism. The deficiency of fumarylacetoacetate hydrolase (FAH), which is the last enzyme in the pathway of tyrosine catabolism, results in the accumulation of toxic metabolites in the FAH-deficient hepatocytes and proximal renal tubular cells and subsequently leads to liver and kidney damage. HT-1 typically manifests in infancy and is characterized by elevated plasma tyrosine levels. For children with HT-1 whose disease is not detected by the newborn screening, liver dysfunction (such as bleeding abnormalities, hypoglycemia, ascites, edema, vomiting, irritability, and jaundice) is the dominant clinical manifestation. Progression of the liver disease can be chronic or acute, with rapid deterioration. Without treatment, the lifetime risk of developing hepatocellular carcinoma (HCC) is as high as 37% in the survivors, according to previous research. Many patients also suffer from neurocognitive deficits. If untreated, the survival in patients with HT-1 is less than 12 months; most of these children die as a result of liver failure and severe coagulopathy. The prevalence of HT-1 ranges from 1 in 12,000 to 1 in 100,000 individuals of Northern European descent. In Canada, higher prevalence (1 in 1,846 live births) was observed in the Saguenay–Lac-Saint-Jean region in Quebec.

Nitisinone (Nitisinone Tablets) is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme upstream of FAH in the tyrosine catabolic pathway. It prevents the accumulation of the catabolic intermediates, which can be converted to the toxic metabolites, succinylacetone (SA) and succinylacetoacetate. The effect of nitisinone on inhibiting catabolism of tyrosine also leads to an increase in plasma tyrosine levels. Therefore, treatment with nitisinone requires restriction of the dietary intake of tyrosine and phenylalanine to prevent tyrosine toxicity.

Nitisinone Tablets received Health Canada approval based on the clinical studies for the reference product (Orfadin), which are the studies included subsequently in this review and which are based on data demonstrating bioequivalence with Orfadin (Appendix 5: Bioequivalence Study).

Version: Final

Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.

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Bookshelf ID: NBK539976PMID: 30973686


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