Home » Drug Information » FDA Approved Drugs » 2002
Medical Areas: Gastroenterology | Pediatrics/Neonatology
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The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
Company: Orphan Pharmaceuticals
Approval Status: Approved January 2002
Treatment Area: Hereditary tyrosinemia type I
The FDA has approved Orfadin (nitisinone) capsules for the
treatment of hereditary tyrosinemia type I (HT-1), a rare pediatric
disease. HT-1 is a genetic metabolic disorder that results from an
inability to break down the amino acid tyrosine. Because of
resulting liver failure and liver cancer, children with HT-1 rarely
survive into their twenties without a liver transplant.
Orfadin was designated an Orphan Drug in May 1995 by the Office
for Orphan Product Development. Orphan products are developed to
treat rare diseases - there are less than 100 children in the
United States with HT-1.
Orfadin capsules are to be used in conjunction with a diet
restricted in tyrosine and phenylalanine.
Orfadin was evaluated in an open-label study conducted at 87
hospitals in 25 countries. Data was obtained from over 180 subjects
with a diagnosis of HT-1, with a median age at enrollment of nine
months. Results showed that Orfadin treatment resulted in a
four-year survival probability of 88% for children under two months
of age at the time of HT-1 diagnosis (subjects also received
dietary restrictions). In contrast, historical controls showed that
children presenting with HT-1 under two months of age who only
received dietary restrictions had a survival rate of 29%.
In clinical testing with Orfadin, transient thrombocytopenia
(decreased number of platelets) and leukopenia (decreased number of
white blood cells) were reported.
Mechanism of Action
Nitisinone is a competitive inhibitor of
4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of
fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic
pathway. By inhibiting the normal catabolism of tyrosine in
patients with HT-1, nitisinone prevents the accumulation of the
catabolic intermediates maleylacetoacetate and fumarylacetoacetate.
In patients with HT-1, these catabolic intermediates are converted
to the toxic metabolites succinylacetone and succinylacetoacetate,
which are responsible for the observed liver and kidney toxicity.
Succinylacetone can also inhibit the porphyrin synthesis pathway
leading to the accumulation of 5-aminolevulinate, a neurotoxin
responsible for the porphyric crises characteristic of HT-1. (from
Orfadin Prescribing Information)