General Information

Orfadin (nitisinone) is a hydroxy-phenylpyruvate dioxygenase inhibitor. 

Orfadin is specifically indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

Orfadin is supplied as capsules and an oral solution. The recommended starting dosage is 0.5 mg/kg orally twice daily.

In patients 5 years of age and older who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone, the total daily dose may be given once daily.

Titrate the dosage based on biochemical and/or clinical response, as described in the full prescribing information.

The maximum total daily dosage is 2 mg/kg orally.

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. 

Side Effects

Adverse effects associated with the use of Orfadin may include, but are not limited to, the following:

• elevated tyrosine levels
• thrombocytopenia
• leukopenia
• conjunctivitis
• corneal opacity
• keratitis
• photophobia
• eye pain
• blepharitis
• cataracts
• granulocytopenia
• epistaxis
• pruritus
• exfoliative dermatitis
• dry skin
• maculopapular rash
• alopecia

Clinical Trial Results

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%.