Nitisinone (Orfadin)

  Manufacturer: Rare Disease Therapeutics

  Drug class: Enzyme inhibitor

  Indication: Adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1

  Dose: 

• Dose should be adjusted for each patient
• Recommended initial dose is 1mg/kg/day divided for morning and evening administration, with increases up to 2 mg/kg/day as clinically indicated
• Total dose may be split unevenly as convenient to limit the total number of capsules given at each administration

Nitisinone (Orfadin - Rare Disease Therapeutics) has been approved to treat hereditary tyrosinemia type 1 (HT-1), a rare pediatric disease that causes progressive liver failure and liver cancer in young children. Untreated, HT-1 is usually fatal in the first year of life. For children treated early enough with nitisinone and a diet restricted in tyrosine and phenylalanine, rates of liver failure and liver cancer are reduced.

HT-1 is caused by a recessively inherited error in the final step of tyrosine metabolism. Present at birth, the disease manifests within weeks or months as the infant fails to thrive.

Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine, nitisinone prevents the accumulation of the catabolic intermediates that in patients with HT-1 are converted to toxic metabolites.

Before the approval of nitisinone, the only treatment for HT-1 was a special low-protein diet that reduced tyrosine intake and thereby curbed the release of toxic breakdown products. According to Robert J. Kuhn, PharmD, professor of pharmacy and clinical specialist at the University of Kentucky Children's Hospital, "Nitisinone is really an extremely valuable drug to have. For children with inborn errors in metabolism, dietary manipulation can only get you so far."

During the clinical trial, the most frequent adverse effects occurred in the following organ systems:

• Liver and biliary system: hepatic neoplasm (8%), liver failure (7%)
• Visual system: conjunctivitis (2%), corneal opacity (2%), keratitis (2%).
• Hematologic system: thrombocytopenia (3%), leukopenia (3%).
• Skin and appendages: pruritus (1%), exfoliative dermatitis (1%).

Diet and dosage

The dose of nitisinone must be adjusted for each patient. The recommended starting dose is 1 mg/kg/day in divided morning and evening doses. Treatment should lead to normalized porphyrin metabolism.

A nutritionist skilled in managing children with inborn metabolic errors should design a low-protein diet deficient in tyrosine and phenylalanine. "It's going to be an essential drug. If you can make the diagnosis early enough, the results from this medication are just unbelievable," said Kuhn.

-Amy K. Erickson