ORFADIN

What it is

ORFADIN (nitisinone) is indicated for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine. The biochemical defect in hereditary tyrosinaemia type 1 is a deficiency of fumarylacetoacetate hydrolase, which is the final enzyme of the tyrosine catabolic pathway. Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme which precedes fumarylacetoacetate hydrolase in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate. ORFADIN is available as capsules containing 2 mg, 5 mg, 10 mg or 20 mg nitisinone, and as an oral suspension containing 4 mg of nitisinone per mL.

Approved indications

— Hereditary tyrosinaemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

Dosing overview

The recommended initial dose is 1 mg/kg body weight per day divided in 2 doses administered orally. If urine succinylacetone is still detectable one month after the start of ORFADIN treatment, the ORFADIN dose should be increased to 1.5 mg/kg body weight per day divided in 2 doses. A dose of 2 mg/kg body weight per day may be needed based on the evaluation of all biochemical parameters. This dose should be considered as a maximal dose for all patients. In patients who weigh 20 kg or more, and who have undetectable plasma and urine succinylacetone concentrations after a minimum of 4 weeks on a stable twice a day dosage of ORFADIN, the total daily dose of ORFADIN may be given once daily (1 to 2 mg/kg once daily). ORFADIN capsules and oral suspension should be administered with food.

Key safety warnings

There is a predictable increase in plasma tyrosine concentrations if nitisinone is administered without a diet restricted in tyrosine and phenylalanine content. Inadequate restriction of tyrosine and phenylalanine intake can result in elevations in plasma tyrosine. Plasma tyrosine levels should be kept below 500 micromole per litre in order to avoid toxic effects to the eyes (corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia), skin (painful hyperkeratotic plaques on the soles and palms) and nervous system (variable degrees of mental retardation and developmental delay). The liver function should be monitored regularly by liver function tests and liver imaging. It is recommended also to monitor serum alpha-fetoprotein concentration. Patients with HT-1 are at increased risk of developing porphyric crises, hepatic neoplasm, and liver failure requiring liver transplantation. Regular monitoring of these complications by hepatic imaging (ultrasound, computerised tomography, and magnetic resonance imaging) and laboratory tests, including serum alpha-fetoprotein concentration is recommended. It is recommended that platelet and white blood cell counts are monitored regularly, as a few cases of reversible thrombocytopenia and leucopenia were observed during clinical evaluation. It is recommended that a slit-lamp examination of the eyes is performed before initiation of nitisinone treatment, and thereafter regularly. Nitisinone is a moderate CYP2C9 inhibitor. Nitisinone treated patients who are concomitantly treated with medicinal products primarily metabolized through CYP2C9, especially those with a narrow therapeutic window, should be monitored.

Contraindications

Hypersensitivity to the active substance or to any of the excipients. Mothers receiving nitisinone must not breast-feed.

Regulatory history

ORFADIN was first approved on 22 November 2010. The 2 mg, 5 mg and 10 mg capsule formulations were registered on the ARTG on 2010-11-22, followed by the 20 mg capsule and 4 mg/mL oral suspension formulations registered on 2019-02-26. In July 2025, the PBAC deferred consideration of ORFADIN for hereditary tyrosinaemia type 1 under the Life Saving Drugs Program, deferring the decision to allow consultation with clinical and patient groups.