Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Orfadin (Orphan)
2 mg, 5 mg and 10 mg capsules
Approved indication: hereditary tyrosinaemia type 1

Tyrosine is one of the amino acids involved in the synthesis of molecules such as dopamine and noradrenaline. The metabolic pathway for tyrosine includes the enzyme fumarylacetoacetase. In hereditary tyrosinaemia there is a deficiency of this enzyme leading to accumulation of its substrates. This causes liver failure, renal tubular dysfunction and neurological crises. In the acute form of the disease death usually occurs before the child is one year old. Children with chronic forms of the disease are at risk of liver cancer. They need to have a diet with a restricted tyrosine intake.

Nitisinone blocks an earlier step in the metabolism of tyrosine. By competitively inhibiting the enzyme hydroxyphenylpyruvate dioxygenase it is thought to reduce the production of the toxic substrates of fumarylacetoacetase.

As hereditary tyrosinaemia type 1 is a rare disease, one of the early studies of nitisinone only included five children. During 7-9 months of treatment plasma and urinary markers of the toxic metabolites declined and liver function improved.1

The approval of nitisinone was based on an international, uncontrolled study of 207 children. They were treated for a median duration of 22 months. The biochemical markers improved and there was some evidence of improved survival. The four-year survival was 93%, but only 35 patients were included in that analysis. (Death or liver transplantation resulted in the withdrawal of 37 patients.) Compared to the treatment of historical controls with diet alone, the probability of surviving for four years increased from 29-60% to 88-94%. The occurrence of liver cancer was reduced, particularly in children who began treatment before their first birthday. Starting treatment before six months of age appears to reduce the need for liver transplantation.

As nitisinone blocks the metabolism of tyrosine, the plasma tyrosine concentration will increase. The patient therefore still needs to follow a diet deficient in tyrosine. High concentrations of tyrosine can have toxic effects on the eyes, skin and nervous system.

Nitisinone was originally developed as a herbicide, but development stopped when animal studies found it had ocular adverse effects. Ophthalmological assessment is needed before treatment and if ocular symptoms develop.

Patients need regular blood counts because leucopenia and thrombocytopenia can occur. These abnormalities may be transient but may require a reduced dose of nitisinone.

The pharmacokinetics of nitisinone have not been studied in detail. There are also no drug interaction studies.

Although it may be a lifelong treatment, much remains unknown about nitisinone. While it improves survival, it may not ameliorate the complications of the disease.2 At present, the benefits of nitisinone with a low tyrosine diet do appear to outweigh the harms in treating hereditary tyrosinaemia type 1.

Read about The Transparency Score manufacturer provided additional useful information

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Notes on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (


  1. Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 1992;340:813-17.
  2. Masurel-Paulet A, Poggi-Bach J, Rolland MO, Bernard O, Guffon N, Dobbelaere D, et al. NTBC treatment in tyrosinaemia type I: long-term outcome in French patients. J Inherit Metab Dis 2008;31:81-7.