Nitisinone

Nitisinone is a weak inducer of CYP2E1 (30% decrease in chlorzoxazone AUC) and a weak inhibitor of OAT1 and OAT3 (1.7-fold increase in AUC of furosemide).

Based on data from a clinical interaction study with 80 mg nitisinone at steady-state, nitisinone is a moderate inhibitor of CYP2C9 (2.3-fold increase in tolbutamide AUC), therefore nitisinone treatment may result in increased plasma concentrations of co-administered medicinal products metabolized primarily via CYP2C9. Nitisinone treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolized through CYP2C9, such as warfarin and phenytoin, should be carefully monitored. Dose-adjustment of these co-administered medicinal products may be needed.

Nitisinone is metabolised in vitro by CYP3A4 and dose-adjustment may therefore be needed when nitisinone is co-administered with inhibitors or inducers of this enzyme.

There are no adequate data from the use of nitisinone in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Nitisinone should not be used during pregnancy unless the clinical condition of the woman requires treatment with nitisinone. Nitisinone crosses the human placenta.

It is unknown whether nitisinone is excreted in human breast milk. Animal studies have shown adverse postnatal effects via exposure of nitisinone in milk. Therefore, mothers receiving nitisinone must not breast-feed, since a risk to the suckling child cannot be excluded.

Fertility

There are no data on nitisinone affecting fertility.

Nitisinone has minor influence on the ability to drive and use machines. Adverse reactions involving the eyes can affect the vision. If the vision is affected the patient should not drive or use machines until the event has subsided.

Summary of the safety profile

By its mode of action, nitisinone increases tyrosine levels in all nitisinone treated patients. Eye-related adverse reactions, such as conjunctivitis, corneal opacity, keratitis, photophobia, and eye pain, related to elevated tyrosine levels are therefore common in both HT-1 and AKU patients. In the HT-1 population other common adverse reactions include thrombocytopenia, leucopenia, and granulocytopenia. Exfoliative dermatitis may occur uncommonly.

Tabulated list of adverse reactions

The adverse reactions listed below by MedDRA system organ class and absolute frequency, are based on data from clinical studies in patients with HT-1 and AKU and post-marketing use in HT-1. Frequency is defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Summary of adverse reactions observed during clinical trials:

¹ The frequency is based on one clinical study in AKU.
² Elevated tyrosine levels are associated with eye-related adverse reaction. Patients in the AKU study did not have a diet restricted in tyrosine and phenylalanine.

Description of selected adverse reactions

Nitisinone treatment leads to elevated tyrosine levels. Elevated levels of tyrosine have been associated with eye-related adverse reactions, such as e.g. corneal opacities and hyperkeratotic lesions in HT-1 and AKU patients. Restriction of tyrosine and phenylalanine in the diet should limit the toxicity associated with this type of tyrosinemia by lowering tyrosine levels. In clinical studies of HT-1, granulocytopenia was only uncommonly severe (<0.5 x 10⁹/L) and not associated with infections. Adverse reactions affecting the MedDRA system organ class 'Blood and lymphatic system disorders' subsided during continued nitisinone treatment.

Paediatric population

The safety profile in HT-1 is mainly based on the paediatric population since nitisinone treatment should be started as soon as the diagnosis of hereditary tyrosinemia type 1 (HT-1) has been established. From clinical study and post marketing data there are no indications that the safety profile is different in different subsets of the paediatric population or different from the safety profile in adult patients.