NITISINONE DIPHARMA

Posology HT-1:

Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of HT-1 patients. Treatment of all genotypes of the disease should be initiated as early as possible to increase overall survival and avoid complications such as liver failure, liver cancer and renal disease.

8). Starting dose HT-1 The recommended initial daily dose in the paediatric and adult population is 1 mg/kg body weight administered orally. The dose of nitisinone should be adjusted individually. It is recommended to administer the dose once daily.

However, due to the limited data in patients with body weight <20 kg, it is recommended to divide the total daily dose into two daily administrations in this patient population. 4). 5 mg/kg body weight/day. A dose of 2 mg/kg body weight/day may be needed based on the evaluation of all biochemical parameters.

This dose should be considered as a maximal dose for all patients. If the biochemical response is satisfactory, the dose should be adjusted only according to body weight gain. e. plasma succinylacetone, urine 5- aminolevulinate (ALA) and erythrocyte porphobilinogen (PBG)-synthase activity).

AKU:

Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of AKU patients. The recommended dose in the adult AKU population is 10 mg once daily. Special populations There are no specific dose recommendations for elderly or patients that have renal or hepatic impairment.

Paediatric population HT-1:

The dose recommendation in mg/kg body weight is the same in children and adults. However, due to the limited data in patients with body weight <20 kg, it is recommended to divide the total daily dose into two daily administrations in this patient population.

AKU:

The safety and efficacy of Nitisinone in children aged 0 to 18 years with AKU have not been established. No data are available. Method of administration The capsule may be opened and the content suspended in a small amount of water, apple juice, soft food, such as apple sauce, or formula diet, including amino acid modified infant formula with iron, immediately before intake.

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 trials 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.

MedDRA system Frequency in Frequency in 1 Adverse reaction Infections and infestations Common Bronchitis, pneumonia Common Thrombocytopenia, leucopenia, granulocytopenia Blood and lymphatic system disorders Uncommon Leukocytosis Common Conjunctivitis, corneal opacity, keratitis, photophobia Eye disorders Very common2 Keratopathy Common Very common2 Eye pain Uncommon Blepharitis Uncommon Exfoliative dermatitis, erythematous rash Skin and subcutaneous tissue disorders Uncommon Common Pruritus, rash Investigations Very common Very common Elevated tyrosine levels 1The frequency is based on one clinical study in AKU.

2Elevated 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.

Monitoring visits should be performed every 6 months; shorter intervals between visits are recommended in case of adverse events. Monitoring of plasma tyrosine levels It is recommended that a slit-lamp examination of the eyes is performed before initiation of nitisinone treatment and thereafter regularly, at least once a year.

A patient displaying visual disorders during treatment with nitisinone should without delay be examined by an ophthalmologist.

HT-1:

It should be established that the patient is adhering to his/her dietary regimen and the plasma tyrosine concentration should be measured. A more restricted tyrosine and phenylalanine diet should be implemented in case the plasma tyrosine level is above 500 micromol/l.

It is not recommended to lower the plasma tyrosine concentration by reduction or discontinuation of nitisinone, since the metabolic defect may result in deterioration of the patient’s clinical condition.

AKU:

In patients who develop keratopathies, plasma tyrosine levels should be monitored. A diet restricted in tyrosine and phenylalanine should be implemented to keep the plasma tyrosine level below 500 micromol/l. In addition, nitisinone should be temporarily discontinued and may be reintroduced when the symptoms have been resolved.

Liver monitoring HT-1:

The liver function should be monitored regularly by liver function tests and liver imaging. It is recommended to also monitor serum alpha-fetoprotein concentrations. Increase in serum alpha- fetoprotein concentration may be a sign of inadequate treatment.

Patients with increasing alpha- fetoprotein or signs of nodules in the liver should always be evaluated for hepatic malignancy. Platelet and white blood cell (WBC) monitoring It is recommended that platelet and WBC counts are monitored regularly for both HT-1 and AKU patients, as a few cases of reversible thrombocytopenia and leucopenia were observed during clinical evaluation of HT-1.

1. 3).