Nitisinone MDK (Previously Nitisinone MendeliKABS)

Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of HT-1 patients. Posology 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). 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). Special populations There are no specific dose recommendations for elderly or patients that have renal or hepatic impairment.

Paediatric population 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.

Method of administration Oral use. Medicinal product no longer authorised 4 Other pharmaceutical forms are available for paediatric patients who have difficulties swallowing capsules. 5.

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.

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 a clinical trial and post-marketing use.

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). Medicinal product no longer authorised 6 MedDRA system organ class Frequency Adverse reaction Blood and lymphatic system disorders Common Thrombocytopenia, leucopenia, granulocytopenia Uncommon Leukocytosis Eye disorders Common Conjunctivitis, corneal opacity, keratitis, photophobia, eye pain Uncommon Blepharitis Skin and subcutaneous tissue disorders Uncommon Exfoliative dermatitis, erythematous rash, pruritus Investigations Very common Elevated tyrosine levels Description of selected adverse reactions Nitisinone treatment leads to elevated tyrosine levels.

g. corneal opacities and hyperkeratotic lesions. 4). 5x109/L) and not associated with infections. Adverse reactions within the MedDRA system organ class ‘Blood and lymphatic system disorders’ subsided during continued nitisinone treatment.

Paediatric population The safety profile is mainly based on the paediatric population since nitisinone treatment should be started as soon as the diagnosis of 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.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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. 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.

Liver monitoring 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, as a few cases of reversible thrombocytopenia and leucopenia were observed during clinical evaluation.

Concomitant use with other medicinal products Nitisinone is a moderate CYP2C9 inhibitor. Nitisinone treatment may therefore result in increased plasma concentrations of co-administered medicinal products metabolised primarily via CYP2C9.

Nitisinone treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, such as warfarin and phenytoin, should be carefully monitored. 5).

1. 3).