Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: MendeliKABS Europe Limited, The Light Box, 111 Power Rd, Unit G.07, Chiswick, London, W4 5PY, United Kingdom
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Mothers receiving nitisinone must not breast-feed (see sections 4.6 and 5.3).
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.
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.
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.
Monitoring visits should be performed every 6 months; shorter intervals between visits are recommended in case of adverse events.
Nitisinone is a moderate CYP2C9 inhibitor. Nitisinone treatment may therefore 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 (see section 4.5).
Nitisinone is metabolised in vitro by CYP 3A4 and dose-adjustment may therefore be needed when nitisinone is co-administered with inhibitors or inducers of this enzyme.
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 (see section 4.4).
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), whereas nitisinone did not inhibit CYP2D6 (see section 5.2).
No formal food interactions studies have been performed with Nitisinone MDK hard capsules. However, nitisinone has been co-administered with food during the generation of efficacy and safety data. Therefore, it is recommended that if nitisinone treatment with Nitisinone MDK hard capsules is initiated with food, this should be maintained on a routine basis, see section 4.2.
There are no adequate data from the use of nitisinone in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Nitisinone MDK should not be used during pregnancy unless the clinical condition of the woman requires treatment with nitisinone.
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 (see sections 4.3 and 5.3).
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 (see section 4.8) can affect the vision. If the vision is affected the patient should not drive or use machines until the event has subsided.
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.
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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Common: Thrombocytopenia, leucopenia, granulocytopenia
Uncommon: Leukocytosis
Common: Conjunctivitis, corneal opacity, keratitis, photophobia, eye pain
Uncommon: Blepharitis
Uncommon: Exfoliative dermatitis, erythematous rash, pruritus
Very common: Elevated tyrosine levels
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. Restriction of tyrosine and phenylalanine in the diet should limit the toxicity associated with this type of tyrosinemia by lowering tyrosine levels (see section 4.4).
In clinical studies, granulocytopenia was only uncommonly severe (<0.5x109/L) and not associated with infections. Adverse reactions affecting the MedDRA system organ class ‘Blood and lymphatic system disorders’ subsided during continued nitisinone treatment.
The safety profile 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.
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.
Not applicable.
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