Drug Description
White, opaque capsules marked “NTBC 5mg” on one side of the capsule.
Presentation
Hard capsules
Indications
Treatment of patients with confirmed diagnosis of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.
Adult Dosage
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. Adjunct to the nitisinone treatment, a diet deficient in phenylalanine and tyrosine is required and should be followed by monitoring of plasma amino acids.
The dose of nitisinone should be adjusted individually.
The recommended initial dose is 1 mg/kg body weight/day divided in 2 doses administered orally. The capsule may be opened and the content suspended in a small amount of water or formula diet immediately before intake.
Dose adjustment
During regular monitoring, it is appropriate to follow urine succinylacetone, liver function test values and alpha-fetoprotein levels (see section 4.4). If urine succinylacetone is still detectable one month after the start of nitisinone treatment, the nitisinone dose should be increased to 1.5 mg/kg body weight/day divided in 2 doses. A dose of 2 mg/kg body weight/day may be needed based on the eva luation 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.
However, in addition to the tests above, during the initiation of therapy or if there is a deterioration it may be necessary to follow more closely all available biochemical parameters (i.e. plasma succinylacetone, urine 5-aminolevulinate (ALA) and erythrocyte porphobilinogen (PBG)-synthase activity).
Contra Indications
Hypersensitivity to the active substance or to any of the excipients.
Mothers receiving nitisinone should not breast-feed.
Special Precautions
Dietary restriction in relation to visual disorders
It is recommended that a slit-lamp examination of the eyes is performed before initiation of nitisinone treatment. 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 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 also to monitor serum alpha-fetoprotein concentration. 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 eva luated for hepatic malignancy.
Platelet and white blood cell (WBC) monitoring
It is recommended that platelet and white cell counts are monitored regularly, as a few cases of reversible trombocytopenia and leucopenia were observed during clinical eva luation.
Monitoring visits should be performed every 6 months; shorter intervals between visits are recommended in case of adverse events.
Interactions
No formal interaction studies with other medicinal products have been conducted.
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 in vitro studies, nitisinone is not expected to inhibit CYP 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4-mediated metabolism.
No formal food interactions studies have been performed. However, nitisinone has been co-administered with food during the generation of efficacy and safety data. Therefore, it is recommended that if nitisinone treatment is initiated with food, this should be maintained on a routine basis.
Adverse Reactions
The adverse reactions considered at least possibly related to treatment are listed below, by body system organ class, and absolute frequency. Frequencies are defined as common (1/100, <1/10) or uncommon (1/1,000, <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders
Common: thrombocytopenia, leucopenia, granulocytopenia
Uncommon: leucocytosis
Eye disorders
Common: conjunctivitis, corneal opacity, keratitis, photophobia, eye pain
Uncommon: blepharitis
Skin and subcutaneous tissue disorders
Uncommon: exfoliative dermatitis, erythematous rash, pruritus
Nitisinone treatment is associated with elevated tyrosine levels. Elevated levels of tyrosine have been associated with corneal opacities and hyperkeratotic lesions. Restriction of tyrosine and phenylalanine in the diet should limit the toxicity associated with this type of tyrosinemia.
Owner
Swedish Orphan International
Drug Availability
POM
Updated
19 March 2009
