warnings and cautions
5 WARNINGS AND PRECAUTIONS Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques Due To Elevated Plasma Tyrosine Levels: Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine and levels above 500 micromol/L may lead to ocular signs and symptoms, intellectual disability and developmental delay, or painful hyperkeratotic plaques on the soles and palms. ( 5.1 ) Do not adjust NITYR dosage in order to lower the plasma tyrosine concentration. ( 5.1 ) Obtain slit-lamp examination prior to treatment and regularly thereafter. Reexamine patients if symptoms develop or tyrosine levels are > 500 micromol/L. Assess plasma tyrosine levels in patients with an abrupt change in neurologic status. ( 5.1 ) Leukopenia and Severe Thrombocytopenia: Monitor platelet and white blood cell counts. ( 5.2 ) 5.1 Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques Due To Elevated Plasma Tyrosine Levels Treatment with NITYR may cause elevated plasma tyrosine levels in patients with HT-1. Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine levels and levels greater than 500 micromol/L may lead to the following: Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia. All of which have been reported in patients treated with nitisinone [see Adverse Reactions ( 6.1 )] . In a clinical study in a non HT-1 population without dietary restriction and reported tyrosine levels > 500 micromol/L both symptomatic and asymptomatic keratopathies have been observed. Therefore, perform a baseline ophthalmologic examination including slit-lamp examination prior to initiating NITYR treatment and regularly thereafter. Patients who develop photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning of the eyes or tyrosine levels are > 500 micromol/L during treatment with NITYR should undergo slit-lamp reexamination and immediate measurement of the plasma tyrosine concentration. Variable degrees of intellectual disability and developmental delay. In patients treated with NITYR who exhibit an abrupt change in neurologic status, perform a clinical laboratory assessment including plasma tyrosine levels. Painful hyperkeratotic plaques on the soles and palms. Maintain concomitant reduction in dietary tyrosine and phenylalanine while on NITYR treatment. In patients with HT-1 who are treated with NITYR and dietary restriction and develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake. Do not adjust NITYR dosage in order to lower the plasma tyrosine concentration. Maintain plasma tyrosine levels below 500 micromol/L. 5.2 Leukopenia and Severe Thrombocytopenia In clinical trials, patients treated with another oral formulation of nitisinone and dietary restriction developed reversible leukopenia (3%), thrombocytopenia (3%), or both (1.5%) [see Adverse Reactions ( 6.1 )] . No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Monitor platelet and white blood cell counts during NITYR therapy.