NITYR

6 ADVERSE REACTIONS Most common adverse reactions (>1%) are elevated tyrosine levels, thrombocytopenia, leukopenia, conjunctivitis, corneal opacity, keratitis, photophobia, eye pain, blepharitis, cataracts, granulocytopenia, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash and alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cycle Pharmaceuticals Ltd. at 1-855-831-5413 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Serious and or clinically significant adverse reactions described elsewhere in labeling include: Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques Due To Elevated Plasma Tyrosine Levels [see Warnings and Precautions ( 5.1 )] Leukopenia and Severe Thrombocytopenia [see Warnings and Precautions ( 5.2 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of NITYR has been established based on studies of another oral formulation of nitisinone in patients with HT-1 [see Clinical Studies ( 14 )] . Below is a display of the adverse reactions of nitisinone in these studies. Nitisinone was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of nitisinone was 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, biochemical, and enzyme markers. The recommended starting dosage of NITYR is 0.5 mg/kg twice daily [see Dosage and Administration ( 2.1 ) ]. Median duration of treatment was 22 months (range 0.1 to 80 months). The most serious adverse reactions reported during nitisinone treatment were thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels [see Warnings and Precautions ( 5.1 , 5.2 )] . Fourteen patients experienced ocular/visual events. The duration of the symptoms varied from 5 days to 2 years. Six patients had thrombocytopenia, three of which had platelet counts 30,000/microL or lower. In 4 patients with thrombocytopenia, platelet counts gradually returned to normal (duration up to 47 days) without change in the nitisinone dose. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Patients with HT-1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure requiring liver transplantation. These complications of HT-1 were observed in patients treated with nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 1%). The most common adverse reactions reported in the clinical trial are summarized in TABLE 1. *reported in at least 1% of patients; ** another oral formulation of nitisinone TABLE 1 Most Common Adverse Reactions * in Patients with HT-1 Treated with Nitisinone ** Elevated tyrosine levels >10% Leukopenia 3% Thrombocytopenia 3% Conjunctivitis 2% Corneal Opacity 2% Keratitis 2% Photophobia 2% Eye Pain 1% Blepharitis 1% Cataracts 1% Granulocytopenia 1% Epistaxis 1% Pruritus 1% Exfoliative Dermatitis 1% Dry Skin 1% Maculopapular Rash 1% Alopecia 1% Adverse reactions reported in less than 1% of the patients, included death, seizure, brain tumor, encephalopathy, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastrointestinal hemorrhage, melena, elevated hepatic enzymes, liver enlargement, hypoglycemia, septicemia, and bronchitis.