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Anwendungsgebiete

Nitisinone capsules are indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine. Nitisinone capsules are a hydroxy-phenylpyruvate dioxygenase inhibitor indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

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Warnhinweise und Vorsichtsmaßnahmen

Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques : Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine, which at levels above 500 micromol/L can result in symptoms, intellectual disability and developmental delay or painful hyperkeratotic plaques on the soles and palms; do not adjust nitisinone capsules dosage in order to lower the plasma tyrosine concentration.

Obtain slit-lamp examination prior to treatment, regularly during treatment; 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 )

5.1Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques

Nitisinone is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway [see Clinical Pharmacology ( 12.1 )] . Therefore, treatment with nitisinone capsules may cause an increase in plasma tyrosine levels in patients with HT-1. Maintain concomitant reduction in dietary tyrosine and phenylalanine while on nitisinone capsules treatment. Do not adjust nitisinone capsules dosage in order to lower the plasma tyrosine concentration.

Anwendungsgebiete

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Warnhinweise und Vorsichtsmaßnahmen

5.1Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques

Nebenwirkungen

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 Analog Pharma Inc. at 1-844-884-5505 or medicalinfo@analogpharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 clinical practice. 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 nitisinone 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 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.

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% *reported in at least 1% of patients 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.

Packung	Code	Status
NITISINONE 10MG	ANDA216201-003	Prescription
NITISINONE 2MG	ANDA216201-001	Prescription
NITISINONE 20MG	ANDA216201-004	Prescription
NITISINONE 5MG	ANDA216201-002	Prescription
NITISINONE 10MG	ANDA215908-003	Discontinued
NITISINONE 2MG	ANDA215908-001	Discontinued
NITISINONE 20MG	ANDA215908-004	Discontinued
NITISINONE 5MG	ANDA215908-002	Discontinued
NITISINONE 5MG	ANDA211041-002	Prescription
NITISINONE 10MG	ANDA211041-003	Prescription
NITISINONE 2MG	ANDA211041-001	Prescription
NITISINONE 2MG	ANDA212390-001	Prescription
NITISINONE 20MG	ANDA212390-004	Prescription
NITISINONE 5MG	ANDA212390-002	Prescription
NITISINONE 10MG	ANDA212390-003	Prescription

Nitisinone

Anwendungsgebiete

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Warnhinweise und Vorsichtsmaßnahmen

5.1Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques

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Nitisinone

Anwendungsgebiete

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Warnhinweise und Vorsichtsmaßnahmen

5.1Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques

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5.2Leukopenia and Severe Thrombocytopenia

Wechselwirkungen

Schwangerschaft und Stillzeit

8.1Pregnancy Risk Summary

Nebenwirkungen

6.1Clinical Trials Experience

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