Class: Enzyme inhibitor
- Capsules, oral 2 mg
- Capsules, oral 5 mg
- Capsules, oral 10 mg
Competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine catabolic pathway. Prevents accumulation of tyrosine catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with hereditary tyrosinemia type 1, these catabolic intermediates are converted into toxic metabolites (succinylacetone and succinylacetoacetate), which are responsible for the liver and kidney toxicity observed in these patients.
Mean T max is 3 h (capsules). More than 90% bioavailable.
Mean terminal half-life is 54 h.
Indications and Usage
Adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1.
None well documented.
Dosage and AdministrationAdults and Children
PO Initial dose is 1 mg/kg/day divided for morning and evening administration. Increase dose to 1.5 mg/kg/day if biochemical parameters (except plasma succinylacetone) are not normalized within 1 mo. Increase to max dose of 2 mg/kg/day if biochemical parameters (including plasma succinylacetone) are not normalized within 3 mo.
- Administer each dose on an empty stomach at least 1 h before meals or at least 2 h after meals.
- For patients who cannot swallow capsules, capsules may be opened and the contents suspended in a small amount of water immediately before use.
Store in the refrigerator at 36° to 46°F.
None well documented.
Alopecia, dry skin, exfoliative dermatitis, maculopapular rash, pruritus (1%).
Conjunctivitis, corneal opacities, keratitis, photophobia (2%); blepharitis, cataracts, eye pain (1%).
Leukopenia, thrombocytopenia (3%); epistaxis, granulocytopenia, porphyria (1%).
Hepatic neoplasm (8%); liver failure (7%).
Regularly monitor urine succinylacetone, LFTs, alpha-fetoprotein, platelet counts and WBC, and serum tyrosine and phenylalanine levels. During initiation of therapy or acute exacerbations, more closely monitor all available biochemical parameters (eg, erythrocyte porphobilinogen synthase activity, plasma nitisinone concentration, plasma succinylacetone levels, urine 5-aminolevulinic acid levels). Perform slit-lamp examinations of the eyes before initiation of therapy and during any eye adverse reactions (eg, eye pain, photophobia, signs of inflammation).
Category C .
Cautiously make dosage selection, usually starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and renal function and comorbidity.
High plasma tyrosine levels
A nutritionist skilled in managing inborn errors of metabolism should design a low-protein diet deficient in tyrosine and phenylalanine. Inadequate restriction of tyrosine and phenylalanine intake can result in elevations of plasma tyrosine. Keep tyrosine levels below 500 mcmol/L to avoid toxic effects to the eyes (conjunctivitis, corneal ulcers or opacities, eye pain, keratitis, photophobia), skin (painful hyperkeratotic plaques on the soles and palms), and nervous system (developmental delay, mental retardation). Implement a more restricted diet if the plasma tyrosine level is above 500 mcmol/L.
Porphyric crises/Liver failure/Hepatic neoplasms
Patients with hereditary tyrosinemia type 1 are at increased risk of developing porphyric crises, liver failure, or hepatic neoplasms requiring liver transplantation. Evaluate patients with increasing alpha-fetoprotein or signs of liver nodules for hepatic malignancy.
Transient thrombocytopenia, leukopenia, or both have been reported.
Elevated tyrosine levels, 1 case of sunlight sensitivity.
- Advise patients or caregivers that medication is taken in the morning and evening.
- Advise patients or caregivers that each dose should be taken on an empty stomach at least 1 h before or at least 2 h after meals.
- Advise patients or caregivers that capsules may be opened and the contents suspended in a small amount of water immediately before use.
- Caution patients or caregivers not to change the dose or stop taking nitisinone unless advised by their health care provider.
- Emphasize to patients and/or caregivers the importance of maintaining dietary restriction of tyrosine and phenylalanine.
- Instruct patients or caregivers to immediately report any of the following to their health care provider: bleeding or unusual bruising, flu-like symptoms, itching, persistent nausea and/or vomiting, rash, unexplained eye symptoms, yellowing of skin or eyes.
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