Trade Names:Orfadin- Capsules 2 mg- Capsules 5 mg- Capsules 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 (HT-1), these catabolic intermediates are converted into toxic metabolites (succinylacetone and succinylacetoacetate), responsible for the liver and kidney toxicity observed in these patients.
Mean time to reach C max is 3 h for the capsule and 15 min for the liquid.
Mean terminal t ½ is 54 h.
Adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1.
PO Initial dose: 1 mg/kg/day divided for morning and evening administration. Dose adjustment: Increase to 1.5 mg/kg/day after 1 mo if biochemical parameters (except plasma succinylacetone) are not normalized. Further increase to max dosage of 2 mg/kg/day may be needed in some patients.
Store capsules in refrigerator (36° to 46°F).
None well documented.
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, porphyria (1%).
Hepatic neoplasm (8%); liver failure (7%).
Regularly monitor urine succinylacetone, LFTs, alpha-fetoprotein, platelet and WBC counts, 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 5î“¸aminolevulinic acid levels).Liver
Regularly monitor liver by imaging (CT scan, MRI, ultrasound) and lab tests, including alpha-fetoprotein.Ophthalmic
Perform slit-lamp examinations of the eyes before initiation of therapy and during any eye adverse reactions (eg, eye pain, photophobia, signs of inflammation).Renal
Measure serum phosphate in patients with renal involvement at risk for secondary hyperphosphatemia and rickets.
Category C .
Nitisinone has been studied in patients ranging in age from birth to 21.7 yr of age.
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 children with inborn errors or 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 plasma tyrosine level is above 500 mcmol/L. Do not adjust nitisinone dose to lower tyrosine level because the HT-1 metabolic defect may result in deterioration of the patient's clinical condition.Porphyric crises/liver failure/hepatic neoplasms
Patients with HT-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.Thrombocytopenia/leukopenia
Transient thrombocytopenia, leukopenia, or both has been reported. In most patients, platelet and WBC counts normalized gradually without change in nitisinone dose.
Elevated tyrosine levels, 1 case of sunlight sensitivity.
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