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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Orfadin: 2 mg, 5 mg, 10 mg
Brand Names: U.S.
- 4-Hydroxyphenylpyruvate Dioxygenase Inhibitor
In patients with HT-1, tyrosine metabolism is interrupted due to a lack of the enzyme (fumarylacetoacetate hydrolase) needed in the last step of tyrosine degradation. Toxic metabolites of tyrosine accumulate and cause liver and kidney toxicity. Nitisinone competitively inhibits 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme present early in the tyrosine degradation pathway, thereby preventing the build-up of the toxic metabolites.
Minor metabolism possibly via CYP3A4
Healthy volunteers: Urine (Hall, 2001)
Time to Peak
Healthy volunteers: Capsule: 3 hours; Liquid: 15 minutes
Healthy volunteers: Terminal half-life: 54 hours
Use: Labeled Indications
Hereditary tyrosinemia type 1: Treatment of hereditary tyrosinemia type 1 (HT-1) as an adjunct to dietary restriction of tyrosine and phenylalanine
There are no contraindications listed in the manufacturer's labeling.
Hereditary tyrosinemia type 1 (HT-1): Oral: Note: Must be used in conjunction with a diet restricted in tyrosine and phenylalanine.
Children, Adolescents, and Adults: Initial: 1 mg/kg/day in 2 divided doses
Dosage adjustment for inadequate response: Note: Inadequate response is defined as continued abnormal biological parameters (erythrocyte PBG-synthase activity, urine 5-ALA, and urine and plasma succinylacetone) despite treatment. Plasma succinylacetone may take up to 3 months to normalize after start of therapy. If the aforementioned parameters are not available, may use urine succinylacetone, liver function tests, alpha-fetoprotein, serum tyrosine, and serum phenylalanine to evaluate response (exceptions may include during initiation of therapy and exacerbations).
Abnormal biological parameters (erythrocyte PBG-synthase activity, urine 5-ALA, and urine succinylacetone) at 1 month: Increase dose to 1.5 mg/kg/day
Abnormal biological parameters (erythrocyte PBG-synthase activity, urine 5-ALA, and urine and plasma succinylacetone) at 3 months: Further increase to maximum dose of 2 mg/kg/day
Dosage adjustment in renal impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Administer in 2 divided doses in the morning and evening at least 1 hour prior to, or 2 hours after a meal. Capsules may be opened and contents suspended in a small quantity of water, formula, or apple sauce; administer immediately.
Because the effect of food is unknown, nitisinone should be taken at least 1 hour prior to, or 2 hours after a meal. Dietary restriction of tyrosine and phenylalanine is required.
Store refrigerated at 2°C to 8°C (36°F to 46°F).
There are no known significant interactions.
1% to 10%:
Dermatologic: Alopecia (1%), dry skin (1%), exfoliative dermatitis (1%), maculopapular rash (1%), pruritus (1%)
Hematologic: Thrombocytopenia (3%), leukopenia (3%), epistaxis (1%), granulocytopenia (1%), porphyria (1%)
Hepatic: Hepatic neoplasm (8%), hepatic failure (7%)
Ocular: Conjunctivitis (2%), corneal opacity (2%), keratitis (2%), photophobia (2%), blepharitis (1%), cataracts (1%), eye pain (1%)
<1% (Limited to important or life-threatening): Abdominal pain, amenorrhea, brain tumor, bronchitis, corneal ulceration, cyanosis, dehydration, diarrhea, enanthema, encephalopathy, gastritis, gastroenteritis, gastrointestinal hemorrhage, headache, hepatic dysfunction, hepatomegaly, hyperkinesias, hypoglycemia, infection, liver enzymes increased, melena, nervousness, otitis, pathologic fracture, respiratory insufficiency, seizure, septicemia, somnolence, thirst, tooth discoloration, tyrosine levels increased
Concerns related to adverse effects:
• Dermatologic effects: Failure to adequately restrict dietary tyrosine and phenylalanine may lead to hyperkeratotic plaques on the soles and palms.
• Hematologic effects: Leukopenia and/or thrombocytopenia have been reported; may be due to underlying liver disease rather than drug-related (McKiernan, 2006). Monitor platelets and WBC regularly during therapy.
• Neurological effects: Failure to adequately restrict dietary tyrosine and phenylalanine may lead to developmental delay and mental retardation; clinical laboratory assessment including tyrosine levels is recommended for any patient exhibiting abrupt changes in neurological status while on therapy.
• Ocular effects: Failure to adequately restrict dietary tyrosine and phenylalanine may lead to ocular toxicities (eg, conjunctivitis, corneal ulcers, corneal opacities, eye pain, keratitis, photophobia). Slit-lamp examination of the eyes is recommended prior to initiation of therapy and in patients who develop symptoms of toxicity. Immediate measurement of plasma tyrosine concentration is also recommended in patients who develop ocular symptoms.
• Dietary restrictions: Must be used with dietary restriction of tyrosine and phenylalanine; inadequate restriction can result in toxic effects to the eyes, skin, and nervous system. Evaluate plasma tyrosine concentrations in patients who develop signs and symptoms of toxicity. Nutritional consultation is recommended.
Dietary tyrosine and phenylalanine; plasma nitisinone concentration, erythrocyte PBG-synthase activity, urine 5-ALA, and urine and plasma succinylacetone (to monitor effectiveness of treatment; if these tests are not available, assessment should include urine succinylacetone, LFTs, alpha-fetoprotein, and serum tyrosine and phenylalanine levels); slit-lamp examination (prior to initiation of therapy and in patients who develop symptoms of ocular toxicity); plasma tyrosine (as clinically indicated with side effects; concentrations should be kept <500 micromole/L to avoid toxicity) platelet and white blood cell counts (regularly during therapy); liver imaging studies (ultrasound, computerized tomography, magnetic resonance imaging, and serum alpha-fetoprotei (to monitor effectiveness of treatment and potential liver neoplasia).
Note: Plasma succinylacetone may take up to 3 months to normalize after start of therapy.
Pregnancy Risk Factor
Adverse events have been observed in animal reproduction studies.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Have patient report immediately to prescriber signs of hepatic impairment, skin changes on extremities, vision changes, ophthalmalgia, severe eye irritation, illogical thinking, chills, pharyngitis, hemorrhaging, or ecchymosis (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.