ORFADIN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ORFADIN (ORFADIN).
Inhibits 4-hydroxyphenylpyruvate dioxygenase (HPPD), leading to reduced accumulation of toxic metabolites (e.g., succinylacetone) in hereditary tyrosinemia type 1 (HT-1).
| Metabolism | Primarily metabolized via glucuronidation (UGT1A6, UGT1A9) and to a lesser extent via CYP3A4. |
| Excretion | Renal excretion is the primary route of elimination, accounting for approximately 60-80% of the dose as nitisinone and its metabolites. Biliary/fecal excretion accounts for about 10-20%. |
| Half-life | Terminal elimination half-life is approximately 54 hours (range 40-70 hours) in adults, allowing once-daily dosing. Half-life may be prolonged in patients with hepatic impairment. |
| Protein binding | Approximately 95% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution (Vd) is approximately 0.4-0.6 L/kg, indicating distribution mainly in extracellular fluid and tissues. |
| Bioavailability | Oral bioavailability is approximately 100% as nitisinone is well-absorbed with minimal first-pass metabolism. |
| Onset of Action | Oral: Clinical effect on plasma tyrosine levels is typically observed within 24-48 hours after initiating therapy. |
| Duration of Action | Duration of action is approximately 24 hours due to once-daily dosing, maintaining therapeutic tyrosine levels throughout the dosing interval. Consistent dosing is required to prevent tyrosine accumulation. |
Oral: 20 mg/kg/day divided into two doses; maximum dose 60 mg/kg/day.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min); not studied in severe renal impairment or ESRD. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B); not studied in severe (Child-Pugh C). |
| Pediatric use | Same as adult: 20 mg/kg/day divided into two doses; maximum 60 mg/kg/day. |
| Geriatric use | No specific recommendations; use with caution due to potential renal and hepatic age-related changes. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ORFADIN (ORFADIN).
| Breastfeeding | No data on human milk excretion. Because many drugs are excreted in milk, a risk to the nursing infant cannot be excluded. M/P ratio not determined. Weigh benefits against potential risks. |
| Teratogenic Risk | Animal studies have shown fetal harm, including low fetal weight and increased skeletal variations, at doses below the maximum human dose. There are no adequate human studies. Risk cannot be ruled out. Avoid use in pregnancy unless benefit outweighs risk. |
| Fetal Monitoring |
■ FDA Black Box Warning
None
| Serious Effects |
["Hypersensitivity to nitisinone or any component of the formulation","Breastfeeding","Concomitant use with drugs that inhibit or induce glucuronidation (e.g., valproic acid, phenytoin) - relative"]
| Precautions | ["Elevated tyrosine levels may cause ocular symptoms (corneal ulcers, keratitis), neurological symptoms, and developmental delay; monitor plasma tyrosine levels.","Risk of thrombocytopenia and neutropenia; monitor blood counts.","Potential for hepatotoxicity; monitor liver function tests.","May cause QT prolongation; monitor ECG in at-risk patients.","Avoid use in patients with severe hepatic impairment."] |
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| Monitor maternal liver function tests, blood tyrosine levels, and ophthalmological exams. Fetal monitoring with ultrasound is recommended to detect potential growth abnormalities. |
| Fertility Effects | Animal studies have shown no impairment of fertility. Human data are insufficient to determine effects on fertility. |