NITISINONE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NITISINONE (NITISINONE).
Inhibits 4-hydroxyphenylpyruvate dioxygenase (HPPD), a key enzyme in tyrosine catabolism, preventing accumulation of toxic metabolites like succinylacetone. In hereditary tyrosinemia type 1 (HT-1), it reduces formation of hepatotoxic and nephrotoxic metabolites.
| Metabolism | Primarily metabolized by CYP3A4-mediated oxidation and glucuronidation (UGT1A6, UGT1A9). Also undergoes reduction and conjugation. |
| Excretion | Renal excretion of unchanged drug and metabolites accounts for approximately 60-70% of the dose; fecal elimination is minimal (<10%). |
| Half-life | Terminal elimination half-life is approximately 54 hours in adults, allowing once-daily dosing in hereditary tyrosinemia type 1. |
| Protein binding | Approximately 99% bound to plasma proteins, primarily to albumin. |
| Volume of Distribution | Volume of distribution is approximately 0.2 L/kg, indicating limited extravascular distribution consistent with high protein binding. |
| Bioavailability | Oral bioavailability is approximately 90%, with minimal first-pass metabolism. |
| Onset of Action | Oral administration: Reduction in plasma succinylacetone levels is detectable within 24 hours; maximal effect on metabolic markers occurs within 1-2 weeks of continuous dosing. |
| Duration of Action | Pharmacodynamic effect (suppression of succinylacetone) persists for 24-48 hours after a single dose, supporting once-daily administration. |
2 mg/kg/day orally in two divided doses; maintenance range 1-10 mg/kg/day.
| Dosage form | CAPSULE |
| Renal impairment | No specific dose adjustments provided; use with caution in severe renal impairment (eGFR <30 mL/min/1.73 m²). |
| Liver impairment | Mild to moderate impairment (Child-Pugh A or B): no adjustment. Severe impairment (Child-Pugh C): not studied; avoid use. |
| Pediatric use | Starting dose 2 mg/kg/day orally divided twice daily; adjust to maintain plasma tyrosine <600 µmol/L; typical range 1-10 mg/kg/day. |
| Geriatric use | No specific adjustments; use with caution due to potential age-related renal decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NITISINONE (NITISINONE).
| Breastfeeding | No human data on excretion in breast milk. M/P ratio unknown. Caution advised; consider alternative feeding or monitor infant for adverse effects. |
| Teratogenic Risk | Animal studies show teratogenicity at high doses. First trimester: potential for structural anomalies; avoid unless benefit outweighs risk. Second/third trimester: no specific human data; monitor fetal growth. |
| Fetal Monitoring |
■ FDA Black Box Warning
None (No boxed warning in FDA labeling). However, nitisinone may cause elevated tyrosine levels, requiring dietary management.
| Serious Effects |
["Hypersensitivity to nitisinone or any component of the formulation"]
| Precautions | ["Monitor plasma tyrosine levels; maintain dietary restriction of tyrosine and phenylalanine to avoid tyrosine-induced toxicities (e.g., keratopathy, neurological symptoms).","Risk of thrombocytopenia and leukopenia; monitor platelet and white blood cell counts.","Hepatic impairment may require dose adjustment.","Use in pregnancy only if benefit outweighs risk; no adequate studies."] |
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| Monitor maternal liver function (ALT, AST), alpha-fetoprotein, and plasma tyrosine levels. Perform fetal ultrasound for growth and anomalies. |
| Fertility Effects | No specific human data on fertility impairment. Animal studies show no significant effects. |