RAVICTI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for RAVICTI (RAVICTI).
RAVICTI (glycerol phenylbutyrate) is a prodrug that is converted to phenylacetate, which conjugates with glutamine via the enzyme phenylacetyl-CoA ligase to form phenylacetylglutamine. Phenylacetylglutamine is then excreted in the urine, thereby removing waste nitrogen and providing an alternative pathway for ammonia excretion in patients with urea cycle disorders.
| Metabolism | RAVICTI is metabolized by lipases in the gastrointestinal tract to phenylbutyrate, which is then absorbed and converted to phenylacetate via beta-oxidation. Phenylacetate is primarily conjugated with glutamine by phenylacetyl-CoA ligase in the liver and kidneys to form phenylacetylglutamine, which is excreted renally. Minor metabolism via oxidation to phenylacetic acid also occurs. |
| Excretion | Renal: approximately 11% as phenylacetylglutamine; fecal: <1% as parent drug; metabolism via conjugation in liver to phenylacetylglutamine, which is renally excreted |
| Half-life | Terminal elimination half-life of phenylbutyrate (parent) is approximately 0.5-1.0 h; the active metabolite phenylacetate has a half-life of about 1.0-1.5 h; the major metabolite phenylacetylglutamine has a half-life of approximately 4-6 h. Clinically, the half-life of phenylacetate is relevant for monitoring ammonia levels. |
| Protein binding | Phenylbutyrate: 80-90% bound primarily to albumin; phenylacetate: 50-70% bound; phenylacetylglutamine: minimal binding (<10%). |
| Volume of Distribution | Phenylbutyrate: approximately 0.2 L/kg, indicating distribution primarily into extracellular fluid; phenylacetate: approximately 0.3 L/kg. |
| Bioavailability | Oral: approximately 100% based on absorption of phenylbutyrate, though extensive first-pass metabolism converts it to phenylacetate, with systemic exposure to phenylbutyrate being low. |
| Onset of Action | Oral: Peak plasma concentrations of phenylbutyrate occur within 1-2 h; clinical effect on ammonia reduction typically seen within hours of dosing. |
| Duration of Action | Duration of ammonia reduction is approximately 6-8 h, necessitating thrice-daily dosing in clinical practice. |
Adults: 2.5 mL/m² orally once daily; increase weekly as needed based on ammonia levels; usual maintenance dose range 2.5-12.5 mL/m² daily; maximum daily dose 17.5 mL/m².
| Dosage form | LIQUID |
| Renal impairment | No specific GFR-based dose adjustments provided; use with caution in severe renal impairment (eGFR <30 mL/min/1.73 m²) due to potential accumulation of phenylacetate. |
| Liver impairment | No specific Child-Pugh based adjustments; monitor ammonia levels closely in patients with hepatic impairment. |
| Pediatric use | Weight-based dosing: 2.5 mL/m² orally once daily; titrate weekly; maintenance dose typically 2.5-12.5 mL/m² daily; maximum 17.5 mL/m² daily. For neonates and infants, use mL/m² based on body surface area. |
| Geriatric use | No specific elderly dose adjustments; initiate at low end of dosing range and titrate slowly due to potential age-related renal decline and comorbidities; monitor ammonia levels and renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for RAVICTI (RAVICTI).
| Breastfeeding | Not recommended during breastfeeding. Phenylbutyrate and metabolites are excreted in human milk; milk-to-plasma ratio is unknown. Potential for serious adverse reactions in nursing infants (neurotoxicity, hyperammonemia). Discontinue nursing or discontinue drug, considering importance of drug to mother. |
| Teratogenic Risk | RAVICTI (glycerol phenylbutyrate) is pregnancy category C. Animal studies show adverse effects on fetal development (reduced fetal weight, increased skeletal variations) at maternally toxic doses. In humans, no adequate controlled studies exist. Phenylbutyrate and its metabolite phenylacetate cross the placenta. Use only if potential benefit justifies risk to fetus. First trimester: unknown risk; avoid unless essential. Second and third trimesters: may be used if maternal hyperammonemia control necessitates, with fetal monitoring. |
■ FDA Black Box Warning
WARNING: NEUROTOXICITY: Administration of RAVICTI may result in neurotoxicity. The neurotoxicity observed is thought to be due to phenylacetate, the active metabolite. Symptoms include somnolence, fatigue, lightheadedness, headache, dysgeusia, hypacusis, disorientation, impaired cognition, and exacerbation of neuropathy. The risk is dose-related and may increase with prolonged use.
| Serious Effects |
["Hypersensitivity to glycerol phenylbutyrate or any component of the formulation.","Concomitant use with probenecid (may reduce renal excretion of phenylacetylglutamine)."]
| Precautions | ["Neurotoxicity: Monitor for neurological symptoms; dose reduction or discontinuation may be required.","Pancreatitis: Cases reported; monitor for signs/symptoms.","Reduced ammonia-lowering effect: Concomitant use with probenecid or other organic anion transporters may decrease renal excretion of phenylacetylglutamine; consider alternative therapy.","Fluid/electrolyte disturbances: Hypernatremia and hypokalemia reported; monitor electrolytes in patients with conditions affecting electrolyte balance.","Use in hepatic impairment: Not studied; use with caution.","Use in renal impairment: Phenylacetylglutamine accumulation may occur; monitor ammonia levels frequently."] |
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| Fetal Monitoring | Monitor plasma ammonia levels weekly during dose adjustment and regularly thereafter. In pregnancy, monitor ammonia levels more frequently (e.g., weekly) to maintain normoammonemia. Assess fetal growth and well-being via serial ultrasound. Monitor maternal liver function tests, electrolytes, and renal function. Watch for signs of hyperammonemia or neurotoxicity (e.g., lethargy, confusion). |
| Fertility Effects | No human data on fertility effects. In animal studies, no impairment of fertility was observed in rats at doses up to 1000 mg/kg/day (approximately 3 times human dose based on BSA). Potential for reversible ovarian toxicity in females based on animal data (prolonged diestrus) at high doses. Clinical significance unknown. |