Dosing and uses of Ravicti (glycerol phenylbutyrate)
Adult dosage forms and strengths
oral liquid
- 1.1 g/mL
Urea Cycle Disorders
Nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone
Give PO in 3 equally divided dosages, each rounded up to nearest 0.5 mL
Not to exceed 17.5 mL/day
Also see Administration section
Switching from sodium phenylbutyrate to glycerol phenylbutyrate
- Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86
- Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81
Phenylbutyrate-naïve
- 4.5-11.2 mL/m²/day (5-12.4 g/m²/day)
- Determine starting dose by patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence
- Dietary protein is ~15% nitrogen by weight
- ~47% of dietary nitrogen is excreted as waste and ~70% of phenylbutyrate dose is converted to urinary phenylacetylglutamine (U-PAGN), so an initial estimated dose is 0.6 mL/g dietary protein ingested per day
Dosage modifications
Adjustment based on plasma ammonia: Adjust dose to produce fasting plasma ammonia level less than half ULN according to age
Adjustment based on urinary phenylacetylglutamine
- Each gram of U-PAGN excreted over 24 hr covers waste nitrogen generated from 1.4 grams of dietary protein
- If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the ULN, adjusted dosage upward
- The amount of dose adjustment should factor in the amount of dietary protein that has not been covered (not to exceed 17.5 mL/day)
- Also consider concomitant medications (eg, probenecid) that may decrease urinary excretion of PAGN
Adjustment based on plasma phenylacetate (PPA)
- PAA levels may be useful to guide dosing if symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or intercurrent illness
- Ammonia levels must be monitored closely when changing the dose
- If a high PAA to PAGN ratio exists, a further dosage increase may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction
- The PAA to PAGN ratio has been observed to be generally <1 in patients without significant PAA accumulation
Hepatic impairment
- Moderate-to-severe hepatic impairment: Use starting dose at lower end of dosage range
Dosing Considerations
Must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements)
Monitor plasma ammonia levels
Pediatric dosage forms and strengths
oral liquid
- 1.1 g/mL
Urea Cycle Disorders
Nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone
<2 years: Safety and efficacy not established
Give PO in 3 equally divided dosages, each rounded up to nearest 0.5 mL
Not to exceed 17.5 mL/day
Also see Administration section
Switching from sodium phenylbutyrate to glycerol phenylbutyrate
- Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86
- Total daily dose of Ravicti (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81
Phenylbutyrate-naïve
- 4.5-11.2 mL/m²/day (5-12.4 g/m²/day)
- Determine starting dose by patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence
- Dietary protein is ~15% nitrogen by weight
- ~47% of dietary nitrogen is excreted as waste and ~70% of phenylbutyrate dose is converted to urinary phenylacetylglutamine (U-PAGN), so an initial estimated dose is 0.6 mL/g dietary protein ingested per day
Dosage modifications
Adjustment based on plasma ammonia: Adjust dose to produce fasting plasma ammonia level less than half ULN according to age
Adjustment based on urinary phenylacetylglutamine
- Each gram of U-PAGN excreted over 24 hr covers waste nitrogen generated from 1.4 grams of dietary protein
- If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the ULN, adjusted dosage upward
- The amount of dose adjustment should factor in the amount of dietary protein that has not been covered (not to exceed 17.5 mL/day)
- Also consider concomitant medications (eg, probenecid) that may decrease urinary excretion of PAGN
Adjustment based on plasma phenylacetate (PPA)
- PAA levels may be useful to guide dosing if symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or intercurrent illness
- Ammonia levels must be monitored closely when changing the dose
- If a high PAA to PAGN ratio exists, a further dosage increase may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction
- The PAA to PAGN ratio has been observed to be generally <1 in patients without significant PAA accumulation
Hepatic impairment
- Moderate-to-severe hepatic impairment: Use starting dose at lower end of dosage range
- Conversion of PAA to PAGN occurs in the liver, hepatic impairment may reduce conversion capability and result in higher plasma PAA and PAA to PAGN ratio
Renal impairment
- Efficacy and safety unknown in patients with renal impairment
- Monitor ammonia levels closely when initiating in patients with impaired renal function
Dosing Considerations
Must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements)
Monitor plasma ammonia levels
Administration
Administer directly into the mouth via oral syringe or dosing cup
May also be administered via nasogastric tube or g-tube
Ravicti (glycerol phenylbutyrate) adverse (side) effects
>10%
Diarrhea (16%)
Flatulence (14%)
Headache (14%)
1-10%
Abdominal pain (7%)
Vomiting (7%)
Decreased appetite (7%)
Fatigue (7%)
Ammonia increased (5%)
Dyspepsia (5%)
Nausea (2%)
Postmarketing Reports
Abnormal body odor, including from skin, hair, and urine
Retching and gagging
Dysgeusia or burning sensation in mouth
Warnings
Contraindications
Age <2 months; may have immature pancreatic exocrine function, which could impair hydrolysis of glycerol phenylbutyrate and lead to impaired absorption of phenylbutyrate and hyperammonemia
Hypersensitivity to phenylbutyrate (eg, wheezing, dyspnea, coughing, hypotension, flushing, nausea, rash)
Cautions
Safety and efficacy not established for N-acetylglutamate synthase (NAGS) deficiency
The major metabolite, phenylacetate (PAA), is associated with neurotoxicity
Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion/absorption of glycerol phenylbutyrate
A registry has been established by Hyperion Therapeutics in order to better assess long-term outcomes in patients with UCDs taking glycerol phenylbutyrate, including growth and neurocognitive outcomes and the outcome of pregnancy for women with UCDs who become pregnant 1-855-823-2495
Pregnancy and lactation
Pregnancy
Limited available data to inform a drug-associated risk of major birth defects and miscarriage
Animal data
- Administration to pregnant rabbits during organogenesis at ≥2.7 x the dose of 6.87 mL/m²/day resulted in maternal toxicity, but had no effects on embryo-fetal development
- Administration to pregnant rats during organogenesis at ≥5.7 x the dose of 6.87 mL/m²/day resulted in maternal toxicity, reduced fetal weights, and variations in skeletal development; no adverse developmental effects were seen at 1.9 x the dose of 6.87 mL/m²/day
Lactation
Unknown if distributed in human breast milk; because of the potential for serious adverse reactions, including neurotoxicity and tumorigenicity in a breastfed infant, advise patients that breastfeeding is not recommended
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Ravicti (glycerol phenylbutyrate)
Mechanism of action
Decreases elevated plasma ammonia glutamine levels
Pre-prodrug that is metabolized by ester hydrolysis and pancreatic lipases to phenylbutyrate (PBA) and then by beta oxidation to phenylacetate (PAA); glutamine is conjugated with phenylacetate to form phenylacetylglutamine (PAGN), a nitrogen waste product that is excreted renally
The phenylacetylglutamine conjugate provides an alternate vehicle to urea for waste nitrogen excretion; for each gram of sodium phenylbutyrate administered, it is estimated that between 0.12–0.15 grams of phenylacetylglutamine nitrogen are produced
Absorption
Peak plasma time: 2 hr (PBA), 4 hr (PAA), 4 hr (PAGN)
Peak plasma concentration: 37 mcg/mL (PBA), 14.9 mcg/mL (PAA), 30.2 mcg/mL (PAGN)
AUC: 930-1400 mcg•h/mL (PBA); 942-2064 mcg•h/mL (PAA)
Distribution
Protein Bound: 80.6-98% (PBA), 37.1-65.6% (PAA), 7-12% (PAGN)
Metabolism
Glycerol phenylbutyrate metabolized by hydrolyzed by pancreatic lipases and release phenylbutyric acid (PBA); PBA undergoes beta-oxidation to phenylacetic acid (PAA)
PAA is conjugated with glutamine in the liver and kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGn
Elimination
Excretion: 66.4-68.9% in urine as PAGn
Administration
Oral Administration
Take with food
Administer directly into the mouth via oral syringe or dosing cup
May also be administered via nasogastric tube or g-tube; flush tube once with 30 mL of water and allow the flush to drain, and then repeat flush to clear the tube
