RAVICTI

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Liquid Formulations
-Administer glycerol phenylbutyrate orally to all patients who can swallow, even those with a nasogastric or gastrostomy tube. For patients who cannot swallow, follow recommendations for nasogastric or gastrostomy tube administration.
-Use a new reclosable bottle cap adapter with each new bottle that is opened.
-Measure each dose with a new and dry oral syringe.
-Storage: Discard bottle and any remaining contents 28 days after opening.
-If water or moisture enters the glycerol phenylbutyrate bottle, the contents will become cloudy. If the contents appear cloudy, do not use the glycerol phenylbutyrate; return the bottle to the pharmacy to be discarded.

Oral Administration
-Administer with food or formula directly into the mouth using an oral syringe.
-Administer just prior to breast-feeding in infants who are breast-feeding.

Nasogastric tube or Gastrostomy tube Administration
-Withdraw prescribed dose from the bottle using an oral syringe.
-Place the tip of the syringe into the tip of the gastrostomy/nasogastric tube to administer dose.
-After administration, use a separate syringe to flush once with 10 mL of water or formula and allow the flush to drain. If needed, flush a second time with an additional 10 mL of water or formula to clear the tube.
-For patients who require a volume of less than 1 mL per dose via nasogastric or gastrotomy tube, the delivered dose may be less than expected due to adherence of glycerol phenylbutyrate to the plastic tubing. Therefore, monitor these patients closely using ammonia concentrations after initiation of glycerol phenylbutyrate dosing or dosage adjustments.

The effect of multiple doses of glycerol phenylbutyrate on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin) clinical trial. In this trial, QT prolongation was not found; however, because assay sensitivity was not established, a potential increase in mean QTc interval of 10 ms cannot be ruled out.

In clinical trials, headache occurred in 10% or more of pediatric patients 2 to 17 years treated with glycerol phenylbutyrate (n = 26). In clinical trials of pediatric patients younger than 2 months (n = 16), lethargy and irritability/agitation were reported in 10% or more of patients. Dizziness (10% or more) and fatigue (7% or more) were also commonly reported in adult clinical trials. Seizures, tremor, and peripheral neuropathy have also been reported. Phenylacetate (PAA), the major metabolite of glycerol phenylbutyrate, is associated with neurotoxicity. Signs and symptoms of PAA neurotoxicity may include somnolence (drowsiness), fatigue, lightheadedness, headache, altered sense of taste, hypoacusis (hearing loss), confusion, memory impairment, and exacerbation of peripheral neuropathy. These symptoms were observed at plasma PAA concentrations of 500 mcg/mL in a study of cancer patients receiving IV PAA. The adverse reactions in this study were reversible. In a trial of healthy subjects who received glycerol phenylbutyrate, a dose-dependent increase in nervous system adverse reactions was observed. Plasma PAA concentrations, which were measured on day 3 and not always at the onset of symptoms, ranged from 8 to 56 mcg/mL with a glycerol phenylbutyrate dose of 4 mL PO 3 times daily and 31 to 242 mcg/mL with a glycerol phenylbutyrate dose of 6 mL PO 3 times daily. If symptoms of headache, somnolence, or confusion are present without high ammonia concentrations or other intercurrent illnesses, reduce the glycerol phenylbutyrate dosage.

Gastrointestinal (GI) effects are among the most common adverse reactions to glycerol phenylbutyrate. In clinical trials in pediatric patients 2 months to 17 years (n = 43), diarrhea, nausea, vomiting, abdominal pain, and decreased appetite (anorexia) were reported in 10% or more of patients receiving glycerol phenylbutyrate. In clinical trials of pediatric patients younger than 2 months (n = 16), GI adverse reactions reported in 10% or more of patients included constipation, diarrhea, feeding disorder (decreased appetite, hypophagia), flatulence, gastroesophageal reflux, and vomiting. Dyspepsia (5%) and flatulence (14%) were also reported commonly in adult patients in a clinical trial. Retching/gagging and dysgeusia or burning sensation in the mouth have been reported in postmarketing surveillance. Nausea/vomiting can also be a symptom of phenylacetate (PAA) toxicity. If vomiting or nausea are present without high ammonia concentrations or other intercurrent illnesses, reduce the glycerol phenylbutyrate dosage.

Rash and/or papule was reported in 10% or more of pediatric patients during long-term studies (n = 59) of glycerol phenylbutyrate. Fever was also reported in 10% or more of infants and young children (younger than 2 years) receiving glycerol phenylbutyrate in clinical trials (n = 33). Abnormal body odor, including from skin, hair, and urine, has been reported in postmarketing surveillance.

Cough, nasal congestion, and rhinorrhea were reported in 10% or more of infants and young children (2 months to younger than 2 years) receiving glycerol phenylbutyrate in clinical trials (n = 17). Cough was also commonly reported (10% or more) in infants younger than 2 months in clinical trials (n = 16).

Neutropenia was reported in 10% or more of infants and young children (younger than 2 years) receiving glycerol phenylbutyrate in clinical trials (n = 33). In clinical trials of infants younger than 2 months (n = 16), anemia, lymphocytosis, thrombocytosis, and thrombocytopenia were also reported in 10% or more of patients.

In clinical trials of glycerol phenylbutyrate in infants younger than 2 months (n = 16), dehydration, elevated hepatic enzymes, and metabolic acidosis were reported in 10% or more of patients.

Glycerol phenylbutyrate is contraindicated in patients with known phenylbutyrate hypersensitivity.

Use glycerol phenylbutyrate cautiously and monitor ammonia concentrations closely in patients with pancreatic insufficiency or fat malabsorption syndromes. Pancreatic enzymes in the small intestine are responsible for separating phenylbutyrate, the active moiety, from the glycerol backbone. This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal conditions resulting in fat malabsorption may impair or prohibit the digestion of glycerol phenylbutyrate, which may result in reduced phenylbutyrate absorption and ultimately less control of plasma ammonia concentrations.

Use glycerol phenylbutyrate cautiously in patients with hepatic disease and initiate therapy at the low end of the dosage range in patients with moderate to severe hepatic impairment. Phenylacetate (PAA) is the major metabolite of phenylbutyrate and is the active moiety. PAA conjugates with glutamine in the liver and kidneys to form phenylacetylglutamine (PAGN), which is excreted in the urine. Because conversion of PAA to PAGN occurs in the liver, patients with hepatic impairment may have reduced conversion ability, which may result in increased PAA concentrations. PAA has been associated with neurotoxicity. Signs of neurotoxicity may include somnolence, fatigue, lightheadedness, headache, dysgeusia, hearing impairment, disorientation, impaired memory, seizures, and exacerbation of preexisting neuropathy. If neurotoxicity symptoms develop in the absence of high ammonia levels or other intercurrent illnesses, reduce the dosage of glycerol phenylbutyrate.

Safety and efficacy of glycerol phenylbutyrate have not been established in patients with renal impairment. Monitor ammonia concentrations closely in patients with impaired renal function. Phenylacetate (PAA) is the major metabolite of phenylbutyrate and is the active moiety. PAA conjugates with glutamine in the liver and kidneys to form phenylacetylglutamine (PAGN); PAGN is then excreted in the urine. The effects of renal disease on the conversion of PAA to PAGN or the excretion of PAGN have not been defined.

The prescribing of glycerol phenylbutyrate requires an experienced clinician familiar with the management of patients with urea cycle disorders.

Description: Glycerol phenylbutyrate is a nitrogen-binding agent that provides an alternative vehicle for waste nitrogen excretion in patients with urea cycle disorders (UCD). In patients with UCD, toxic concentrations of ammonia accumulate due to inherited deficiencies of necessary enzymes or transporters, preventing the synthesis of urea from ammonia. It often results in hyperammonemia and subsequent damage to the central nervous system and can be fatal if left untreated. Glycerol phenylbutyrate is indicated for chronic management of urea cycle disorders that cannot be managed by a protein-restricted diet and amino acid supplements alone; it is not indicated for the treatment of acute hyperammonemia. Increased exposure to phenylacetate (PAA), the major metabolite of glycerol phenylbutyrate, may be associated with neurotoxicity. Glycerol phenylbutyrate is FDA-approved for pediatric patients as young as neonates.

General dosing information:
-Glycerol phenylbutyrate must be used in combination with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
-Glycerol phenylbutyrate is not indicated for the treatment of acutely elevated ammonia concentrations in patients with urea cycle disorders (UCDs) because rapidly acting interventions are essential to reduce plasma ammonia concentrations.
-The safety and efficacy of glycerol phenylbutyrate for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.

For the chronic management of hyperammonemia in patients with urea cycle disorders:
NOTE: Glycerol phenylbutyrate is designated as an orphan drug for the maintenance treatment of patients with urea cycle enzyme deficiencies.
Oral dosage:
Neonates switching from sodium phenylbutyrate: For switching from sodium phenylbutyrate tablets: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86. For switching from sodium phenylbutyrate powder: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.81. Divide the total daily dosage into at least 3 equal doses and round each dose up to the nearest 0.1 mL. Max daily dose: 17.5 mL (19 g).
Neonates who are phenylbutyrate-naive: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) PO divided into at least 3 equal doses, each rounded up to the nearest 0.1 mL. Start with 4.5 mL/m2/day in patients with some residual enzyme activity. When determining a starting dosage, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. In general, an estimated initial glycerol phenylbutyrate dosage per 24-hour period is 0.6 mL per gram of dietary protein ingested per 24 hours (Max: 17.5 mL/day). Adjust dosage as needed based on plasma ammonia, urinary phenylacetylglutamine, and/or plasma phenylacetate concentrations.
Infants and Children 1 month to 1 year switching from sodium phenylbutyrate: For switching from sodium phenylbutyrate tablets: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86. For switching from sodium phenylbutyrate powder: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.81. Divide the total daily dosage into at least 3 equal doses and round each dose up to the nearest 0.1 mL. Max daily dose: 17.5 mL (19 g).
Infants and Children 1 month to 1 year who are phenylbutyrate-naive: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) PO divided into at least 3 equal doses, each rounded up to the nearest 0.1 mL. Start with 4.5 mL/m2/day in patients with some residual enzyme activity. When determining a starting dosage, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. In general, an estimated initial glycerol phenylbutyrate dosage per 24-hour period is 0.6 mL per gram of dietary protein ingested per 24 hours (Max: 17.5 mL/day). Adjust dosage as needed based on plasma ammonia, urinary phenylacetylglutamine, and/or plasma phenylacetate concentrations.
Children and Adolescents 2 to 17 years switching from sodium phenylbutyrate: For switching from sodium phenylbutyrate tablets: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86. For switching from sodium phenylbutyrate powder: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.81. Divide the total daily dosage into 3 equal doses and round each dose up to the nearest 0.5 mL. Max daily dose: 17.5 mL (19 g).
Children and Adolescents 2 to 17 years who are phenylbutyrate naive: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) PO divided into 3 equal doses, each rounded up to the nearest 0.5 mL. Start with 4.5 mL/m2/day in patients with some residual enzyme activity. When determining a starting dosage, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. In general, an estimated initial glycerol phenylbutyrate dosage per 24-hour period is 0.6 mL per gram of dietary protein ingested per 24 hours (Max: 17.5 mL/day). Adjust dosage as needed based on plasma ammonia, urinary phenylacetylglutamine, and/or plasma phenylacetate concentrations.

Therapeutic Drug Monitoring:
-The methods used for measuring plasma ammonia concentrations may vary among different laboratories and values obtained by different assay methods may not be interchangeable. Normal and therapeutic target concentrations of ammonia depend upon the assay method used by the individual laboratory. During treatment with glycerol phenylbutyrate, refer to assay-specific normal and therapeutic target ranges for plasma ammonia.
-Dosage adjustment based on plasma ammonia: If patients experience symptoms of vomiting, nausea, headache, somnolence, or confusion in the absence of high ammonia concentrations or other intercurrent illnesses, reduce the glycerol phenylbutyrate dosage and monitor patient clinically. In patients with high ammonia concentrations, increase the glycerol phenylbutyrate dosage to reduce the fasting ammonia concentration to less than half the upper limit of normal (ULN) in patients 6 years and older. For infants and children younger than 6 years, where obtaining a fasting ammonia concentration is problematic due to frequent feedings, adjust the glycerol phenylbutyrate dosage to keep the first ammonia of the morning below the ULN.
-Dosage adjustment based on urinary phenylacetylglutamine (U-PAGN): If available, U-PAGN may be used to help guide dosage adjustments. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the upper limit of normal (ULN), increase the glycerol phenylbutyrate dosage. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. The amount of dose adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-hour U-PAGN concentration and the estimated glycerol phenylbutyrate dose needed per gram of dietary protein ingested. Consider concomitant medications when making a dosage adjustment (e.g., probenecid may reduce the urinary excretion of PAGN).
-Dosage adjustment based on plasma phenylacetate: Plasma phenylacetate (PAA) concentrations 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. In patients with a high PAA to PAGN ratio, a further increase in glycerol phenylbutyrate dose 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 less than 1 in patients without significant PAA accumulation.

Maximum Dosage Limits:
-Neonates
17.5 mL/day (19 g/day) PO.
-Infants
17.5 mL/day (19 g/day) PO.
-Children
17.5 mL/day (19 g/day) PO.
-Adolescents
17.5 mL/day (19 g/day) PO.

Patients with Hepatic Impairment Dosing
For patients with moderate to severe hepatic impairment, initiate therapy with a dosage at the lower end of the recommended dosing range (4.5 mL/m2/day); use the lowest dosage necessary to achieve acceptable ammonia concentrations.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available. Initial dosage adjustments are not required; however, ammonia concentrations should be closely monitored and dosages adjusted accordingly.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Glycerol phenylbutyrate is a triglyceride that contains 3 molecules of phenylbutyrate. It serves as an alternative vehicle for waste nitrogen excretion, which helps to reduce blood ammonia and glutamine concentrations in patients with certain urea cycle disorders. Patients with high blood ammonia and glutamine concentrations are at particular risk for encephalopathies and neurotoxicity.

The urea cycle is responsible for maintaining low blood concentrations of ammonia and glutamine produced by protein breakdown. The normal urea cycle requires numerous enzyme-catalyzed steps to convert ammonia into nitrogenous waste (i.e., urea) that can be excreted from the body. Hyperammonemia may occur when there is a deficiency in one or more urea cycle enzymes or transporters. Ammonia in the blood is converted to glutamine. Phenylacetate, the major metabolite of glycerol phenylbutyrate, conjugates with glutamine in the liver and kidneys to form glutamine phenylacetate, which is then acetylated to form phenylacetylglutamine. Phenylacetylglutamine is excreted by the kidneys. Similar to urea, two moles of nitrogen are removed per mole of phenylacetylglutamine.

Pharmacokinetics: Glycerol phenylbutyrate is administered orally. Pancreatic lipases hydrolyze glycerol phenylbutyrate and release phenylbutyrate (PBA) from the glycerol backbone. PBA is converted by beta-oxidation to phenylacetate (PAA), which is then conjugated with glutamine in the liver and kidneys to form phenylacetylglutamine (PAGN). In healthy subjects, exposure to PAA, PBA, and PAGN increased in a dose-dependent manner. PAGN is eliminated in the urine. In vitro pharmacokinetic studies found protein binding to be 81% to 98% for PBA (over 1 to 250 mcg/mL); 37% to 66% for PAA (over 5 to 500 mcg/mL); and 7% to 12% for PAGN (no concentration effects noted). During a premarketing pharmacokinetic study, the mean percentage of administered PBA excreted as PAGN was approximately 69% in adult patients with a urea cycle disorder (UCD) and 66% in pediatric UCD patients. PAA and PBA were also detected in the urine and accounted for less than 1% of the administered dose. In healthy adult volunteers, women generally had higher plasma concentrations of all metabolites than men; gender differences in pediatric patients have not been described.

Possibly affected cytochrome P450 isoenzymes: CYP2C9, CYP2D6, and CYP3A4/5
During in vitro studies, phenylbutyrate (PBA), at a concentration of 800 mcg/mL, caused more than 60% reversible inhibition of cytochrome P450 isoenzymes CYP2C9, CYP2D6, and CYP3A4/5. In addition, inhibition of CYP1A2, CYP2C8, CYP2C19, and CYP2D6 by phenylacetate (PAA) at a concentration of 2,800 mcg/mL was observed in vitro. However, in healthy subjects who received glycerol phenylbutyrate 6 mL PO 3 times daily for 3 days, the mean PBA and PPA Cmax were 100 mcg/mL and 65 mcg/mL, respectively. The clinical implications of the in vitro data are not known.


-Route-Specific Pharmacokinetics
Oral Route
Glycerol phenylbutyrate is a prodrug. When orally ingested, pancreatic lipases in the gastrointestinal tract release phenylbutyrate (PBA) from the glycerol backbone. In healthy fasting adults who received a single oral dose of glycerol phenylbutyrate 2.9 mL/m2, peak PBA, PAA, and PAGN plasma concentrations occurred at 2 hours, 4 hours, and 4 hours, respectively. In adult UCD patients who received multiple doses, maximum plasma concentrations at steady state of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day. The mean peak PAA concentration was 39 mcg/mL in adults.


-Special Populations
Pediatrics
In clinical studies in pediatric patients, mean peak PAA concentrations were 257, 142, and 70 mcg/mL for patients younger than 2 months, 2 months to younger than 2 years, and 2 to 17 years, respectively. Population pharmacokinetic modeling and dosing simulations suggest body surface area is the most significant covariate explaining the variability of PAA clearance in children. PAA clearance was 3.8 L/hour, 6.8 L/hour, 10.9 L/hour, 16.4 L/hour, and 24.4 L/hour for UCD patients younger than 2 months, 2 months to younger than 2 years, 3 to 5, 6 to 11, and 12 to 17 years, respectively. The mean peak ratio of PAA to PAGN in UCD patients younger than 2 months was higher (mean: 1.6; range: 0.1 to 7.1) than that of patients 2 months to younger than 2 years (mean: 0.5; range: 0.1 to 1.2).

Hepatic Impairment
The disposition of glycerol phenylbutyrate in urea cycle disorder patients with hepatic impairment has not been determined; however, because conversion of PAA to PAGN occurs in the liver, patients with hepatic impairment may have reduced conversion ability, which may result in increased PAA concentrations and a decreased ability to eliminate nitrogen via PAGN. In adult volunteers with hepatic impairment (Child-Pugh A, B, and C), PBA AUC was 42%, 84%, and 50% higher, respectively, than in healthy subjects. PAA AUC was 22%, 53%, and 94% higher than in healthy subjects. In contrast, the PAGN AUC was 42%, 27%, and 22% lower in patients with Child-Pugh A, B, and C hepatic impairment compared to that of healthy volunteers.

Renal Impairment
The disposition of glycerol phenylbutyrate in patients with renal impairment has not been studied.