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Overview
Glycerol phenylbutyrate is a {{{drugClass}}} that is FDA approved for the treatment of patients with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone.. Common adverse reactions include diarrhea, flatulence and headache.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
Limitations of Use:
RAVICTI is not indicated for the treatment of acute hyperammonemia in patients with UCDs because more rapidly acting interventions are essential to reduce plasma ammonia levels.
The safety and efficacy of RAVICTI for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.
The use of RAVICTI in patients <2 months of age is contraindicated.
DOSAGE
Important Instructions
The recommended dosages for patients switching from sodium phenylbutyrate to RAVICTI and patients naïve to phenylbutyric acid are different . For both subpopulations:
Give RAVICTI in 3 equally divided dosages, each rounded up to the nearest 0.5 mL.
The maximum total daily dosage is 17.5 mL (19 g).
RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
Switching From Sodium Phenylbutyrate to RAVICTI
Patients switching from sodium phenylbutyrate to RAVICTI should receive the dosage of RAVICTI that contains the same amount of phenylbutyric acid. The conversion is as follows:
Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86
Initial Dosage in Phenylbutyrate-Naïve Patients
The recommended dosage range, based upon body surface area, in patients naïve to phenylbutyrate (PBA) is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day). For patients with some residual enzyme activity who are not adequately controlled with protein restriction, the recommended starting dosage is 4.5 mL/m2/day.
In determining the starting dosage of RAVICTI in treatment-naïve patients, consider the patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated RAVICTI dose for a 24-hour period is 0.6 mL RAVICTI per gram of dietary protein ingested per 24 hour period. The total daily dosage should not exceed 17.5 mL.
Dosage Adjustment and Monitoring
Adjustment based on Plasma Ammonia: Adjust the RAVICTI dosage to produce a fasting plasma ammonia level that is less than half the upper limit of normal (ULN) according to age.
Adjustment Based on Urinary Phenylacetylglutamine: If available, U-PAGN measurements may be used to help guide RAVICTI dose adjustment. Each gram of U-PAGN excreted over 24 hours 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, the RAVICTI dose should be adjusted upward. The amount of dose adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-h U-PAGN level and the estimated RAVICTI dose needed per gram of dietary protein ingested and the maximum total daily dosage i.e., 17.5 mL.
Consider a patient’s use of concomitant medications, such as probenecid, when making dosage adjustment decisions based on U-PAGN. Probenecid may result in a decrease of the urinary excretion of PAGN.
Adjustment Based on Plasma Phenylacetate: If available, measurements of the plasma 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 of RAVICTI. The ratio of PAA to PAGN in plasma may provide additional information to assist in dose adjustment decisions. In patients with a high PAA to PAGN ratio, a further increase in RAVICTI 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.
Dosage Modifications in Patients with Hepatic Impairment
For patients with moderate to severe hepatic impairment, the recommended starting dosage is at the lower end of the range
DOSAGE FORMS AND STRENGTHS
Oral liquid: colorless to pale yellow, 1.1 g/mL of glycerol phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate).
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Glycerol phenylbutyrate in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Glycerol phenylbutyrate in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Glycerol phenylbutyrate in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Glycerol phenylbutyrate in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Glycerol phenylbutyrate in pediatric patients.
Contraindications
RAVICTI is contraindicated in patients
Less than 2 months of age. Children <2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of RAVICTI, leading to impaired absorption of phenylbutyrate and hyperammonemia.
The major metabolite of RAVICTI, PAA, is associated with neurotoxicity. Signs and symptoms of PAA neurotoxicity, including somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy, were observed at plasma PAA concentrations ≥500 µg/mL in a study of cancer patients who were administered IV PAA. In this study, adverse events were reversible.
In healthy subjects, after administration of 4 mL and 6 mL RAVICTI 3 times daily for 3 days, a dose-dependent increase in all-grade nervous system adverse reactions was observed, even at exposure levels of PAA <100 µg/mL.
In clinical trials in UCD patients who had been on sodium phenylbutyrate prior to administration of RAVICTI, peak PAA concentrations after dosing with RAVICTI ranged from 1.6 to 178 µg/mL (mean: 39 µg/mL) in adult patients and from 7 to 480 µg/mL (mean: 90 µg/mL) in pediatric patients. Some UCD patients experienced headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor and/or dizziness. No correlation between PAA levels and neurotoxicity symptoms was identified but PAA levels were generally not measured at the time of neurotoxicity symptoms.
If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or other intercurrent illnesses, reduce the RAVICTI dosage.
Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption
Exocrine pancreatic enzymes hydrolyze RAVICTI in the small intestine, separating the active moiety, phenylbutyrate, from glycerol. This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion of RAVICTI and/or absorption of phenylbutyrate and reduced control of plasma ammonia. Monitor ammonia levels closely in patients with pancreatic insufficiency or intestinal malabsorption.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Assessment of adverse reactions was based on exposure of 45 adult patients (31 female and 14 male) with UCD subtype deficiencies of ornithine transcarbamylase (OTC, n=40), carbamyl phosphate synthetase (CPS, n=2), and argininosuccinate synthetase (ASS, n=1) in a randomized, double-blind, active-controlled (RAVICTI vs sodium phenylbutyrate), crossover, 4-week study (Study 1) that enrolled patients ≥18 years of age [see Clinical Studies (14.1)]. One of the 45 patients received only sodium phenylbutyrate prior to withdrawing on day 1 of the study due to an adverse reaction.
Table 1 summarizes adverse reactions occurring in ≥2 patients treated with RAVICTI or sodium phenylbutyrate. The most common adverse reactions (occurring in ≥10% of patients) reported during short-term treatment with RAVICTI were diarrhea, flatulence, and headache.
This image is provided by the National Library of Medicine.
Other Adverse Reactions
RAVICTI has been evaluated in 77 UCD patients (51 adult and 26 pediatric) in 2 open-label long-term studies, in which 69 patients completed 12 months of treatment with RAVICTI (median exposure = 51 weeks). During these studies there were no deaths.
There is limited information regarding Postmarketing Experience of Glycerol phenylbutyrate in the drug label.
Drug Interactions
Potential for Other Drugs to Affect Ammonia
Corticosteroids
Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Monitor ammonia levels closely when corticosteroids and RAVICTI are used concomitantly.
Valproic Acid and Haloperidol
Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia levels closely when use of valproic acid or haloperidol is necessary in UCD patients.
Potential for Other Drugs to Affect RAVICTI
Probenecid
Probenecid may inhibit the renal excretion of metabolites of RAVICTI including PAGN and PAA.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glycerol phenylbutyrate in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Glycerol phenylbutyrate during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Glycerol phenylbutyrate with respect to nursing mothers.
Pediatric Use
There is no FDA guidance on the use of Glycerol phenylbutyrate with respect to pediatric patients.
Geriatic Use
There is no FDA guidance on the use of Glycerol phenylbutyrate with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Glycerol phenylbutyrate with respect to specific gender populations.
Race
There is no FDA guidance on the use of Glycerol phenylbutyrate with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Glycerol phenylbutyrate in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Glycerol phenylbutyrate in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Glycerol phenylbutyrate in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Glycerol phenylbutyrate in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
RAVICTI should be prescribed by a physician experienced in the management of UCDs. Instruct patients to take RAVICTI with food and to administer directly into the mouth via oral syringe or dosing cup. See the instructions on the use of RAVICTI by nasogastric tube or g-tube .
Preparation for Nasogastric Tube or Gastrostomy Tube Administration
For patients who have a nasogastric tube or gastrostomy tube in place, administer RAVICTI as follows:
Utilize an oral syringe to withdraw the prescribed dosage of RAVICTI from the bottle.
Place the tip of the syringe into to the tip of the gastrostomy/nasogastric tube.
Utilizing the plunger of the syringe, administer RAVICTI into the tube.
Flush once with 30 mL of water and allow the flush to drain.
Flush a second time with an additional 30 mL of water to clear the tube.
Monitoring
There is limited information regarding Monitoring of Glycerol phenylbutyrate in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Glycerol phenylbutyrate in the drug label.
Overdosage
While there is no experience with overdosage in human clinical trials, PAA, a toxic metabolite of RAVICTI, can accumulate in patients who receive an overdose. In case of overdosage, discontinue the drug and contact poison control.
Pharmacology
There is limited information regarding Glycerol phenylbutyrate Pharmacology in the drug label.
