Version May 2024
Urea cycle disorders: Note: Glycerol phenylbutyrate must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements).
Phenylbutyrate-naive patients:
BSA-directed dosing: Note: In patients with some residual enzyme activity and not adequately controlled with protein restriction, the initial dose should be 4.5 mL/m2/day (5 g/m2/day). Dosing presented as mL. 1 mL = 1.1 g of glycerol phenylbutyrate = 1.02 g of phenylbutyrate.
Neonates: Oral: Initial: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) in equally divided doses with food/formula 3 or more times daily; round doses up to the nearest 0.1 mL.
Protein intake directed dosing: Oral: Initial: 0.6 mL for every 1 g dietary protein ingested in a 24-hour period; maximum daily dose: 17.5 mL/day (19 g/day); administer in equally divided doses with food; round up to the nearest 0.1 mL.
Patients switching from sodium phenylbutyrate powder to glycerol phenylbutyrate: Note: Patients should receive the same amount of phenylbutyric acid from the sodium phenylbutyrate dose. Calculate the dosage of glycerol phenylbutyrate (mL) using the following equation:
Neonates: Oral:
Total daily dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81
Note: Doses should be given in equally divided doses with food/formula 3 or more times daily; round doses up to the nearest 0.1 mL.
Dosing adjustment: If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or other intercurrent illnesses, reduce the dose.
Plasma ammonia: When ammonia concentrations are elevated, adjust dose to produce a first ammonia concentration of the morning below the ULN for age. Note: First morning ammonia concentration is preferred in this group as it is harder to obtain a fasting concentration due to frequent feedings.
Urinary phenylacetylglutamine (U-PAGN): If U-PAGN excretion is insufficient to cover daily dietary protein intake (1 g U-PAGN excreted covers waste nitrogen from 1.4 g dietary protein) and fasting ammonia is greater than half the ULN, increase the glycerol phenylbutyrate dose (taking into consideration dietary protein, glycerol phenylbutyrate dose/g of dietary protein, maximum daily dose, and concomitant medications).
Plasma phenylacetate (PAA) and Phenylacetylglutamine (PAGN): No specific dosage adjustment recommendations provided; however, if available, the PAA:PAGN ratio may be helpful in guiding dosage decisions. In patients with a high PAA:PAGN ratio, a further increase in glycerol phenylbutyrate dose may not be beneficial as PAGN formation may not increase (even if PAA concentrations are increased) due to saturation of the conjugation reaction.
Urea cycle disorders: Note: Glycerol phenylbutyrate must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements).
Phenylbutyrate-naive patients:
BSA-directed dosing: Note: In patients with some residual enzyme activity and not adequately controlled with protein restriction, the initial dose should be 4.5 mL/m2/day (5 g/m2/day). Dosing presented as mL. 1 mL = 1.1 g of glycerol phenylbutyrate = 1.02 g of phenylbutyrate.
Infants and Children <2 years: Oral: Initial: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) in equally divided doses with food/formula 3 or more times daily; round doses up to the nearest 0.1 mL.
Children ≥2 years and Adolescents: Oral: Initial: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) in equally divided doses with food 3 times daily; round doses up to the nearest 0.5 mL; maximum daily dose: 17.5 mL/day (19 g/day).
Protein intake directed dosing: Infants, Children, and Adolescents: Oral: Initial: 0.6 mL for every 1 g dietary protein ingested in a 24-hour period; maximum daily dose: 17.5 mL/day (19 g/day); administer in equally divided doses with food; round up to the nearest 0.1 mL (infants and children <2 years) or 0.5 mL (children ≥2 years and adolescents).
Patients switching from sodium phenylbutyrate to glycerol phenylbutyrate: Note: Patients should receive the same amount of phenylbutyric acid from the sodium phenylbutyrate dose. Calculate the dosage of glycerol phenylbutyrate (mL) using the following equation:
Infants, Children, and Adolescents: Oral:
Previously taking tablets: Total daily dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate tablets (g) x 0.86
Previously taking powder: Total daily dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81
Note: Doses should be given in equally divided doses and doses rounded up for infants and children <2 years to the nearest 0.1 mL and for children ≥2 years and adolescents to the nearest 0.5 mL.
Dosing adjustment: If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or other intercurrent illnesses, reduce the dose.
Plasma ammonia: When ammonia concentrations are elevated, increase dose to produce a fasting plasma ammonia concentration to achieve the following goals:
Infants and Children <6 years: First ammonia concentration of the morning: Below the ULN. Note: First morning ammonia concentration is preferred in this group as it is harder to obtain a fasting concentration due to frequent feedings.
Children ≥6 years and Adolescents: Fasting ammonia concentration: Less than half the ULN.
Urinary phenylacetylglutamine (U-PAGN): If U-PAGN excretion is insufficient to cover daily dietary protein intake (1 g U-PAGN excreted covers waste nitrogen from 1.4 g dietary protein) and fasting ammonia is greater than half the ULN, increase the glycerol phenylbutyrate dose (taking into consideration dietary protein, glycerol phenylbutyrate dose/g of dietary protein, maximum daily dose, and concomitant medications).
Plasma phenylacetate (PAA) and Phenylacetylglutamine (PAGN): No specific dosage adjustment recommendations provided; however, if available, the PAA:PAGN ratio may be helpful in guiding dosage decisions. In patients with a high PAA:PAGN ratio, a further increase in glycerol phenylbutyrate dose may not be beneficial as PAGN formation may not increase (even if PAA concentrations are increased) due to saturation of the conjugation reaction.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.
Mild impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Moderate or severe impairment (Child-Pugh class B or C): Initiate dose at the low end of the dosing range (4.5 mL/m2/day [5 g/m2/day]) and keep at lowest dose necessary; use with caution.
(For additional information see "Glycerol phenylbutyrate: Drug information")
Urea cycle disorders: Oral: Note: Doses should be administered in 3 equally divided doses and rounded up to the nearest 0.5 mL; maximum dose: 17.5 mL/day (19 g/day).
Phenylbutyrate-naive patients: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day); Note: In patients with some residual enzyme activity and not adequately controlled with protein restriction, the initial dose should be 4.5 mL/m2/day (5 g/m2/day).
Patients switching from sodium phenylbutyrate to glycerol phenylbutyrate: Patients should receive the same amount of phenylbutyric acid from the sodium phenylbutyrate dose. Calculate the dosage of glycerol phenylbutyrate (mL) using the following equation:
Total daily dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate tablets (g) x 0.86.
Total daily dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81.
Dosing adjustment: If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or other intercurrent illnesses, reduce the dose.
Plasma ammonia: When ammonia concentrations are elevated, increase dose to produce a fasting plasma ammonia level that is less than half the ULN.
Urinary phenylacetylglutamine (U-PAGN): If U-PAGN excretion is insufficient to cover daily dietary protein intake (1 g U-PAGN excreted covers waste nitrogen from 1.4 g dietary protein) and fasting ammonia is greater than half the upper limit of normal, increase the glycerol phenylbutyrate dose (taking into consideration dietary protein, glycerol phenylbutyrate dose/g of dietary protein, maximum daily dose, and concomitant medications).
Plasma phenylacetate (PAA) and phenylacetylglutamine: No specific dosage adjustment recommendations provided; however, PAA concentrations and determination of the PAA:PAGN ratio may be helpful in guiding dosage decisions. Clinicians should note that in patients with a high PAA:PAGN ratio, an increase in dose may not be beneficial as PAGN formation may not increase due to saturation of the conjugation reaction.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.
Mild impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Moderate or severe impairment (Child-Pugh class B or C): Initiate dose at the low end of the dosing range (4.5 mL/m2/day [5 g/m2/day]) and keep at lowest dose necessary; use with caution.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Gastrointestinal: Diarrhea, flatulence
Nervous system: Headache
1% to 10%:
Gastrointestinal: Abdominal pain, decreased appetite, dyspepsia, nausea, vomiting
Nervous system: Fatigue
Postmarketing:
Dermatologic: Body odor (including from hair, abnormal skin odor, and malodorous urine)
Gastrointestinal: Burning sensation of mouth, dysgeusia, gag reflex, retching
Hypersensitivity to glycerol phenylbutyrate or any component of the formulation
Canadian labeling: Additional contraindications (not in US labeling): Breastfeeding.
Concerns related to adverse effects:
• Neurotoxicity: Signs and symptoms of neurotoxicity may occur due to the presence of phenylacetate (PAA; the active metabolite of phenylbutyrate); reduce dose if symptoms are present (eg, confusion, headache, nausea, sleepiness, somnolence, or vomiting) without increased ammonia levels or other illnesses.
Disease-related concerns:
• Altered absorption: Use with caution in patients with pancreatic insufficiency or intestinal malabsorption; absorption of glycerol phenylbutyrate may be reduced; monitor ammonia levels closely in these patients.
• Hepatic impairment: Use caution; conversion of PAA to phenylacetylglutamine (PAGN) occurs in the liver and may lead to a higher plasma PAA concentration and higher PAA:PAGN ratio.
• Renal impairment: Use caution; closely monitor ammonia levels in patients with renal impairment.
Other warnings:
• Appropriate use: Must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements). Not indicated for the treatment of acute hyperammonemia; safety and efficacy for the treatment of N-acetylglutamate synthase deficiency has not been established.
It is recommended that all patients who can swallow take glycerol phenylbutyrate orally, even if a nasogastric and/or gastrostomy tube is present. If patient cannot swallow, glycerol phenylbutyrate may be administered via nasogastric or gastrostomy tube however administration must be followed by a flush of water or formula. Patients requiring <1 mL per dose via nasogastric or gastrostomy should have ammonia concentrations closely monitored during initiation and dosage adjustments; delivered dose may be less than expected due to adherence to plastic tubing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Liquid, Oral:
Ravicti: 1.1 g/mL (25 mL)
No
Liquid (Ravicti Oral)
1.1 g/mL (per mL): $273.22
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Liquid, Oral:
Ravicti: 1.1 g/mL (25 mL)
Ravicti is only available via select specialty pharmacies. Contact UCD Support Services (833-830-7273 or http://www.ucdsupport.com/) for additional information.
Oral: Attach a new reclosable bottle cap adapter with each new bottle. Administer with food or formula. For breastfeeding infants, administer just prior to breastfeeding. Administer directly into mouth using a new, dry oral syringe for each prescribed dose from bottle; discard oral syringe after each dose. Do not rinse reclosable bottle cap adapter; any water or moisture inside the bottle will cause the drug to become cloudy; if this occurs do not use remaining liquid. It is recommended that all patients who can swallow take glycerol phenylbutyrate orally, even if a nasogastric and/or gastrostomy tube is present. If patient cannot swallow, may be administered via nasogastric or gastrostomy tube.
Nasogastric/gastrostomy tube administration: Use a new, dry oral syringe for each dose. Withdraw the prescribed dosage from bottle; place tip of syringe into tip of nasogastric or gastrostomy tube and administer drug. Using a separate syringe, flush nasogastric or gastronomy tube with 10 mL of water or formula and allow the flush to drain. If needed, flush tube a second time with 10 mL of water or formula to clear the tube. Patients requiring <1 mL per dose via nasogastric or gastrostomy tube should have ammonia concentrations closely monitored during initiation and dosage adjustments; delivered dose may be less than expected due to adherence to plastic tubing.
Oral: Attach a new reclosable bottle cap adapter with each new bottle. Administer with food. Administer directly into mouth using a new, dry oral syringe for each prescribed dose from bottle; discard oral syringe after each dose. Do not rinse reclosable bottle cap adapter; water or moisture inside the bottle will cause liquid to become cloudy; if this occurs do not use remaining liquid. It is recommended that all patients who can swallow take glycerol phenylbutyrate orally, even if a nasogastric and/or gastrostomy tube is present. May be administered via nasogastric or gastronomy tube if patient cannot swallow.
Nasogastric/gastrostomy tube administration: Use a new, dry oral syringe to withdraw the prescribed dosage from bottle; place tip of syringe into nasogastric or gastronomy tube and administer drug. Flush nasogastric or gastronomy tube with a separate syringe of 10 mL of water and allow the flush to drain. If needed, flush tube a second time with 10 mL of water to clear the tube. Patients requiring <1 mL per dose via nasogastric or gastrostomy tube should have ammonia concentrations closely monitored during initiation and dosage adjustments; delivered dose may be less than expected due to adherence to plastic tubing.
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Discard any amount not used within 28 days after opening bottle.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203284s012lbl.pdf#page=27, must be dispensed with this medication.
Chronic management of urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone (FDA approved in all ages); Note: NOT indicated for the treatment of acute hyperammonemia in patients with UCDs. The safety and efficacy for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.
Induces CYP3A4 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Atogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider therapy modification
Benperidol: May diminish the therapeutic effect of Urea Cycle Disorder Agents. Risk C: Monitor therapy
CarBAMazepine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy
CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Risk C: Monitor therapy
Corticosteroids (Systemic): May diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Corticosteroids (Systemic) may increase protein catabolism and plasma ammonia concentrations, thereby increasing the doses of Urea Cycle Disorder Agents needed to maintain these concentrations in the target range. Risk C: Monitor therapy
Haloperidol: May diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Haloperidol may increase plasma ammonia concentrations and thereby increase the doses of Urea Cycle Disorder Agents needed to maintain concentrations in the target range. Risk C: Monitor therapy
Hormonal Contraceptives: CYP3A4 Inducers (Weak) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification
NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Risk C: Monitor therapy
Probenecid: May increase serum concentrations of the active metabolite(s) of Urea Cycle Disorder Agents. Specifically, concentrations of phenylacetate and phenylacetylglutamine may be increased. Risk C: Monitor therapy
Selpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy
Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Risk D: Consider therapy modification
Valproate Products: May diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Valproate Products may increase plasma ammonia concentrations and thereby increase the doses of Urea Cycle Disorder Agents needed to maintain concentrations in the target range. Risk C: Monitor therapy
Take with food or formula. Treatment must also consist of dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements).
Phenylbutyrate-naive patients: Determine the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence prior to initiating glycerol phenylbutyrate. An initial daily dose is 0.6 mL/g of dietary protein ingested in 24 hours.
Adverse events have been observed in animal reproduction studies with doses also causing maternal toxicity.
Health care providers are encouraged to report any prenatal exposure to the manufacturer (www.ucdregistry.com or 1-855-823-2595).
Plasma ammonia, PAA, U-PAGN, PAA:PAGN ratio, hepatic and renal function tests; signs/symptoms of neurotoxicity/hyperammonemia (eg, confusion, headache, nausea, sleepiness, somnolence, vomiting)
Glycerol phenylbutyrate is a prodrug of phenylbutyrate (PBA) which is converted to phenylacetate (PAA) by β-oxidation. Phenylacetate conjugates glutamine to form phenylacetylglutamine (PAGN); PAGN serves as a substitute for urea and clears nitrogenous waste from the body when excreted in the urine.
Protein binding: Phenylbutyrate: 81% to 98%; Phenylacetate: 37% to 66%; Phenylacetylglutamine: 7% to 12%
Metabolism: Hepatic and renal: Phenylbutyrate (PBA), a prodrug, is activated by GI lipases. PBA is further metabolized to phenylacetate (PAA) which conjugates with glutamine to form phenylacetylglutamine (PAGN)
Time to peak, plasma: Phenylbutyrate: 2 hours; Phenylacetate: 4 hours; Phenylacetylglutamine: 4 hours
Time to steady state, plasma: Phenylbutyrate: 8 hours; Phenylacetate: 12 hours; Phenylacetylglutamine: 10 hours
Excretion: Urine (primarily as phenylacetylglutamine: Adults ~69%; children ~66%; hepatic impairment 58% to 85%)
Hepatic function impairment: PBA and PAA AUC is increased while PAGN AUC is decreased.
Sex: Women appear to have higher plasma concentrations of metabolites (Cmax 120% higher) and AUC (108% higher) compared to men at a given dosing level.
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