Ravicti (Glycerol phenylbutyrate) is an FDA-approved drug for use in children older than 2 months of age for the treatment of urea cycle disorders. It removes the excessive ammonia from the blood via urine.

Ravicti (Glycerol phenylbutyrate) Uses:

• Urea cycle disorders:

  • Glycerol phenylbutyrate is used in the management of urea cycle disorders (UCDs) that cannot be treated by dietary protein restriction or amino acid supplementation alone.

Ravicti (Glycerol phenylbutyrate) Dose in Adults

Ravicti (Glycerol phenylbutyrate) Dose in the treatment of Urea cycle disorders: Oral:

Note:

• The dose should be administered in 3 equal divided doses and approximated up to the nearest 0.5 mL.
• Its maximum dose is 17.5 mL/day (19 g/day).

• Phenylbutyrate-naïve patients:

  • Those patients who never received this drug should be started as 5 to 11.2 mL/m² (5 to 12.4 g/m²) daily.
  • Note: In patients with some residual enzyme activity and not having good control over protein restriction, their initial dose should be 4.5 mL/m² (5 g/m²) daily.

• Patients switching from sodium phenylbutyrate to glycerol phenylbutyrate:

  • Patients should receive the same amount of phenyl butyric acid from the sodium phenylbutyrate dose.
  • The dose should be calculated using the following formula.
    • 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, cut down the dose.
    • Plasma ammonia:
      • When ammonia concentrations are increased, adjust the dose to produce a fasting plasma ammonia level that is less than half the upper limit of normal according to age.
    • 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 particular dose adjustment recommendations are provided.
      • However, PAA concentrations and determination of the PAA: PAGN ratio may be helpful in guiding dose adjustment decisions.
      • Clinicians should note that in patients with a high PAA: PAGN ratio, an increase in medication may not be beneficial as PAGN formation may not increase due to saturation of the conjugation reaction.

Ravicti (Glycerol phenylbutyrate) Dose in Childrens

Ravicti (Glycerol phenylbutyrate) Dose in the treatment of 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-naïve patients:

  • BSA-directed dosing:

Note:

• In patients with some residual enzyme activity and not having requred control with protein restriction, the initial dose should be 4.5 mL/m²/day (5 g/m²/day).
• The dosing presented as mL. 1 mL=1.1 grams of glycerol phenylbutyrate=1.02 grams of phenylbutyrate.
  • • Infants ≥2 months and Children <2 years:
      • Oral: Initial: 4.5 to 11.2 mL/m /day (5 to 12.4 g/m /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 ≥2 months, Children, and Adolescents:
      • Oral: Initial: 0.6 mL for every 1 g dietary protein ingested in a 24-hour period;
      • The 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 ≥2 months and children <2 years) or 0.5 mL (children ≥2 years and adolescents)

  • Patients switching from sodium phenylbutyrate to glycerol phenylbutyrate:

    • Infants ≥2 months, Children, and Adolescents:
    • Note:
      • Patients should receive the same amount of phenyl butyric acid from the sodium phenylbutyrate dose.
      • Calculate the dosage of glycerol phenylbutyrate (mL) using the following equation:
    • 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 ≥2 months and children <2 years to the nearest 0.1 mL and for children ≥2 years and adolescents to the nearest 0.5 mL.

• Ravicti (Glycerol phenylbutyrate) 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 the dose to produce a fasting plasma ammonia concentration to achieve the following goals:
    • Infants ≥2 months and Children <6 years:
      • First ammonia concentration of the morning: Below the upper limit of normal.
      • Note: First-morning ammonia concentration preferred as this group is harder to obtain a fasting concentration due to frequent feedings.
    • Children ≥6 years and Adolescents:
      • Fasting ammonia concentration: Less than half the upper limit of normal.

  • 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 particular dosage adjustment recommendations are required.
    • 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.

Ravicti (Glycerol phenylbutyrate) Pregnancy Risk Category: C

• Animal reproduction studies have shown adverse events, with maternal toxicities also being observed.
• Health care providers are encouraged to report any prenatal exposure to the manufacturer (www.ucdregistry.com or 1-855-823-2595).

Use of glycerol phenylbutyrate during breastfeeding

• It is unknown if glycerol-phenylbutyrate is secreted into breast milk.
• The manufacturer does not recommend breastfeeding due to the risk of serious adverse reactions in nursing infants.

Dose in Kidney Disease:

There are no dosage adjustments provided by the manufacturer’s labeling (it has not been studied). It should be used with caution.

Ravicti (Glycerol phenylbutyrate) Dose in Liver disease:

• Mild impairment (Child-Pugh class A):
  • There are no dosage adjustments provided in the manufacturer’s labeling, it should be used 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/m [5 g/m ]) daily and keep at the lowest dose necessary; use with caution.

Common Side Effects of Ravicti (Glycerol phenylbutyrate):

• Central Nervous System:

  • Headache

• Gastrointestinal:

  • Diarrhea
  • Flatulence

Less Common Side Effects Of Ravicti (Glycerol phenylbutyrate):

• Central Nervous System:

  • Fatigue

• Gastrointestinal:

  • Abdominal Pain
  • Decreased Appetite
  • Vomiting
  • Dyspepsia
  • Nausea

Side effects of Ravicti (Glycerol phenylbutyrate) Frequency Not Defined:

• Central Nervous System:

  • Dizziness
  • Peripheral Neuropathy
  • Seizure

• Neuromuscular & Skeletal:

  • Tremor

Contraindications to Ravicti (Glycerol phenylbutyrate):

Hypersensitivity to glycerol Phenylbutyrate, or any other component of the formulation

Canadian labeling: Additional contraindications not in US labeling

• Breastfeeding

Warnings and precautions

• Neurotoxicity:

  • Neurotoxicity can be caused by the presence of Phenylacetate (PAA, the active metabolite phenylbutyrate).
  • If symptoms (eg, confusion headache, nausea, somnolence or vomiting), are present, reduce the dose without increasing ammonia levels.

• Absorption altered:

  • Patients with intestinal malabsorption or pancreatic insufficiency should be cautious.
  • Absorption of glycerol Phenylbutyrate can be decreased; closely monitor ammonia levels in these patients.

• Hepatic impairment

  • Be careful
  • Patients with severe or moderate hepatic impairment may need to adjust their dosage.

• Renal impairment

  • Patients with kidney impairment should be cautious and closely monitor their ammonia levels.

Glycerol phenylbutyrate: Drug Interaction

Monitoring parameters:

• Plasma ammonia, PAA, U-PAGN.
• Hepatic and renal function tests.
• Signs & symptoms of neurotoxicity/hyperammonemia (eg, confusion, headache, nausea, sleepiness, somnolence, and vomiting)

How to administer Ravicti (Glycerol phenylbutyrate)?

Oral:

• Administration with food is recommended.
• Administer directly into the mouth using an oral syringe or dosing cup.
• It is recommended that all patients who can swallow take glycerol phenylbutyrate orally, even if a nasogastric and/or gastrostomy tube is present.
• It may be administered via nasogastric or gastronomy tube if the patient cannot swallow.
• Use an oral syringe to withdraw the prescribed dosage from the bottle.
• Place the tip of the syringe into the nasogastric or gastronomy tube and administer the drug.
• Flush nasogastric or gastronomy tube with 10 mL of water or formula and allow the flush to drain.
• If needed, flush the 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.
• The delivered dose may be less than expected due to adherence to plastic tubing.

Mechanism of action of Ravicti (Glycerol phenylbutyrate):

• Glycerol-phenylbutyrate, a prodrug for phenylbutyrates (PBA), is converted by boxidation to phenylacetate. 
• Phenylacetate conjugates glutamine to form phenylacetylglutamine (PAGN).
• PAGN is a replacement for urea. It clears the body of nitrogenous waste when it is 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%)

International Brand Names of Glycerol phenylbutyrate:

• Ravicti

Glycerol phenylbutyrate Brand Names in Pakistan:

No Brands Available in Pakistan.