Glycerol phenylbutyrate (brand name Ravicti) is a medication used to treat urea cycle disorders (UCDs), a group of rare genetic disorders that affect the body's ability to remove ammonia from the blood. It is specifically approved for the chronic management of UCDs in adult and pediatric patients aged two months and older. Glycerol phenylbutyrate works by providing an alternative pathway for waste nitrogen excretion, which helps to reduce the buildup of ammonia in the blood.

Glycerol phenylbutyrate is a prodrug, meaning it is converted into phenylbutyric acid in the body, which then conjugates with glutamine in the liver to form phenylacetylglutamine. This compound is then excreted through the urine, removing excess nitrogen from the body.

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:

When treating urea cycle disorders with glycerol phenylbutyrate orally:

• The dose should be divided into three equal parts and rounded up to the nearest 0.5 mL.
• The maximum daily dose is 17.5 mL or 19 grams.

For patients who haven't taken phenylbutyrate before:

• The daily dose ranges from 4.5 to 11.2 mL per square meter (5 to 12.4 grams per square meter).
• Patients with some remaining enzyme activity and insufficient control with protein restriction should start with 4.5 mL per square meter (5 grams per square meter) daily.

For patients switching from sodium phenylbutyrate to glycerol phenylbutyrate:

• The glycerol phenylbutyrate dose should provide the same amount of phenylbutyric acid as the sodium phenylbutyrate dose.
• Calculate the glycerol phenylbutyrate dosage using the provided equations.

Dosing adjustments:

• If experiencing symptoms like vomiting, nausea, headache, sleepiness, or confusion without high ammonia or other illnesses, reduce the dose.
• Adjust the dose to maintain fasting plasma ammonia levels below half the upper limit of normal for age when ammonia levels are high.
• If urinary phenylacetylglutamine (U-PAGN) levels are insufficient to cover daily protein intake and fasting ammonia levels are high, increase the glycerol phenylbutyrate dose, considering dietary protein, maximum daily dose, and other medications.
• While there are no specific dosage adjustments recommended based on plasma phenylacetate (PAA) and phenylacetylglutamine levels, monitoring these levels may help guide dosage decisions. If the PAA:PAGN ratio is high, increasing the dose may not be beneficial as PAGN formation may not increase due to saturation of the conjugation reaction.

Ravicti (Glycerol phenylbutyrate) Dose in Children

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

For patients who haven't used phenylbutyrate before:

• Infants (2 months and older) and children under 2 years: Start with 4.5 to 11.2 mL per square meter of body surface area daily, divided into several doses with food.
• Children (2 years and older) and adolescents: Same initial dose as infants, also divided into three doses daily with food. The maximum daily dose is 17.5 mL or 19 grams.

Another dosing method is based on protein intake:

• Infants, children, and adolescents: Start with 0.6 mL for every 1 gram of dietary protein ingested per day. The maximum daily dose remains 17.5 mL or 19 grams.

For patients switching from sodium phenylbutyrate to glycerol phenylbutyrate:

• Use an equation to calculate the glycerol phenylbutyrate dose based on the previous sodium phenylbutyrate dose.

Dosage adjustments may be needed based on symptoms and test results:

• If experiencing certain symptoms without high ammonia levels, reduce the dose.
• Adjust the dose to achieve specific fasting plasma ammonia concentrations.
• If urinary phenylacetylglutamine levels are low and fasting ammonia levels are high, increase the dose.
• Plasma phenylacetate and phenylacetylglutamine levels can guide dosage decisions, particularly the ratio between them.

Ravicti (Glycerol phenylbutyrate) Pregnancy Risk Category: C

• In animal studies, adverse effects were seen when doses were given during pregnancy, which also caused harm to the mothers.
• It's essential for healthcare providers to report any instances of prenatal exposure to the manufacturer.

Use of glycerol phenylbutyrate during breastfeeding

• It's uncertain whether glycerol phenylbutyrate passes into breast milk.
• Because of the possibility of serious side effects in nursing infants, the manufacturer doesn't recommend breastfeeding while using this medication.

Dose in Kidney Disease:

• The manufacturer's instructions do not include specific dosage adjustments for individuals with renal impairment since this has not been studied.
• Therefore, if someone has kidney problems, it's essential to use glycerol phenylbutyrate cautiously and under close medical supervision.

Ravicti (Glycerol phenylbutyrate) Dose in Liver disease:

• For individuals with mild impairment (Child-Pugh class A), the manufacturer's labeling does not offer specific dosage adjustments, so it's recommended to use glycerol phenylbutyrate cautiously in such cases.

• In cases of moderate or severe impairment (Child-Pugh class B or C), it's advised to start treatment at the lower end of the dosing range, typically 4.5 mL/m or 5 g/m daily.

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 of its components is a contraindication for its use.
• Additionally, in Canadian labeling, breastfeeding is listed as an additional contraindication, though this information may not be present in US labeling.
• This means that if someone is allergic to glycerol phenylbutyrate or any of its ingredients, or if they are breastfeeding, they should not use this medication.

Warnings and precautions

Neurotoxicity:

• Neurotoxicity can happen because of phenylacetate (PAA), which is the active form of phenylbutyrate.
• If someone experiences symptoms like confusion, headache, nausea, sleepiness, or vomiting without increased ammonia levels or other illnesses, it may indicate neurotoxicity.
• In such cases, the dose of glycerol phenylbutyrate should be reduced.

Absorption altered:

• Patients with conditions such as pancreatic insufficiency or intestinal malabsorption may have altered absorption of glycerol phenylbutyrate.
• As a result, it's important to use this medication cautiously in such individuals.

Hepatic impairment

• In individuals with moderate to severe hepatic impairment, caution should be exercised when using glycerol phenylbutyrate.
• Depending on the severity of the impairment, dosage adjustments may be necessary.

Renal impairment

• In individuals with renal impairment, it's important to use glycerol phenylbutyrate with caution.

Glycerol phenylbutyrate: Drug Interaction

Monitoring parameters:

Plasma Ammonia Levels:

• Regular monitoring of plasma ammonia levels is important to assess the effectiveness of glycerol phenylbutyrate in managing urea cycle disorders.
• Adjustments to the dosage may be necessary based on plasma ammonia concentrations to ensure they remain within the desired range.

Plasma Phenylacetate (PAA) and Phenylacetylglutamine (U-PAGN) Levels:

• Monitoring these levels can help evaluate the metabolism of glycerol phenylbutyrate and guide dosage decisions.
• Changes in PAA and U-PAGN concentrations may indicate the need for dose adjustments or further evaluation.

Hepatic and Renal Function Tests:

• Patients' liver and kidney function should be assessed regularly to ensure they can safely metabolize and eliminate glycerol phenylbutyrate from their bodies.
• Monitoring hepatic and renal function helps identify any potential complications or the need for dosage adjustments in patients with liver or kidney impairment.

Signs and Symptoms of Neurotoxicity/Hyperammonemia:

• Healthcare providers should closely monitor patients for signs and symptoms of neurotoxicity or hyperammonemia, such as confusion, headache, nausea, sleepiness, somnolence, and vomiting.
• Prompt identification and management of these symptoms are crucial to prevent complications and optimize patient outcomes.

How to administer Ravicti (Glycerol phenylbutyrate)?

Oral Administration:

• Glycerol phenylbutyrate should be taken with food.
• Administer the medication directly into the mouth using an oral syringe or dosing cup.
• It's recommended that all patients who are able to swallow take glycerol phenylbutyrate orally, even if they have a nasogastric or gastrostomy tube.
• If a patient cannot swallow, the medication may be administered via a nasogastric or gastrostomy tube.
• Use an oral syringe to withdraw the prescribed dosage from the bottle.
• Place the tip of the syringe into the nasogastric or gastrostomy tube and administer the drug.
• Flush the nasogastric or gastrostomy tube with 10 mL of water or formula and allow the flush to drain.
• If necessary, flush the tube a second time with 10 mL of water or formula to clear it.
• Patients requiring less than 1 mL per dose via nasogastric or gastrostomy tube should have their ammonia concentrations closely monitored during initiation and dosage adjustments, as the delivered dose may be less than expected due to adherence to plastic tubing.

Mechanism of action of Ravicti (Glycerol phenylbutyrate):

• Glycerol phenylbutyrate works as a prodrug of phenylbutyrate (PBA).
• Once ingested, it undergoes a process called β-oxidation, converting it into phenylacetate (PAA).
• Phenylacetate then combines with glutamine to create phenylacetylglutamine (PAGN).
• This compound acts as a substitute for urea, aiding in the removal of nitrogenous waste from the body.
• Ultimately, PAGN is excreted in the urine, helping to clear nitrogenous waste products from the body.
• This mechanism is essential in managing conditions like urea cycle disorders, where the body struggles to remove ammonia efficiently.

Protein Binding:

• Phenylbutyrate: Binds to proteins in the range of 81% to 98%.
• Phenylacetate: Protein binding ranges from 37% to 66%.
• Phenylacetylglutamine: Shows protein binding in the range of 7% to 12%.

Metabolism:

• Hepatic and Renal: Phenylbutyrate (PBA), the prodrug, is activated by gastrointestinal lipases. It is then metabolized further to phenylacetate (PAA), which conjugates with glutamine to form phenylacetylglutamine (PAGN).

Time to Peak Plasma Concentration:

• Phenylbutyrate: Reaches peak plasma concentration approximately 2 hours after administration.
• Phenylacetate: Peaks in plasma around 4 hours after administration.
• Phenylacetylglutamine: Attains peak plasma concentration approximately 4 hours after administration.

Time to Steady State Plasma Concentration:

• Phenylbutyrate: Takes approximately 8 hours to reach steady-state plasma concentration.
• Phenylacetate: Requires about 12 hours to reach steady-state plasma concentration.
• Phenylacetylglutamine: Reaches steady state in plasma around 10 hours after administration.

Excretion:

• Glycerol phenylbutyrate and its metabolites are primarily excreted in urine.
• Phenylacetylglutamine, the major metabolite, is excreted primarily in urine.
• In adults, approximately 69% of the drug is excreted in urine, while in children, it's around 66%.
• Hepatic impairment may affect excretion rates, with 58% to 85% of the drug excreted in urine in such cases.

International Brand Names of Glycerol phenylbutyrate:

• Ravicti

Glycerol phenylbutyrate Brand Names in Pakistan:

No Brands Available in Pakistan.