glycerol phenylbutyrate

General

Pronunciation:
gli-ser-ol fen-il-bue-ti-rate


Trade Name(s)

  • Ravicti

Ther. Class.
orphan drugs

Pharm. Class.
nitrogen-binding agents

Indications

  • Chronic treatment of hyperammonemia associated with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation, which must be continued.
  • Not to be use for acute treatment of hyperammonemia.

Action

Binds nitrogen.

Therapeutic Effect(s):

Decreased ammonia levels with decreased sequelae of hyperammonemia.

Pharmacokinetics

Absorption: Well absorbed following oral administration.

Distribution: Unknown.

Protein Binding: PBA–80.6–98%.

Metabolism and Excretion: Glycerol phenylbutyrate is a triglyceride prodrug that releases phenylbutyrate (PBA) following the action of lipases in the GI tract. Further metabolism results in conversion to phenylacetate (PAA), the active moiety. PAA binds glutamine in the liver and kidneys forming phenylacetylglutamine (PAGN), which is then renally eliminated (68.9%). Women form a higher percentage of metabolites.

Half-life: Unknown.

TIME/ACTION PROFILE (PAA levels)

ROUTEONSETPEAKDURATION
POunknown4 hr8 hr

Contraindication/Precautions

Contraindicated in:

  • Known hypersensitivity to phenylbutyrate (wheezing, dyspnea, coughing, hypotension, flushing, nausea, rash);
  • Lactation: Avoid breastfeeding;
  • Pedi: Age <2 mo.

Use Cautiously in:

  • Moderate to severe hepatic impairment (initiate treatment at low end of dose range);
  • Pancreatic insufficiency/ intestinal malabsorption (may ↓ absorption of phenylbutyrate);
  • Renal impairment (monitor ammonia levels carefully);
  • Geri: Consider age-related ↓ in renal/hepatic/cardiac function, concurrent disease states and medications;
  • OB: Use only if maternal benefit justifies potential fetal risk.

Adverse Reactions/Side Effects

CNS: headache, fatigue (↑ in adults)

GI: abdominal pain (↑ in children), ↓ appetite, diarrhea, flatulence, nausea, dyspepsia, vomiting

Derm: rash (↑ in children)

Metabolic: hyerammonemia

Neuro: neurotoxicity

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

Route/Dosage

Total daily dose is given in three equally divided doses, adjustments based on plasma ammonia, urinary phenylacetylglutamine or plasma phenylacetate. Consider estimated ability to synthesize urea, dietary protein intake and adherence to dietary recommendations.

PO: (Adults and Children) ≥2 yr): Switching from sodium phenylbutyrate–total daily dose of glycerol phenylbutyrate (mL) = daily dose of sodium phenylbutyrate tablets (g) x 0.86; total daily dose of glycerol phenylbutyrate (mL) = daily dose of sodium phenylbutyrate powder (g) x 0.81; Initial dose in phenylbutyrate naïve patients–4.5–11.2 mL/m2/day (5–12.4 g/m2/day). Total daily dose is divided into three equal doses, rounded up to the nearest 0.5 mL.Hepatic Impairment
PO: (Adults and Children) ≥2 yr): Initiate therapy at lower end of dose range.

Availability

Oral liquid: 1.1 g/mL

Assessment

  • Monitor for signs and symptoms of high blood ammonia (headache, feeling tired, lightheadedness, confusion) periodically during therapy.
  • Monitor for signs and symptoms of neurotoxicity (somnolence, fatigue, lightheadedness, headache, dysgeusia, partial hearing loss, disorientation, impaired memory, exacerbation of preexisting neuropathy). May be seen with plasma PAA concentrations ≥500 mcg/mL.

Lab Test Considerations: Monitor fasting plasma ammonia levels frequently during dose changes. less than half the upper limit of normal according to age.

  • Urinary phenylacetylglutamine (U-PAGN) may be used to help guide dosing. Each gram of U-PAGN excreted over 24 hr covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and fasting ammonia is > half upper limit of normal, adjust dose of glycerol phenylbutyrate upward. Factor in amount of dietary protein not covered in dose adjustment indicated by 24-h U-PAGN level.
  • Monitoring plasma PAA levels can assist with dosing if side effect occur. Ratio of PAA to PAGN in plasma may also assist in dose adjustment.

Potential Diagnoses

Implementation

  • Glycerol phenylbutyrate should only be prescribed by clinicians with experience treating patients with urea cycle disorders.
  • PO: Administer with food and directly into mouth via oral syringe or dosing cup. Store at room temperature.
    • For administration via nasogastric or gastrostomy tube, use oral syringe to withdraw dose, place tip of syringe into tip of gastrostomy/nasogastric tube. Use plunger of syringe to administer medication into tube. Flush once with 30 mL of water and allow flush to drain. Flush a second time with an additional 30 mL of water to clear tube.

Patient/Family Teaching

  • Instruct patient to take glycerol phenylbutyrate as directed along with dietary protein restriction and, if prescribed, dietary supplements (essential amino acids, arginine, citrulline, protein-free calorie supplements). Advise patient to read Medication Guide before starting and with each Rx refill in case of changes.
  • Advise patient to notify health care professional promptly if signs and symptoms of neurotoxicity (sleepiness, worsening neuropathy, weakness, numbness, tingling, lightheadedness, burning in hands or feet, change in taste, problems with hearing, headache, confusion, problems with memory) occur.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Advise female patient to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding. Encourage patients who take Ravicti just before becoming pregnant or who become pregnant during therapy to enroll the pregnancy registry by calling 1-855-823-2595 or visit www.ucdregistry.com.

Evaluation/Desired Outcomes

Decreased ammonia levels for a fasting plasma ammonia level less than half the upper limit of normal according to age with decreased sequelae of hyperammonemia. If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or other illnesses, reduce dose of glycerol phenylbutyrate.

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