glycerol phenylbutyrate

Absorption: Well absorbed following oral administration.

Distribution: Unknown.

Protein Binding: PBA: 80.6–98%.

Metabolism/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)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	4 hr	8 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Known hypersensitivity to phenylbutyrate (wheezing, dyspnea, coughing, hypotension, flushing, nausea, rash);
Acute hyperammonemia;
Lactation: Lactation.

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);
OB: Safety not established in pregnancy;
Geri: Consider age-related ↓ in renal/hepatic/cardiac function, concurrent disease states and medications in older adults.

Adv. Reactions/Side Effects ⬆ ⬇

Derm: rash (↑ in children)

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

Metab: hyperammonemia

Neuro: fatigue (↑ in adults), headache, neurotoxicity

Interactions ⬆ ⬇

Drug-drug:

Ammonia levels may be ↑ by corticosteroids, .haloperidol or valproic acid, monitor carefully.
Probenecid↓ renal excretion of metabolites PAGN and PAA.
May ↓ levels and effects of CYP3A4 substrates, including cyclosporine, midazolam, and quinidine.

Route/Dosage ⬆ ⬇

Total daily dose is given in 3 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 ): 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). For patients ≥2 yr, total daily dose is divided into 3 equal doses, rounded up to the nearest 0.5 mL. For patients <2 yr, total daily dose is divided into 3 equal doses, rounded up to the nearest 0.1 mL. Maximum daily dose = 19 g (17.5 mL).

Hepatic Impairment

PO (Adults and Children ): 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.
- 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 phenylacetate (PAA) levels can assist with dosing if side effect occur. Ratio of PAA to PAGN in plasma may also assist in dose adjustment.

Implementation ⬆ ⬇

Glycerol phenylbutyrate should only be prescribed by clinicians with experience treating patients with urea cycle disorders.
PO: Administer with food or formula directly into mouth via oral syringe. For breastfeeding infants, administer just prior to breastfeeding. Use a new and dry oral syringe to withdraw each dose. Discard oral syringe after each dose. Attach a new reclosable bottle cap adapter with each new bottle; do not rinse. If water or moisture enters the bottle, contents will become cloudy. If solution is cloudy at any time, do not use the remaining solution in the bottle; return it to the pharmacy to be discarded. Store at room temperature. Discard bottle and any remaining contents 28 days after opening.
- 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 using a separate syringe with 10 mL of water or formula and allow flush to drain. Flush a second time with an additional 10 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.
Rep: Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding. .

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.

US Brand Names ⬆ ⬇

Code ⬆

NDC Code

14501- MSN Laboratories Private Limited
- 14501-0097-
  - 14501-0097-4- 10 kg in 1 DRUM (14501-0097-4)

45941- Patheon Austria GmbH & CoKG
- 45941-3054-
  - 45941-3054-1- 200 kg in 1 DRUM (45941-3054-1)

58159- NURAY CHEMICALS PRIVATE LIMITED
- 58159-034-
  - 58159-034-01- 35 kg in 1 BOTTLE (58159-034-01)

58159- NURAY CHEMICALS PRIVATE LIMITED
- 58159-034-
  58159-034-02- 20 kg in 1 BOTTLE (58159-034-02)

58159- NURAY CHEMICALS PRIVATE LIMITED
- 58159-034-
  58159-034-03- 15 kg in 1 BOTTLE (58159-034-03)

58159- NURAY CHEMICALS PRIVATE LIMITED
- 58159-034-
  58159-034-04- 10 kg in 1 BOTTLE (58159-034-04)

58159- NURAY CHEMICALS PRIVATE LIMITED
- 58159-034-
  58159-034-05- 5 kg in 1 BOTTLE (58159-034-05)

59651- Aurobindo Pharma Limited
- 59651-990-
  59651-990-37- 1 kg in 1 BOTTLE, GLASS (59651-990-37)

63069- PENN PHARMACEUTICAL SERVICES LIMITED
- 63069-106-
  63069-106-01- 25 mL in 1 BOTTLE (63069-106-01)

65977- Hetero Drugs Limited
- 65977-0121-
  65977-0121-1- 5 kg in 1 DRUM (65977-0121-1)

67262- HAS Healthcare Advanced Synthesis SA
- 67262-0008-
  67262-0008-1- 50 kg in 1 DRUM (67262-0008-1)

67262- HAS Healthcare Advanced Synthesis SA
- 67262-0009-
  67262-0009-1- 200 kg in 1 DRUM (67262-0009-1)

75987- Horizon Therapeutics USA, Inc.
- 75987-050- Ravicti
  75987-050-06- 1 BOTTLE in 1 CARTON (75987-050-06) / 25 mL in 1 BOTTLE

75987- Horizon Therapeutics USA, Inc.
- 75987-050- Ravicti
  - 75987-050-07- 4 BOTTLE in 1 CARTON (75987-050-07) / 25 mL in 1 BOTTLE

83786- LUPIN MANUFACTURING SOLUTIONS LIMITED
- 83786-009-
  - 83786-009-03- 1 BOTTLE, GLASS in 1 BOTTLE, GLASS (83786-009-03) / 10 kg in 1 BOTTLE, GLASS

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇