Usual Adult Dose for Urea Cycle Disorders

Administer orally in 3 equally divided dosages rounded up to the nearest 0.5 mL:

• Initial dose (Phenylbutyrate-Naive): 5 to 12.4 g/m2/day (4.5 to 11.2 mL/m2/day)
• Initial dose (Phenylbutyrate-Naive with Some Residual Enzyme Activity): 5 g/m2/day (4.5 mL/m2/day)

Switching from Sodium Phenylbutyrate:

• Tablets: Total daily dose of glycerol phenylbutyrate (mL)=total daily dose of sodium phenylbutyrate tablets (g) x 0.86
• Powder: Total daily dose of glycerol phenylbutyrate (mL)=total daily dose of sodium phenylbutyrate powder (g) x 0.81

MAINTENANCE DOSES: Follow clinically and with plasma ammonia levels, especially with changing doses; for elevated plasma ammonia, increase dose to maintain fasting plasma ammonia to less than half the upper limit of normal; if the phenylacetate (PAA) to phenylacetylglutamine (PAGN) ratio and urinary phenylacetylglutamine (U-PAGN) measurement are available, this will help guide dosing; product labeling may be consulted for additional information

MAXIMUM DOSE: 17.5 mL (19 g) per day

Comments:

• See Administration Advice for important administration instructions.
• When determining the starting dose, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence; may consider an initial estimated daily dose of 0.6 mL per gram of dietary protein ingested per 24-hour period.
• Must use with dietary protein restriction and in some cases, with dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
• Not indicated for the treatment of acute hyperammonemia as more rapid interventions should be used.
• Safety and efficacy for treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.

Use: As a nitrogen-binding agent for chronic management of patients with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone.

Usual Pediatric Dose for Urea Cycle Disorders

Administer in 3 equally divided dosages with food or formula directly into mouth via oral syringe; for patients less than 2 years, round up to the nearest 0.1 mL; for patients 2 years or older, round up to the nearest 0.5 mL

Initial dose (Phenylbutyrate-Naive): 5 to 12.4 g/m2/day (4.5 to 11.2 mL/m2/day)
Initial dose (Phenylbutyrate-Naive with Some Residual Enzyme Activity): 5 g/m2/day (4.5 mL/m2/day)

Switching from Sodium Phenylbutyrate:

• Tablets: Total daily dose of glycerol phenylbutyrate (mL)=total daily dose of sodium phenylbutyrate tablets (g) x 0.86
• Powder: Total daily dose of glycerol phenylbutyrate (mL)=total daily dose of sodium phenylbutyrate powder (g) x 0.81

MAINTENANCE DOSES:

• Patients 6 years or older: Follow clinically and with plasma ammonia levels, especially with changing doses; for elevated plasma ammonia, increase dose to maintain fasting plasma ammonia to less than half the upper limit of normal; if the phenylacetate (PAA) to phenylacetylglutamine (PAGN) ratio and urinary phenylacetylglutamine (U-PAGN) measurement are available, this will help guide dosing; product labeling may be consulted for additional information
• Patients less than 6 years: Follow above guidance, however, if obtaining fasting ammonia is problematic due to frequent feedings, adjust the dose to keep the first ammonia of the morning below the upper limit for age

MAXIMUM DOSE: 17.5 mL (19 g) per day

Comments:

• See Administration Advice for important administration instructions.
• When determining the starting dose, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence; may consider an initial estimated daily dose of 0.6 mL per gram of dietary protein ingested per 24-hour period.
• Must use with dietary protein restriction and in some cases, with dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
• Not indicated for the treatment of acute hyperammonemia as more rapid interventions should be used.
• Safety and efficacy for treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.

Use: As a nitrogen-binding agent for chronic management of patients with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone.

Renal Dose Adjustments

Monitor ammonia levels closely when starting treatment

Liver Dose Adjustments

Moderate to severe liver dysfunction: Starting dose should be at the lower end of the dose range; maintain at lowest dose necessary to control ammonia levels

Note: Conversion of PAA to PAGN occurs in the liver, therefore patients with hepatic impairment may have reduced conversion capability and higher plasma PAA and PAA to PAGN ratio

Dose Adjustments

Elderly: Start at the low end of the dosing range to account for decreased hepatic, renal, or cardiac function and concomitant disease or other drug therapies.

Therapeutic drug monitoring/range: Patients should be followed clinically and with plasma ammonia levels.

• Normal ranges and therapeutic target levels for plasma ammonia depend upon the assay method used by the individual laboratory; refer to the laboratory's assay-specific normal ranges and therapeutic target ranges for plasma ammonia.
• Dose adjustments should be made to produce fasting plasma ammonia levels that are less than half the upper limit of normal (ULN) according to age; for pediatric patients below 6 years old for whom obtaining fasting ammonia may be problematic due to frequent feedings, adjust dose so that the first ammonia of the morning is below ULN for age.

DIETARY PROTEIN INTAKE: Urinary Phenylacetylglutamine (U-PAGN) Measurements, when available may be used to guide dose adjustments: 1 g of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 g of dietary protein

• If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia level is greater than half the ULN, the dose should be adjusted upward based on the amount of dietary protein that has not been covered (indicated by the 24 hour U-PAGN level), estimated dose per gram of dietary protein ingested, and maximum total daily dosage.
• Consider concomitant medications, such as probenecid, when making dosage adjustment decisions based on U-PAGN; probenecid may decrease urinary excretion of PAGN.

ELEVATED PLASMA AMMONIA: High plasma phenylacetate (PAA) levels may increase risk for neurotoxicity; the ratio of PAA to PAGN in plasma may provide additional information to assist in dose adjustment decisions.

• The PAA to PAGN ratio has generally been less than 1 in patients who do not have significant plasma PAA accumulation; with a high PAA to PAGN ratio, a further increase in the dose may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction.

Precautions

CONTRAINDICATIONS:

• Hypersensitivity to phenylbutyrate; signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash

Consult WARNINGS section for dosing related precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Take orally with food or formula; for breastfeeding infants, administer just prior to breastfeeding
• Administer directly into mouth via oral syringe as follows:
• Use a new reclosable bottle cap adapter with each new bottle that is opened
• Open bottle and twist on the new reclosable bottle cap adapter
• Use a new and dry oral syringe to withdraw each dose
• Discard oral syringe after each dose
• Tightly close the tethered tab on the reclosable bottle cap adapter after each use
• Do not rinse the reclosable bottle cap adapter
• Discard bottle 28 days after opening
• If water or moisture enters the bottle, the contents will become cloudy in appearance; if contents appear cloudy at any time, do not use; return to the pharmacy to be discarded

Nasogastric Tube or Gastrostomy Tube Administration:

• It is recommended that all patients who can swallow take this drug orally, even those with nasogastric and/or gastrostomy tubes; however, for patients who cannot swallow, administer via a nasogastric tube or gastrostomy tube as follows:
• Use a new dry oral syringe to withdraw each dose from bottle
• Place tip of syringe into the nasogastric or gastrostomy tube
• Using the plunger of the syringe, administer drug into tube
• Using a separate syringe, flush once with 10 mL of water and allow the flush to drain
• If needed, flush a second time with an additional 10 mL of water to clear tube
• For patients who require a volume of less than 1 mL per dose, the delivered dose may be less than anticipated due to adherence to the tubing; closely monitor ammonia levels, especially following initiation and dose adjustments

General:

• This drug should be prescribed by a physician experienced in the management of urea cycle disorders.
• This drug should be used with dietary protein restriction, and possibly, dietary supplements (e.g. essential amino acids, arginine, citrulline, protein-free calorie supplements).
• A voluntary registry for urea cycle disorder (UCD) patients has been established to better assess long-term outcomes including growth and neurocognitive outcomes and pregnancy outcomes. Patients and their caregivers are encouraged to participate; visit www.ucdregistry.com or call 1-855-823-2595.

Monitoring:

• Ammonia levels should be monitored closely during therapy
• If available, Urinary Phenylacetylglutamine (U-PAGN) and Plasma Phenylacetate (PAA) levels may be useful to guide therapy.

Patient advice:

• Patients should be instructed to read the US FDA-approved patient labeling (Medication Guide).
• This drug may cause nervous system side effects and patients should be instructed to contact their healthcare professional promptly if these side effects occur.
• This drug is to be used in conjunction with dietary protein restriction, and in some cases, dietary supplements.
• Patients should talk to their health care provider if they are pregnant, planning on becoming pregnant, or are breastfeeding.