Glycerol phenylbutyrate

Glycerol phenylbutyrate oral liquid is indicated for 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. Glycerol phenylbutyrate oral liquid must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements). Limitations of Use: Glycerol phenylbutyrate oral liquid is not indicated for the treatment of acute hyperammonemia in patients with UCDs because more rapidly acting interventions are essential to reduce plasma ammonia levels. …

• Glycerol phenylbutyrate oral liquid should be prescribed by a physician experienced in management of UCDs
• For administration and preparation, see full prescribing information
• Switching From Sodium Phenylbutyrate Tablets or Powder to Glycerol Phenylbutyrate Oral Liquid : Patients should receive the dosage of glycerol phenylbutyrate oral liquid that contains the same amount of phenylbutyric acid, see full prescribing information for conversion
• Initial Dosage in Phenylbutyrate-Naïve Patients : Recommended dosage range is 4.5 to 11.2 mL/m 2 /day (5 to 12.4 g/m 2 /day)
• For patients with some residual enzyme activity not adequately controlled with dietary restriction, the recommended starting dose is 4.5 mL/m 2 /day
• Take into account patient's estimated urea synthetic capacity, dietary protein intake, and diet adherence
• Dosage Adjustment and Monitoring : Follow plasma ammonia levels to determine the need for dosage titration
• Dosage Modifications in Patients with Hepatic Impairment : Start dosage at lower end of range
• Important Administration Instructions Glycerol phenylbutyrate oral liquid should be prescribed by a physician experienced in the management of UCDs
• Instruct patients to take glycerol phenylbutyrate oral liquid with food or formula and to administer directly into the mouth via oral syringe
• Instruct patients to use the glycerol phenylbutyrate oral liquid bottle and oral syringe as follows: Use a new reclosable bottle cap adapter with each new bottle that is opened. …

Oral liquid: a clear colorless to pale yellow, 1.1 g/mL of glycerol phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate). Oral liquid: 1.1 g/mL. ( 3 )

• Patients 2 Years to 17 Years of Age The safety and effectiveness of glycerol phenylbutyrate in patients 2 years to less than 18 years of age have been established in 3 clinical studies: 2 open-label, fixed-sequence, switchover clinical studies from sodium phenylbutyrate to glycerol phenylbutyrate, and 1 long-term, open label safety study [see Adverse Reactions , Clinical Studies ]
• Patients Less Than 2 Years of Age The safety and effectiveness of glycerol phenylbutyrate in patients with UCDs less than 2 years of age have been established in 3 open-label studies. …

Clinical studies of glycerol phenylbutyrate did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. …

• Advise the patient to read the FDA-approved patient labeling (Medication Guide)
• Neurotoxicity [see Warnings and Precautions ]
• Inform patients/caregivers that adverse reactions of glycerol phenylbutyrate are sometimes the same as symptoms of high blood ammonia
• Neurological adverse reactions may also be associated with the major metabolite of glycerol phenylbutyrate, PAA, and may be reversible
• Blood tests for PAA may be done to measure the amount of PAA in the blood. …

• Glycerol phenylbutyrate oral liquid is contraindicated in patients with known hypersensitivity to phenylbutyrate
• Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash
• Known hypersensitivity to phenylbutyrate

Corticosteroids, valproic acid, or haloperidol : May increase plasma ammonia level; monitor ammonia levels closely. ( 7.1 ) Probenecid : May affect renal excretion of metabolites of glycerol phenylbutyrate, including phenylacetylglutamine (PAGN) and PAA. ( 7.2 ) CYP3A4 Substrates with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine) : Glycerol phenylbutyrate may decrease exposure; monitor for decreased efficacy of the narrow therapeutic index drug. ( 7.3 ) Midazolam : Decreased exposure; monitor for suboptimal effect of midazolam. …

Neurotoxicity : Phenylacetate (PAA), the active moiety of glycerol phenylbutyrate, may be toxic; reduce dosage for symptoms of neurotoxicity. ( 5.1 ) Pancreatic Insufficiency or Intestinal Malabsorption: Monitor ammonia levels closely. ( 5.2 ) 5.1 Neurotoxicity Increased exposure to PAA, the major metabolite of glycerol phenylbutyrate, may be associated with neurotoxicity in patients with UCDs. In a study of adult cancer patients, subjects received sodium phenylacetate administered as a 1-hour infusion twice daily at two dose levels of 125 and 150 mg/kg for a 2-week period. Of 18 subjects enrolled, 7 had a history of primary central nervous system tumor. …

The following clinically significant adverse reactions are described elsewhere in the labeling: Neurotoxicity [see Warnings and Precautions (5.1) ] Pancreatic insufficiency or Intestinal Malabsorption [see Warnings and Precautions (5.2) ] Most common adverse reactions (≥10%) in adults are: diarrhea, flatulence, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . …

8.1 Pregnancy Risk Summary Limited available data with glycerol phenylbutyrate use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In an animal reproduction study, administration of oral glycerol phenylbutyrate to pregnant rabbits during organogenesis at doses up to 2.7–times the dose of 6.87 mL/m 2 /day in adult patients resulted in maternal toxicity, but had no effects on embryo-fetal …

While there is no experience with overdosage in human clinical trials, PAA, a toxic metabolite of glycerol phenylbutyrate, can accumulate in patients who receive an overdose [see Warnings and Precautions (5.1) ] . If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

Take it when you remember, unless it is nearly time for the next dose. Then skip the missed one. Never take two doses at once to make up for it. Check your leaflet, as some medicines are different.