Active Ingredient: Glycerol phenylbutyrate
Glycerol phenylbutyrate is indicated for use as adjunctive therapy for chronic management of patients with urea cycle disorders (UCDs) including deficiencies of carbamoyl phosphate synthetase I (CPS), ornithine carbamoyltransferase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), arginase I (ARG) and ornithine translocase deficiency hyperornithinaemia-hyperammonaemia homocitrullinuria syndrome (HHH) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone.
Glycerol phenylbutyrate must be used with dietary protein restriction and, in some cases, dietary supplements (e.g. essential amino acids, arginine, citrulline, protein-free calorie supplements).
For this indication, competent medicine agencies globally authorize below treatments:
Oral
5.3 - 12.4 g per m² of body surface area (BSA)
From 1.767 To 4.133 g per m² of body surface area (BSA) 3 time(s) per day every day
Glycerol phenylbutyrate must be used with dietary protein restriction and sometimes dietary supplements (e.g. essential amino acids, arginine, citrulline, protein-free calorie supplements) depending on the daily dietary protein intake needed to promote growth and development.
The daily dose should be individually adjusted according to the patient’s protein tolerance and the daily dietary protein intake needed.
Glycerol phenylbutyrate therapy may be required life long unless orthotopic liver transplantation is elected.
The recommended dosages for patients naïve to phenylbutyric acid and for patients switching from sodium phenylbutyrate or from sodium phenylacetate/sodium benzoate injection to glycerol phenylbutyrate are different.
The recommended total daily dose of glycerol phenylbutyrate is based on body surface area and ranges from 4.5 ml/m²/day to 11.2 ml/m²/day [5.3 g/m²/day to 12.4 g/m²/day) and should take into account the following:
The total daily dose should be divided into equal amounts and given with each meal or feeding (e.g. three times to six times per day). Each dose should be rounded up to the nearest 0.1 ml for patients less than 2 years of age and 0.5 ml for patients 2 years of age and older.
Recommended starting dosage in phenylbutyrate-naïve patients:
Initial dosage in patients switching from sodium phenylbutyrate to glycerol phenylbutyrate:
Patients switching from sodium phenylbutyrate to glycerol phenylbutyrate should receive the dosage of glycerol phenylbutyrate that contains the same amount of phenylbutyric acid. The conversion is as follows:
Initial dosage in patients switching from sodium phenylacetate/sodium benzoate injection to glycerol phenylbutyrate:
Once stable with controlled ammonia, patients switching from sodium phenylacetate/sodium benzoate to glycerol phenylbutyrate should receive a dose of glycerol phenylbutyrate at the higher end of the treatment range (11.2 ml/m²/day) with measurements of plasma ammonia to guide further dosing.
The recommended daily dose schedule of 8.5 ml/m²/day-11.2 mL/m²/day over a period of up to 24 hours for patients stabilised with no further hyperammonaemia is as follows:
The daily dose should be individually adjusted according to the patient’s estimated urea synthetic capacity, if any, protein tolerance and the daily dietary protein intake needed to promote growth and development. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered 4-phenylbutyric acid (PBA) dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated glycerol phenylbutyrate dose for a 24-hour period is 0.6 ml glycerol phenylbutyrate per gram of dietary protein ingested per 24 hour period assuming all the waste nitrogen is covered by glycerol phenylbutyrate and excreted as phenylacetylglutamine (PAGN).
The dose of glycerol phenylbutyrate should be adjusted to produce a fasting plasma ammonia level that is less than half the upper limit of normal (ULN) in patients 6 years and older. In infants and young children (generally below 6 years of age) where obtaining fasting ammonia is problematic due to frequent feedings, the first ammonia of the morning should be kept below the ULN.
U-PAGN measurements may be used to help guide glycerol phenylbutyrate dose adjustment and assess compliance. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the recommended ULN, the glycerol phenylbutyrate dose should be adjusted upward. The amount of dose adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-h U-PAGN level and the estimated glycerol phenylbutyrate dose needed per gram of dietary protein ingested.
Spot U-PAGN concentrations below the following levels may indicate improper medicinal product administration and/or lack of compliance:
If spot U-PAGN concentrations fall below these levels, assess compliance with medicinal product and/or effectiveness of medicinal product administration (e.g. via feeding tube) and consider increasing the glycerol phenylbutyrate dose in compliant patients to achieve optimal ammonia control (within normal limit for patients under 2 years of age and less than half ULN in older patients when fasted).
Symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness in the absence of high ammonia or intercurrent illness may be signs of phenylacetic acid (PAA) toxicity. Therefore, measurement of plasma PAA and PAGN levels may be useful to guide dosing. The plasma PAA to PAGN (both measured in mcg/ml) ratio has been observed to be generally less than 1 in patients without PAA accumulation. In patients with a PAA to PAGN ratio exceeding 2.5, a further increase in glycerol phenylbutyrate dose may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction. In such cases, increasing the dosing frequency may result in a lower plasma PAA level and PAA to PAGN ratio. Ammonia levels must be monitored closely when changing the dose of glycerol phenylbutyrate.
The safety and efficacy of glycerol phenylbutyrate for the treatment of patients with N-acetylglutamate synthase (NAGS) and CITRIN (citrullinaemia type 2) deficiency have not been established.
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