Sodium phenylbutyrate

INDICATIONS AND USAGE Sodium Phenylbutyrate Tablets is indicated as adjunctive therapy in the chronic management of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). It is indicated in all patients with neonatal-onset deficiency (complete enzymatic deficiency, presenting within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzymatic deficiency, presenting after the first month of life) who have a history of hyperammonemic encephalopathy. It is important that the diagnosis be made early and treatment initiated immediately to improve survival. Any episode of acute hyperammonemia should be treated as a life-threatening emergency. Sodium Phenylbutyrate Tablets must be combined with dietary protein restriction and, in some cases, essential amino acid supplementation. (See Nutritional Supplementation subsection of the DOSAGE AND ADMINISTRATION section.) Previously, neonatal-onset disease was almost universally fatal within the first year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen-free analogs. However, with hemodialysis, use of alternative waste nitrogen excretion pathways (sodium phenylbutyrate, sodium benzoate, and sodium phenylacetate), dietary protein restriction, and, in some cases, essential amino acid supplementation, the survival rate in newborns diagnosed after birth but within the first month of life is almost 80%. Most deaths have occurred during an episode of acute hyperammonemic encephalopathy. Patients with neonatal-onset disease have a high incidence of mental retardation. Those who had IQ tests administered had an incidence of mental retardation as follows: ornithine transcarbamylase deficiency, 100% (14/14 patients tested); argininosuccinic acid synthetase deficiency, 88% (15/17 patients tested); and carbamylphosphate synthetase deficiency, 57% (4/7 patients tested). Retardation was severe in the majority of the retarded patients. In patients diagnosed during gestation and treated prior to any episode of hyperammonemic encephalopathy, survival is 100%, but even in these patients, most subsequently demonstrate cognitive impairment or other neurologic deficits. In late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase deficiency, who recover from hyperammonemic encephalopathy and are then treated chronically with Sodium Phenylbutyrate Tablets and dietary protein restriction, the survival rate is 98%. The two deaths in this group of patients occurred during episodes of hyperammonemic encephalopathy. However, compliance with the therapeutic regimen has not been adequately documented to allow evaluation of the potential for Sodium Phenylbutyrate Tablets and dietary protein restriction to prevent mental deterioration and recurrence of hyperammonemic encephalopathy if carefully adhered to. The majority of these patients tested (30/46 or 65%) have IQ's in the average to low average/borderline mentally retarded range. Reversal of pre-existing neurologic impairment is not likely to occur with treatment and neurologic deterioration may continue in some patients. Even on therapy, acute hyperammonemic encephalopathy recurred in the majority of patients for whom the drug is indicated. Sodium Phenylbutyrate Tablets may be required life-long unless orthotopic liver transplantation is elected. (See CLINICAL PHARMACOLOGY , Pharmacodynamics subsection for the biochemical effects of Sodium Phenylbutyrate Tablets).

DOSAGE AND ADMINISTRATION For oral use only. The use of sodium phenylbutyrate Tablets is indicated for children weighing more than 20 kg and for adults. The usual total daily dose of sodium phenylbutyrate tablets for patients with urea cycle disorders is 450–600 mg/kg/day in patients weighing less than 20 kg, or 9.9–13.0 g/m 2 /day in larger patients. The tablets are to be taken in equally divided amounts with each meal or feeding (i.e., three to six times per day). The effect of food on sodium phenylbutyrate has not been determined. The safety or efficacy of doses in excess of 20 grams (40 tablets) per day has not been established. NUTRITIONAL MANAGEMENT To promote growth and development, plasma levels of ammonia, arginine, branched-chain amino acids, and serum protein should be maintained within normal limits while plasma glutamine is maintained at levels less than 1,000 μmol/L. Minimum daily protein intake for a patient of a particular age should be taken from, for example, "Recommended Dietary Allowances", 10th ed., Food and Nutrition Board, National Academy of Sciences, 1989. The allocation of dietary nitrogen into natural protein and essential amino acids is a function of age, residual urea cycle enzyme activity, and the dose of sodium phenylbutyrate. At the recommended dose of sodium phenylbutyrate, it is suggested that infants with neonatal-onset CPS and OTC deficiencies initially receive a daily dietary protein intake limited to approximately 1.6 g/kg/day for the first 4 months of life. If tolerated, the daily protein intake may be increased to 1.9 g/kg/day during this period. Protein tolerance will decrease as the growth rate decreases, requiring a reduction in dietary nitrogen intake. From 4 months to 1 year of age, it is recommended that the infant receive at least 1.4 g/kg/day, but 1.7 g/kg/day is advisable. From 1 to 3 years of age, the protein intake should not be less than 1.2 g/kg/day; 1.4 g/kg/day is advisable during this period. For neonatal-onset patients with carbamylphosphate synthetase deficiency or ornithine transcarbamylase deficiency who are at least 6 months of age, it is recommended that the daily protein intake be equally divided between natural protein and supplemental essential amino acids. Patients with argininosuccinic acid synthetase deficiency and those with late-onset disease (partial deficiencies, including females heterozygous for ornithine transcarbamylase), initially may receive a diet containing the age-determined minimal daily natural protein allowance. The protein intake may be increased as tolerated and determined by plasma glutamine and other amino acid levels. However, many patients with partial deficiencies avoid dietary protein. Citrulline supplementation is required and recommended for patients diagnosed with neonatal-onset deficiency of carbamylphosphate synthetase or ornithine transcarbamylase; citrulline daily intake is recommended at 0.17 g/kg/day or 3.8 g/m 2 /day. The free-base form of arginine may be used instead of citrulline in patients with -milder forms of carbamylphosphate synthetase and ornithine transcarbamylase deficiency (daily intake is recommended at 0.17 g/kg/day or 3.8 g/m 2 /day). Arginine supplementation is needed for patients diagnosed with deficiency of argininosuccinic acid synthetase; arginine (free base) daily intake is recommended at 0.4–0.7 g/kg/day or 8.8–15.4 g/m 2 /day. If caloric supplementation is indicated, a protein-free product is recommended. Caloric intake should be based upon the "Recommended Dietary Allowances", 10th ed., Food and Nutrition Board, National Research Council, National Academy of Sciences, 1989.

CONTRAINDICATIONS Sodium phenylbutyrate tablets should not be used to manage acute hyperammonemia, which is a medical emergency.

ADVERSE REACTIONS The assessment of clinical adverse events came from 206 patients treated with sodium phenylbutyrate. Adverse events (both clinical and laboratory) were not collected systematically in these patients, but were obtained from patient visit reports by the 65 co-investigators. Causality of adverse effects is sometimes difficult to determine in this patient population because they may result from either the underlying disease, the patient’s restricted diet, intercurrent illness, or sodium phenylbutyrate. Furthermore, the rates may be underestimated because they were reported primarily by parent or guardian and not the patient. Clinical Adverse Events In female patients, the most common clinical adverse event reported was amenorrhea/menstrual dysfunction (irregular menstrual cycles), which occurred in 23% of the menstruating patients. Decreased appetite occurred in 4% of all patients. Body odor (probably caused by the metabolite, phenylacetate) and bad taste or taste aversion were each reported in 3% of patients. Other adverse events reported in 2% or fewer patients were: Gastrointestinal : abdominal pain, gastritis, nausea and vomiting; constipation, rectal bleeding, peptic ulcer disease, and pancreatitis each occurred in one patient. Hematologic : aplastic anemia and ecchymoses each occurred in one patient. Cardiovascular : arrhythmia and edema each occurred in one patient. Renal : renal tubular acidosis Psychiatric : depression Skin : rash Miscellaneous : headache, syncope, and weight gain Neurotoxicity was reported in cancer patients receiving intravenous phenylacetate, 250 to 300 mg/kg/day for 14 days, repeated at 4-week intervals. Manifestations were predominately somnolence, fatigue, and lightheadedness; with less frequent -headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of a pre-existing neuropathy. These adverse events were mainly mild in severity. The acute onset and reversibility when the phenylacetate infusion was discontinued suggest a drug effect. Laboratory Adverse Events: In patients with urea cycle disorders, the frequency of laboratory adverse events by body system were: Metabolic : acidosis (14%), alkalosis and hyperchloremia (each 7%), hypophosphatemia (6%), hyperuricemia and hyperphosphatemia (each 2%), and hypernatremia and hypokalemia (each 1%). Nutritional : hypoalbuminemia (11%) and decreased total protein (3%). Hepatic : increased alkaline phosphatase (6%), increased liver transaminases (4%), and hyperbilirubinemia (1%). Hematologic : anemia (9%), leukopenia and leukocytosis (each 4%), thrombocytopenia (3%), and thrombocytosis (1%). The clinician is advised to routinely perform urinalysis, blood chemistry profiles, and hematologic tests.

DESCRIPTION Sodium Phenylbutyrate Tablets, USP for oral administration contain sodium phenylbutyrate, USP. Sodium phenylbutyrate is a white to yellowish-white powder which is freely soluble in water and has a strong salty taste. Sodium phenylbutyrate also is freely soluble in methanol, sparingly soluble in ethanol and practically insoluble in methylene chloride, acetone and diethyl ether. It is known chemically as 4-phenylbutyric acid, sodium salt with a molecular weight of 186.18 g/mol and the molecular formula C 10 H 11 O 2 Na. Chemical Structure: Each tablet of sodium phenylbutyrate tablets, USP contains 500 mg of sodium phenylbutyrate, USP and the inactive ingredients calcium stearate, colloidal silicon dioxide, magnesium stearate and microcrystalline cellulose. FDA approved dissolution specifications differs from the USP. structure

OVERDOSAGE Overdoses of sodium phenylbutyrate tablets exceeding ten-fold the maximum recommended dosage may produce emesis, CNS depression, metabolic acidosis with or without respiratory alkalosis, hypernatremia, hypokalemia, and hypophosphatemia. Symptoms of overdose overlap with those of acute hyperammonemia. If overdose occurs, discontinue sodium phenylbutyrate, monitor plasma phenylacetate and ammonia levels closely, and institute appropriate emergency management, which may include hemodialysis, continuous veno-venous hemofiltration (CVVH), or extracorporeal membrane oxygenation (ECMO).

HOW SUPPLIED Sodium Phenylbutyrate Tablets, USP are available in 300 cc bottles which contain 250 sodium phenylbutyrate tablets, USP (NDC 68462-853-20). The bottles are equipped with child-resistant caps. Each tablet is off-white, oval shaped, and debossed with ‘G853’ on one side and plain on the other side. Each tablet contains 500 mg of sodium phenylbutyrate, USP. Store at 20oC to 25oC (68oF to 77oF); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. AFTER OPENING, KEEP BOTTLE TIGHTLY CLOSED. Preserve in tight containers. All trademarks are the property of their respective owners. Distributed by: Glenmark Pharmaceuticals Inc., USA Elmwood Park, NJ 07407 Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com August 2025 logo