Sodium Phenylbutyrate

PHEBURANE is indicated as adjunctive therapy to standard of care, which includes dietary management, for the chronic management of adult and pediatric patients with urea cycle disorders (UCDs), involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC) or argininosuccinic acid synthetase (AS). Limitations of Use Episodes of acute hyperammonemia may occur in patients while on PHEBURANE. PHEBURANE is not indicated for the treatment of acute hyperammonemia, which can be a life-threatening medical emergency that requires rapid acting interventions to reduce plasma ammonia levels. PHEBURANE is a nitrogen-binding agent indicated as adjunctive therapy to standard of care, which includes dietary management, for the chronic management of adult and pediatric patients with urea cycle disorders (UCDs), involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC) or argininosuccinic acid synthetase (AS). ( 1 ) Limitations of Use PHEBURANE is not indicated for the treatment of acute hyperammonemia. ( 1 )

Oral pellets: 84 g of sodium phenylbutyrate per PHEBURANE bottle as white to off-white coated pellets. Oral pellets: 84 g of sodium phenylbutyrate per bottle. ( 3 )

None None. ( 4 )

Neurotoxicity of Phenylacetate : Increased exposure to phenylacetate, the major metabolite of PHEBURANE, may be associated with neurotoxicity in patients with UCDs. Consider reducing the dose if neurotoxicity symptoms are present. ( 5.1 ) Hypokalemia : Renal excretion of phenylacetylglutamine may induce urinary loss of potassium. Monitor serum potassium during therapy and initiate appropriate treatment when necessary. ( 5.2 ) Conditions Associated with Edema : Calculate the total amount of sodium patients will be exposed to based on their weight or body surface area. If a patient develops new-onset edema or worsening edema while on treatment, discontinue administration of PHEBURANE and initiate appropriate therapy. ( 5.3 ) Diabetes Mellitus, Hereditary Fructose Intolerance, Glucose-Galactose Malabsorption or Sucrase-Isomaltase Insufficiency : Avoid use of PHEBURANE in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency. ( 5.4 )

5.1 Neurotoxicity of Phenylacetate Increased exposure to phenylacetate, the major metabolite of PHEBURANE, may be associated with neurotoxicity in patients with UCDs. In a study of adult cancer patients receiving intravenous phenylacetate, 250-300 mg/kg/day for 14 days, repeated at 4-week intervals, signs and symptoms of neurotoxicity, which were reversible upon discontinuation, were seen at plasma concentrations ≥ 3.5 mmol/L, and included somnolence, fatigue, and light headedness [see Adverse Reactions ( 6 ) ] . PHEBURANE is not approved for intravenous use or for treatment of patients with cancer. If symptoms of vomiting, nausea, headache, somnolence or confusion are present in the absence of high ammonia levels or other intercurrent illnesses, consider reducing the dose of PHEBURANE [see Dosage and Administration ( 2.2 )] . Phenylacetate caused neurotoxicity when given subcutaneously in rat pups [see Use in Specific Populations ( 8.4 )] .

5.2 Hypokalemia Renal excretion of phenylacetylglutamine may induce urinary loss of potassium. Monitor serum potassium during therapy and initiate appropriate treatment when necessary.

5.3 Conditions Associated with Edema PHEBURANE contains 124 mg (5.4 mmol) of sodium per gram of sodium phenylbutyrate, corresponding to 2.5 g (108 mmol) of sodium in the maximum daily dose of 20 g of sodium phenylbutyrate. In order to decide if administration of PHEBURANE is appropriate in patients with diseases that involve edema such as heart failure, cirrhosis, or nephrosis, calculate the total amount of sodium patients will be exposed to based on their weight or body surface area (BSA) [see Dosage and Administration ( 2.1 )] . If a patient develops new-onset edema or worsening edema while on treatment, discontinue administration of PHEBURANE and initiate appropriate therapy.

5.4 Diabetes Mellitus, Hereditary Fructose Intolerance, Glucose-Galactose Malabsorption or Sucrase-Isomaltase Insufficiency PHEBURANE contains 768 mg of sucrose per gram of sodium phenylbutyrate, corresponding to 15.4 g of sucrose in the maximum daily dose of 20 g of sodium phenylbutyrate. This should be considered in patients with diabetes mellitus. Avoid use of PHEBURANE in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

The following adverse reactions associated with the use of sodium phenylbutyrate were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Most common adverse reactions (incidence ≥ 3%) are amenorrhea or menstrual dysfunction (irregular menstrual cycles), decreased appetite, body odor and bad taste or taste aversion. Less Common Clinical Adverse Reactions Blood and lymphatic system disorders: aplastic anemia, ecchymoses Cardiac disorders : arrhythmia Gastrointestinal disorders : abdominal pain, decreased appetite, gastritis, nausea and vomiting, constipation, rectal bleeding, peptic ulcer disease, pancreatitis Metabolism and nutrition disorders: increased weight, edema Nervous system disorders : syncope, headache Psychiatric disorders : depression Renal and urinary disorders : renal tubular acidosis Skin and subcutaneous tissue disorders : rash Laboratory Adverse Reactions Blood and lymphatic system disorders : anemia, leukopenia and leukocytosis, thrombocytopenia, thrombocytosis Hepatobiliary disorders: hyperbilirubinemia, increased blood alkaline phosphatase, increased transaminases Metabolism and nutrition disorders: acidosis, alkalosis, hyperchloraemia, hypophosphataemia, hyperuricemia, hyperphosphatemia, hypernatremia, hypokalemia, hypoalbuminemia, decreased total protein Clinical Adverse Reactions with Use of Phenylacetate Nervous system disorders: Neurotoxicity was reported in cancer patients receiving intravenous phenylacetate, the major metabolite of PHEBURANE (PHEBURANE is not approved for intravenous use or for treatment of patients with cancer). Signs and symptoms were predominately somnolence, fatigue, and dizziness (lightheadedness); less frequently reported were headache, dysgeusia, hypoacusis, disorientation, memory impairment, and exacerbation of a pre-existing neuropathy. Most common adverse reactions (incidence ≥ 3%) are menstrual dysfunction, decreased appetite, body odor and bad taste or taste aversion. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Medunik USA, Inc. at 1-844-884-5520 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Valproic Acid, Haloperidol, or Corticosteroids : May increase plasma ammonia level; monitor ammonia levels closely. ( 7.1 ) Probenecid : May inhibit renal excretion of metabolites of PHEBURANE including phenylacetate and phenylacetylglutamine; monitor for potential neurotoxicity. ( 7.2 )

7.1 Potential for Other Drugs to Affect Ammonia Corticosteroids Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Valproic Acid and Haloperidol Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor plasma ammonia levels closely when PHEBURANE is used concomitantly with corticosteroids, valproic acid, or haloperidol.

7.2 Effects of Other Drugs on PHEBURANE Probenecid Probenecid may inhibit renal excretion of the metabolites of PHEBURANE including phenylacetate and phenylacetylglutamine. Monitor patients for potential neurotoxicity and measure plasma phenylacetate and phenylacetylglutamine levels when probenecid is used concomitantly with PHEBURANE [see Dosage and Administration ( 2.2 )] .

8.1 Pregnancy Risk Summary Available data with sodium phenylbutyrate use in pregnant women are insufficient to identify a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with sodium phenylbutyrate. Based on published animal data, phenylacetate may be neurotoxic to the developing brain (see Data ) . There are serious risks to the mother and fetus associated with untreated urea cycle disorders during pregnancy which can result in serious morbidity and mortality to the mother and fetus (see Clinical Considerations ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnancy is a time of increased metabolic demand which increases the risk for hyperammonemic episodes when metabolic demands are not met. Hyperammonemic episodes in pregnancy are associated with impaired cognition in the mother and an increased risk of maternal and fetal death. Data In rats, intrauterine exposure to phenylacetate produced lesions in the neonatal brain in layer 5 of the cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number.

8.2 Lactation Risk Summary There are no data on the presence of sodium phenylbutyrate and its metabolite in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PHEBURANE and any potential adverse effects on the breastfed infant from PHEBURANE or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of PHEBURANE have been established as adjunctive therapy to the standard of care, which includes dietary management, in the chronic management of pediatric patients with urea cycle disorders (UCDs), involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC) or argininosuccinic acid synthetase (AS). PHEBURANE is not indicated for the treatment of acute hyperammonemia, which can be a life-threatening medical emergency that requires rapid acting interventions to reduce plasma ammonia levels. The sodium content of PHEBURANE has the potential to cause new-onset edema or worsening edema from salt and water retention, particularly in patients with underlying predisposing conditions [see Warnings and Precautions ( 5.3 )] . Neurotoxicity has been observed in juvenile animals with phenylacetate exposure [see Warnings and Precautions ( 5.1 )] . Juvenile Animal Toxicity Data When given subcutaneously to rat pups, 190–474 mg/kg phenylacetate caused decreased proliferation and increased loss of neurons, and it reduced CNS myelin. Cerebral synapse maturation was retarded, and the number of functioning nerve terminals in the cerebrum was reduced, which resulted in impaired brain growth.

8.5 Geriatric Use Clinical studies of PHEBURANE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

8.6 Renal Impairment No studies with PHEBURANE were conducted in subjects with renal impairment. Monitor plasma ammonia levels when starting patients with impaired renal function on PHEBURANE [see Clinical Pharmacology ( 12 )].

8.7 Hepatic Impairment No studies with PHEBURANE were conducted in subjects with hepatic impairment. Start at the lower end of the recommended dosing range and maintain patients with hepatic impairment on the lowest dose necessary to control plasma ammonia levels [see Clinical Pharmacology ( 12.3 ), Dosage and Administration ( 2.3 )] .

Sodium phenylbutyrate is a pro-drug and is metabolized to phenylacetate. Phenylacetate is a metabolically-active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine. Phenylacetylglutamine is excreted by the kidneys, hence providing an alternate vehicle for waste nitrogen excretion.