PHEBURANE

PHEBURANE (sodium phenylbutyrate) oral pellets is a nitrogen binding agent. Sodium phenylbutyrate is a white or yellowish-white powder, freely soluble in water and in methanol, and practically insoluble in methylene chloride. It is known chemically as sodium 4-phenylbutanoate with a molecular weight of 186.19 and the molecular formula C 10 H 11 NaO 2 . Structural formula: Each bottle of PHEBURANE contains 84 g of sodium phenylbutyrate (equivalent to 74 g of phenylbutyrate) in 174 g of oral pellets. Each gram of pellets contains 483 mg of sodium phenylbutyrate (equivalent to 423 mg of phenylbutyrate). PHEBURANE contains the following inactive ingredients: ethylcellulose, hypromellose, polyethylene glycol 1500, povidone K25, and sugar spheres. Structural formula

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 )

PHEBURANE treatment should be supervised by a healthcare provider experienced in the treatment of UCDs. For administration, see full prescribing information. ( 2.1 , 2.4 ) The recommended dosage measured as sodium phenylbutyrate is: Patients weighing < 20 kg: 450–600 mg/kg/day of sodium phenylbutyrate orally. ( 2.1 ) Patients weighing ≥ 20 kg: 9.9–13.0 g/m 2 /day of sodium phenylbutyrate orally. ( 2.1 ) Monitor plasma ammonia levels to determine the need for dosage adjustment. ( 2.2 ) Monitor patients for potential neurotoxicity. ( 2.2 ) For patients with hepatic impairment, start at the lower end of the recommended dosing range. ( 2.3 ) 2.1 Recommended Dosage PHEBURANE treatment should be supervised by a healthcare provider experienced in the treatment of urea cycle disorders. The recommended dosage of PHEBURANE (measured as sodium phenylbutyrate) for patients with urea cycle disorders is: Patients weighing less than 20kg: 450 – 600 mg/kg/day of sodium phenylbutyrate orally. Divide the calculated total daily dose into three to six doses. Administer as three to six divided doses and take with food. Patients weighing greater than or equal to 20 kg: 9.9 – 13 g/m 2 /day of sodium phenylbutyrate orally. Divide the calculated total daily dose into three to six doses. Administer as three to six divided doses and take with food. The maximum dosage is 20 grams per day. Combine PHEBURANE with dietary protein restriction and, in some cases, amino acid supplementation (e.g., essential amino acids, arginine, citrulline, and protein-free calorie supplements). Measure the dose using only the calibrated spoon provided in the packaging. This calibrated dosing spoon directly measures PHEBURANE oral pellets as sodium phenylbutyrate [see Dosage and Administration ( 2.4 ) ] . If a dose is missed, take the missed dose as soon as possible. There should be at least 3 hours between two doses and doses should not be doubled to make up for the missed dose. 2.2 Dosage Adjustment and Monitoring Monitor plasma ammonia levels to determine the need for dosage adjustment. Adjust the PHEBURANE dosage to maintain the plasma ammonia level within the normal range for the patient’s age, taking into consideration their clinical condition (e.g., nutritional requirements, protein intake, growth parameters, etc.). Monitor patients for potential neurotoxicity and obtain measurements of plasma phenylacetate and phenylacetylglutamine levels [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6 )] . If neurologic symptoms (e.g. 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. 2.3 Dosage Adjustment in Patients with Hepatic Impairment For patients with hepatic impairment, start at the lower end of the recommended dosing range and maintain patients on the lowest dose necessary to control plasma ammonia levels [see Use in Specific Populations ( 8.7 )] . 2.4 Administration Instructions For oral administration only. Administration via gastrostomy or nasogastric tubes has not been evaluated. Schedule PHEBURANE dosages at the same time as food consumption (meal or snack). Use the calibrated dosing spoon to measure PHEBURANE oral pellets. The dosing spoon is directly calibrated in grams of sodium phenylbutyrate. Swallow the coated oral pellets with a drink (e.g., water, fruit juices, protein-free infant formulas) or sprinkle onto spoonful of apple sauce or carrot puree. Do not chew PHEBURANE oral pellets directly or mix into liquids. Swallow immediately to minimize dissolution of coating. Administration of PHEBURANE oral pellets with other foods has not been studied and is not recommended. Additionally, administration with soft food is only recommended in patients old enough to consume soft foods.

None None. ( 4 )

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 corticosteroids, valproic acid, or haloperidol is used concomitantly with PHEBURANE. 7.2 Potential for Other Drugs to Affect 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 )] .