PHEBURANE

5 WARNINGS AND PRECAUTIONS 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.

6 ADVERSE REACTIONS 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 .