SODIUM PHENYLACETATE AND SODIUM BENZOATE

Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% (a nitrogen binding agent), is a sterile, concentrated, aqueous solution of sodium phenylacetate and sodium benzoate. The pH of the solution is between 6 and 8. Sodium phenylacetate is a crystalline, white to off-white powder with a strong, offensive odor. It is soluble in water. Sodium benzoate is a white and odorless, crystalline powder that is readily soluble in water. Figure 1 Sodium phenylacetate has a molecular weight of 158.13 and the molecular formula C 8 H 7 NaO 2 . Sodium benzoate has a molecular weight of 144.11 and the molecular formula C 7 H 5 NaO 2 . Each mL of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% contains 100 mg of sodium phenylacetate and 100 mg of sodium benzoate, and Water for Injection. Sodium hydroxide and/or hydrochloric acid may have been used for pH adjustment. Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% injection is a sterile, concentrated solution intended for intravenous administration via a central line only after dilution [see Dosage and Administration (2) ]. Chemical Structure

Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% is indicated as adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle. During acute hyperammonemic episodes, arginine supplementation, caloric supplementation, dietary protein restriction, hemodialysis, and other ammonia lowering therapies should be considered [see Warnings and Precautions (5) ]. Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% is a nitrogen binding agent indicated as adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle. ( 1 )

Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% must be diluted with sterile 10% Dextrose Injection (D10W) before administration. Administration must be through a central venous catheter. Administration through a peripheral line may cause burns. ( 2 ) Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% is administered intravenously as a loading dose infusion administered over 90 to 120 minutes, followed by an equivalent maintenance dose infusion administered over 24 hours. ( 2 ) 2.1 Recommended Dose Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% must be diluted with sterile 10% Dextrose Injection (D10W) before administration. The dilution and dosage of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% are determined by weight for neonates, infants and young children, and by body surface area for larger patients, including older children, adolescents, and adults (Table 1). Table 1: Dosage and Administration Patient Population Components of Infusion Solution Sodium Phenylacetate and Sodium Benzoate Injection must be diluted with sterile 10% Dextrose Injection at ≥25 mL/kg before administration. Dosage Provided Sodium Phenylacetate and Sodium Benzoate Injection Arginine HCl Injection, 10% Sodium Phenylacetate Sodium Benzoate Arginine HCl Patients 0 to 20 kg: CPS and OTC Deficiency Dose Loading: over 90 to 120 minutes 2.5 mL/kg 2 mL/kg 250 mg/kg 250 mg/kg 200 mg/kg Maintenance: over 24 hours ASS and ASL Deficiency Dose Loading: over 90 to 120 minutes 2.5 mL/kg 6 mL/kg 250 mg/kg 250 mg/kg 600 mg/kg Maintenance: over 24 hours Patients > 20 kg: CPS and OTC Deficiency Dose Loading: over 90 to 120 minutes 55 mL/m 2 2 mL/kg 5.5 g/m 2 5.5 g/m 2 200 mg/kg Maintenance: over 24 hours ASS and ASL Deficiency Dose Loading: over 90 to 120 minutes 55 mL/m 2 6 mL/kg 5.5 g/m 2 5.5 g/m 2 600 mg/kg Maintenance: over 24 hours 2.2 Administration Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% is a concentrated solution and must be diluted before intravenous administration via a central venous catheter. Administration through a peripheral intravenous catheter may cause burns. Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% may not be administered by any other route. Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% should be administered as a loading dose infusion over 90 to 120 minutes, followed by the same dose repeated as a maintenance infusion administered over 24 hours. Because of prolonged plasma levels achieved by phenylacetate in pharmacokinetic studies, repeat loading doses of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% should not be administered. Maintenance infusions may be continued until elevated plasma ammonia levels have been normalized or the patient can tolerate oral nutrition and medications. An antiemetic may be administered during Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% infusion to aid control of infusion-associated nausea and vomiting. Administration of analogous oral drugs, such as sodium phenylbutyrate, should be terminated prior to Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% infusion. Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% infusion should be started as soon as the diagnosis of hyperammonemia is made. Treatment of hyperammonemia also requires caloric supplementation and restriction of dietary protein. Non-protein calories should be supplied principally as glucose (8–10 mg/kg/min) with an intravenous fat emulsion added. Attempts should be made to maintain a caloric intake of greater than 80 kcal/kg/day. During and after infusion of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%, ongoing monitoring of the following clinical laboratory values is crucial: plasma ammonia, glutamine, quantitative plasma amino acids, blood glucose, electrolytes, venous or arterial blood gases, AST and ALT. On-going monitoring of the following clinical responses is also crucial to assess patient response to treatment: neurological status, Glasgow Coma Scale, tachypnea, CT or MRI scan or fundoscopic evidence of cerebral edema, and/or of gray matter and white matter damage. Hemodialysis should be considered in patients with severe hyperammonemia or who are not responsive to Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% administration [see Warnings and Precautions (5.1) ]. In the non-neonatal study patient population treated with Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%, dialysis was required in 13% of hyperammonemic episodes. Standard hemodialysis was the most frequently used dialysis method. High levels of ammonia can be reduced quickly when Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% is used with hemodialysis, as the ammonia-scavenging of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% suppresses the production of ammonia from catabolism of endogenous protein and hemodialysis eliminates the ammonia and ammonia conjugates. Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% solutions are physically and chemically stable for up to 24 hours at room temperature and room lighting conditions. No compatibility information is presently available for Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% infusion solutions except for Arginine HCl Injection, 10%, which may be mixed in the same container as Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%. Other infusion solutions and drug products should not be administered together with Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% infusion solution. Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% solutions may be prepared in glass and PVC containers. Arginine Administration Intravenous arginine is an essential component of therapy for patients with carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) deficiency. Because hyperchloremic acidosis may develop after high-dose arginine hydrochloride administration, chloride and bicarbonate levels should be monitored and appropriate amounts of bicarbonate administered. In hyperammonemic infants with suspected, but unconfirmed urea cycle disorders, intravenous arginine should be given (6 mL/kg of Arginine HCl Injection 10%, over 90 minutes followed by the same dose given as a maintenance infusion over 24 hours). If deficiencies of ASS or ASL are excluded as diagnostic possibilities, the intravenous dose of Arginine HCl should be reduced to 2 mL/kg/day Arginine HCl Injection 10%. Converting To Oral Treatment Once elevated ammonia levels have been reduced to the normal range, oral therapy, such as sodium phenylbutyrate, dietary management and maintenance protein restrictions should be started or reinitiated.

None. None ( 4 )

The most frequently reported adverse reactions (incidence ≥6%) are vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ailex Pharmaceuticals, LLC at 1-888-514-4727 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety data were obtained from 316 patients who received Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% as emergency (rescue) or prospective treatment for hyperammonemia as part of an uncontrolled, open-label study. The study population included patients between the ages of 0 to 53 years with a mean (SD) of 6.2 (8.54) years; 51% were male and 49% were female who had the following diagnoses: OTC (46%), ASS (22%), CPS (12%), ASL (2%), ARG (<1%), THN (<1%), and other (18%). Table 2: Adverse Reactions Occurring in ≥3% of Patients Treated with Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% Patients N=316 Number of patients with any adverse event 163 (52%) Blood and lymphatic system disorders 35 (11%) Anemia 12 (4%) Disseminated intravascular coagulation 11 (3%) Cardiac disorders 28 (9%) Gastrointestinal disorders 42 (13%) Diarrhea 10 (3%) Nausea 9 (3%) Vomiting 29 (9%) General disorders and administration-site conditions 45 (14%) Injection-site reaction 11 (3%) Pyrexia 17 (5%) Infections 39 (12%) Urinary tract infection 9 (3%) Injury, poisoning and procedural complications 12 (4%) Investigations 32 (10%) Metabolism and nutrition disorders 67 (21%) Acidosis 8 (3%) Hyperammonemia 17 (5%) Hyperglycemia 22 (7%) Hypocalcemia 8 (3%) Hypokalemia 23 (7%) Metabolic acidosis 13 (4%) Nervous system disorders 71 (22%) Brain edema 17 (5%) Coma 10 (3%) Convulsions 19 (6%) Mental impairment 18 (6%) Psychiatric disorders 16 (5%) Agitation 8 (3%) Renal and urinary disorders 14 (4%) Respiratory, thoracic and mediastinal disorders 47 (15%) Respiratory distress 9 (3%) Skin and subcutaneous tissue disorders 19 (6%) Vascular disorders 19 (6%) Hypotension 14 (4%) Adverse reactions were reported with similar frequency in patients with OTC, ASS, CPS, and diagnoses categorized as "other." Nervous system disorders were more frequent in patients with OTC and CPS, compared with patients with ASS and patients with "other" diagnoses. Convulsions and mental impairment were reported in patients with OTC and CPS. These observations are consistent with literature reports that patients with enzyme deficiencies occurring earlier in the urea cycle (i.e., OTC and CPS) tend to be more severely affected. Adverse reactions profiles differed by age group. Patients ≤30 days of age had more blood and lymphatic system disorders and vascular disorders (specifically hypotension), while patients >30 days of age had more gastrointestinal disorders (specifically nausea, vomiting and diarrhea). Less common adverse reactions (<3% of patients) that are characterized as severe are listed below by body system. BLOOD AND LYMPHATIC SYSTEM DISORDERS: coagulopathy, pancytopenia, thrombocytopenia CARDIAC DISORDERS: atrial rupture, bradycardia, cardiac or cardiopulmonary arrest/failure, cardiogenic shock, cardiomyopathy, pericardial effusion EYE DISORDERS: blindness GASTROINTESTINAL DISORDERS: abdominal distension, gastrointestinal hemorrhage GENERAL DISORDERS AND ADMINISTRATION-SITE CONDITIONS: asthenia, brain death, chest pain, multiorgan failure, edema HEPATOBILIARY DISORDERS: cholestasis, hepatic artery stenosis, hepatic failure/hepatotoxicity, jaundice INFECTIONS AND INFESTATIONS: sepsis/septic shock INJURY, POISONING AND PROCEDURAL COMPLICATIONS: brain herniation, subdural hematoma, overdose INVESTIGATIONS: blood carbon dioxide changes, blood glucose changes, blood pH increased, cardiac output decreased, pCO 2 changes, respiratory rate increased METABOLISM AND NUTRITION DISORDERS: alkalosis, dehydration, fluid overload/retention, hypoglycemia, hyperkalemia, hypernatremia, alkalosis, tetany NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED: hemangioma acquired NERVOUS SYSTEM DISORDERS: areflexia, ataxia, brain infarction, brain hemorrhage, cerebral atrophy, clonus, depressed level of consciousness, encephalopathy, nerve paralysis, intracranial pressure increased, subdural hematoma, tremor PSYCHIATRIC DISORDERS: acute psychosis, aggression, confusional state, hallucinations RENAL AND URINARY DISORDERS: anuria, renal failure, urinary retention RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: acute respiratory distress syndrome, dyspnea, hypercapnia, hyperventilation, Kussmaul respiration, pneumonia aspiration, pneumothorax, pulmonary hemorrhage, pulmonary edema, respiratory acidosis or alkalosis, respiratory arrest/failure SKIN AND SUBCUTANEOUS TISSUE DISORDERS: alopecia, blister, pruritis generalized, rash, urticaria VASCULAR DISORDERS: flushing, hemorrhage, hypertension, phlebothrombosis/thrombosis

Formal drug interaction studies have not been performed with Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%. Some antibiotics such as penicillin may compete with phenylacetylglutamine and hippurate for active secretion by renal tubules, which may affect the overall disposition of the infused drug. Probenecid is known to inhibit the renal transport of many organic compounds, including aminohippuric acid, and may affect renal excretion of phenylacetylglutamine and hippurate. There have been reports that valproic acid can induce hyperammonemia through inhibition of the synthesis of N-acetylglutamate, a co-factor for carbamyl phosphate synthetase. Therefore, administration of valproic acid to patients with urea cycle disorders may exacerbate their condition and antagonize the efficacy of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%. Use of corticosteroids may cause a protein catabolic state and, thereby, potentially increase plasma ammonia levels in patients with impaired ability to form urea. Some antibiotics such as penicillin may affect the overall disposition of the infused drug. ( 7 ) Probenecid may affect renal excretion of phenylacetylglutamine and hippurate. ( 7 ) Valproic acid given to patients with urea cycle disorders may exacerbate their condition and antagonize the efficacy of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% through inhibition of the synthesis of N-acetylglutamate, a co-factor for carbamyl phosphate synthetase. ( 7 ) Use of corticosteroids may cause the breakdown of body protein and potentially increase plasma ammonia levels in patients with impaired ability to form urea. ( 7 )

Storage: Store at 25°C (77°F), excursions permitted to 15°–30°C (59°–86°F).