sodium phenylacetate and sodium benzoate

1 INDICATIONS AND USAGE Sodium Phenylacetate and Sodium Benzoate Injection is a nitrogen binding agent indicated as adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in paediatric and adult patients with deficiencies in enzymes of the urea cycle. ( 1 ) Sodium Phenylacetate and Sodium Benzoate Injection 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) ].

2 DOSAGE AND ADMINISTRATION Sodium Phenylacetate and Sodium Benzoate Injection 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 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 ) See Full Prescribing Information for complete dosing recommendations. 2.1 Recommended Dosage Sodium Phenylacetate and Sodium Benzoate Injection must be diluted with sterile 10% Dextrose Injection (D10W) before administration. The dilution and dosage of Sodium Phenylacetate and Sodium Benzoate Injection 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 Abbreviations: CPS - carbamyl phosphate synthetase; OTC - ornithine transcarbamylase; ASS - argininosuccinate synthetase; ASL - argininosuccinate lyase 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 CPS and OTC Deficiency Patients 0 to 20 kg: Dose Loading: over 90 to 120 minutes Maintenance: over 24 hours 2.5 mL/kg 2 mL/kg 250 mg/kg 250 mg/kg 200 mg/kg ASS and ASL Deficiency Dose Loading: over 90 to 120 minutes Maintenance: over 24 hours 2.5 mL/kg 6 mL/kg 250 mg/kg 250 mg/kg 600 mg/kg CPS and OTC Deficiency Patient>20kg: Dose Loading: over 90 to 120 minutes Maintenance: over 24 hours 55 mL/m 2 2 mL/kg 5.5g/m 2 5.5 g/m 2 200 mg/kg ASS and ASL Deficiency Dose Loading: over 90 to 120 minutes Maintenance: over 24 hours 55 mL/m 2 6 mL/kg 5.5 g/m 2 5.5 g/m 2 600 mg/kg 2.2 Administration Sodium Phenylacetate and Sodium Benzoate Injection 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 may not be administered by any other route. Sodium Phenylacetate and Sodium Benzoate Injection 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 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 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 infusion. Sodium Phenylacetate and Sodium Benzoate Injection 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, ongoing monitoring of the following clinical laboratory values is crucial: plasma ammonia, glutamine, quantitative plasma amino acids, blood glucose, electro …

3 DOSAGE FORMS AND STRENGTHS Injection: 10% per 10% sterile, concentrated, aqueous solution of sodium phenylacetate and sodium benzoate. ( 3 ) Sodium Phenylacetate and Sodium Benzoate Injection 10% per 10% is a sterile, clear and almost colorless concentrated, aqueous solution of sodium phenylacetate and sodium benzoate.

4 CONTRAINDICATIONS None ( 4 ) None.

6 ADVERSE REACTIONS The most frequently reported adverse reactions (incidence ≥ 6%) are vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc. Pennington, NJ 08534 at 1-877-993-8779 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 practice. The safety data were obtained from 316 patients who received Sodium Phenylacetate and Sodium Benzoate Injection 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 ( 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, pruritus generalized, rash, urticarial. VASCULAR DISORDERS: flushing, hemorrhage, hypertension, phlebothrombosis/thrombosis. Table 2 : Adverse Reactions Occurring in ≥3% of Patients Treated with Sodium Phenylacetate and Sodium Benzoate Injection 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%) …

7 DRUG INTERACTIONS 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 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data on the combination use of Sodium Phenylacetate and Sodium Benzoate 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 Phenylacetate and Sodium Benzoate Injection. 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. 8.2 Lactation Risk Summary There are no data on the presence of sodium phenylacetate, sodium benzoate 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 Sodium Phenylacetate and Sodium Benzoate Injection and any potential adverse effects on the breastfed infant from Sodium Phenylacetate and Sodium Benzoate Injection or from the underlying maternal condition. 8.4 Pediatric Use Sodium Phenylacetate and Sodium Benzoate Injection has been used as a treatment for acute hyperammonemia in pediatric patients including patients in the early neonatal period [ see Dosage and Administration (2) ]. 8.5 Geriatric Use Clinical studies of Sodium Phenylacetate and Sodium Benzoate Injection did not include any patients aged 65 and over to determine whether they respond differently from younger patients. Urea cycle disorders are presently diseases of the pediatric and younger adult populations. No pharmacokinetic studies of Sodium Phenylacetate and Sodium Benzoate Injection have been performed in geriatric 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 concomitant disease or other drug therapy in this patient population. 8.6 Gender Pharmacokinetic parameters of Sodium Phenylacetate and Sodium Benzoate Injection were compared in healthy males and females. Bioavailability of both benzoate and phenylacetate was slightly higher in females than in males. However, conclusions cannot be drawn due to the limited number of subjects in this study. 8.7 Hepatic Insufficiency Limited information is available on the metabolism and excretion of sodium phenylacetate and sodium benzoate in patients with impaired hepatic function. However, metabolic conjugation of sodium phenylacetate and sodium benzoate is known to take place in the liver and kidney. Therefore, caution should be used in administering Sodium Phenylacetate and Sodium Benzoate Injection to patients with hepatic insufficiency. 8.8 Renal Impairment The drug metabolites of Sodium Phenylacetate and Sodium Benzoate Injection (phenylacetylglutamine and hippurate) and subsequently ammonia are primarily excreted by the kidney. Therefore, use caution and closely monitor patients with impaired renal function who receive Sodium Phenylacetate and Sodium Benzoate Injection.

12.1 Mechanism of Action Urea cycle disorders can result from decreased activity of any of the following enzymes: N -acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), argininosuccinate lyase (ASL), or arginase (ARG). Sodium phenylacetate and sodium benzoate are metabolically active compounds that can serve as alternatives to urea for the excretion of waste nitrogen. Figure 2 is a schematic illustrating how the components of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%, phenylacetate and benzoate, provide an alternative pathway for nitrogen disposal in patients without a fully functioning urea cycle. Phenylacetate conjugates with glutamine in the liver and kidneys to form phenylacetylglutamine, via acetylation. Phenylacetylglutamine is excreted by the kidneys via glomerular filtration and tubular secretion. The nitrogen content of phenylacetylglutamine per mole is identical to that of urea (both contain two moles of nitrogen). Two moles of nitrogen are removed per mole of phenylacetate when it is conjugated with glutamine. Similarly, preceded by acylation, benzoate conjugates with glycine to form hippuric acid, which is rapidly excreted by the kidneys by glomerular filtration and tubular secretion. One mole of hippuric acid contains one mole of waste nitrogen. Thus, one mole of nitrogen is removed per mole of benzoate when it is conjugated with glycine. Figure 2 CPS = carbamyl phosphate synthetase; OTC = ornithine transcarbamylase; ASS = argininosuccinate synthetase; ASL = argininosuccinate lyase; ARG = arginase; NAGS = N -acetylglutamate synthetase Figure 2

11 DESCRIPTION Sodium phenylacetate and sodium benzoate injection (sodium phenylacetate and sodium benzoate) Injection 10% per 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 to off-white and odorless, crystalline powder that is readily soluble in water. Figure 1 Sodium phenylacetate has a molecular weight of 158.14 and the molecular formula C 8 H 7 NaO 2 . Sodium benzoate has a molecular weight of 144.10 and the molecular formula C 7 H 5 NaO 2 . Each mL of sodium phenylacetate and sodium benzoate injection 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 injection is a sterile, concentrated solution intended for intravenous administration via a central venous catheter only after dilution [ see Dosage and Administration (2) ]. Chemical Structure

10 OVERDOSAGE Overdosage has been reported during Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% treatment in urea cycle-deficient patients. All patients in the uncontrolled open-label study were to be treated with the same dose of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%. However, some patients received more than the dose level specified in the protocol. In 16 of the 64 deaths, the patient received a known overdose of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%. Causes of death in these patients included cardiorespiratory failure/arrest (6 patients), hyperammonemia (3 patients), increased intracranial pressure (2 patients), pneumonitis with septic shock and coagulopathy (1 patient), error in dialysis procedure (1 patient), respiratory failure (1 patient), intractable hypotension and probable sepsis (1 patient), and unknown (1 patient). Additionally, other signs of intoxication may include obtundation (in the absence of hyperammonemia), hyperventilation, a severe compensated metabolic acidosis, perhaps with a respiratory component, large anion gap, hypernatremia and hyperosmolarity, progressive encephalopathy, cardiovascular collapse, and death. In case of overdose of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%, discontinue the drug and institute appropriate emergency medical monitoring and procedures. In severe cases, the latter may include hemodialysis (procedure of choice) or peritoneal dialysis (when hemodialysis is unavailable).

16 HOW SUPPLIED/STORAGE AND HANDLING Sodium Phenylacetate and Sodium Benzoate Injection 10% per 10% is clear and almost colorless solution supplied in a sterile, non-pyrogenic, single-dose glass vial. NDC 68475-513-01 single-dose vial containing 20 mL of Sodium Phenylacetate and Sodium Benzoate Injection 10% per 10%. Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).