NDC 68475-001 Sodium Phenylacetate And Sodium Benzoate

Sodium Phenylacetate And Sodium Benzoate

NDC Product Code 68475-001

NDC Code: 68475-001

Proprietary Name: Sodium Phenylacetate And Sodium Benzoate What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Sodium Phenylacetate And Sodium Benzoate What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

NDC Code Structure

  • 68475 - Navinta Llc
    • 68475-001 - Sodium Phenylacetate And Sodium Benzoate

NDC 68475-001-50

Package Description: 1 VIAL in 1 CARTON > 50 mL in 1 VIAL

NDC Product Information

Sodium Phenylacetate And Sodium Benzoate with NDC 68475-001 is a a human prescription drug product labeled by Navinta Llc. The generic name of Sodium Phenylacetate And Sodium Benzoate is sodium phenylacetate and sodium benzoate. The product's dosage form is injection, solution, concentrate and is administered via intravenous form.

Labeler Name: Navinta Llc

Dosage Form: Injection, Solution, Concentrate - A sterile preparation for parenteral use which, upon the addition of suitable solvents, yields a solution conforming in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Sodium Phenylacetate And Sodium Benzoate Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • SODIUM PHENYLACETATE 100 mg/mL
  • SODIUM BENZOATE 100 mg/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • HYDROCHLORIC ACID (UNII: QTT17582CB)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Ammonium Ion Binding Activity - [MoA] (Mechanism of Action)
  • Nitrogen Binding Agent - [EPC] (Established Pharmacologic Class)
  • Ammonium Ion Binding Activity - [MoA] (Mechanism of Action)
  • Nitrogen Binding Agent - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Navinta Llc
Labeler Code: 68475
FDA Application Number: ANDA205880 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 05-07-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Sodium Phenylacetate And Sodium Benzoate Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

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% 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 C o m ponents of Infusion Solution Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% must be diluted with sterile 10% Dextrose Injection at ≥ 25 mL/Kg before administration . Dosage Provided Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% Arginine HCl Injection, 10% Sodium Phenylacetate Sodium Benzoate Arginine HClPatients 0 to 20 kg: CPS and OTC Deficiency D os e 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 D os e 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/kgPatients > 20 kg: CPS and OTC Deficiency D os e Loading: over 90 to 120 minutes Maintenance: over 24 hours 55 mL/m2 2 mL/kg 5.5g/m2 5.5 g/m2 200 mg/kg ASS and ASL Deficiency D os e Loading: over 90 to 120 minutes Maintenance: over 24 hours 55 mL/m2 6 mL/kg 5.5 g/m2 5.5 g/m2 600 mg/kg

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.

3 Dosage Forms And Strengths

Sodium Phenylacetate and Sodium Benzoate Injection Injection 10% per 10% is a sterile, concentrated, aqueous solution of sodium phenylacetate and sodium benzoate.

4 Contraindications

None.

5.1 Management Of Acute Hyperammonemia

Any episode of acute symptomatic hyperammonemia should be treated as a life-threatening emergency. Uncontrolled hyperammonemia can rapidly result in brain damage or death, and prompt use of all therapies necessary, including hemodialysis, to reduce ammonia levels is essential. Hyperammonemic coma (regardless of cause) in the newborn infant should be aggressively treated while the specific diagnosis is pursued.Hemodialysis should be promptly initiated in all newborn patients. A blood flow rate of 150 mL/min/m2should be targeted (ammonia clearance [mL/min] is similar to the blood flow rate [mL/min] through the dialyzer). Clearance of ammonia is approximately ten times greater by hemodialysis than by peritoneal dialysis or hemofiltration. Exchange transfusion is ineffective in the management of hyperammonemia. Hemodialysis may be repeated until the plasma ammonia level is stable at normal or near normal levels.Hyperammonemia due to urea cycle disorders should be managed in coordination with medical personnel experienced in metabolic disorders. Ongoing monitoring of plasma ammonia levels, neurological status, laboratory tests, and clinical response in patients receiving Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% is crucial to assess patient response to treatment.

5.2 Decreased Potassium Levels

Because urine potassium loss is enhanced by the excretion of the non-reabsorbable anions, phenylacetylglutamine and hippurate, plasma potassium levels should be carefully monitored and appropriate treatment given when necessary.

5.3 Conditions Associated With Fluid Overload

Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% contains 30.5 mg of sodium per mL of undiluted product. Thus, Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% should be used with great care, if at all, in patients with congestive heart failure or severe renal insufficiency, and in clinical states in which there is sodium retention with edema. Discontinue administration of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%, evaluate the patient, and institute appropriate therapeutic countermeasures if an adverse event occurs.

5.4 Extravasation

Administration must be through a central line. Administration through a peripheral line may cause burns. Bolus infusion flow rates are relatively high, especially for infants [see Dosage and Administration (2)]. Extravasation of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% into the perivenous tissues may lead to skin necrosis. If extravasation is suspected, discontinue the infusion and resume at a different infusion site, if necessary. The infusion site must be monitored closely for possible infiltration during drug administration. Do not administer undiluted product.

5.5 Neurotoxicity Of Phenylacetate

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. Additionally, neurotoxicity was reported in cancer patients receiving intravenous phenylacetate, 250–300 mg/kg/day for 14 days, repeated at 4-week intervals. Manifestations were predominantly somnolence, fatigue, and lightheadedness, with less frequent headaches, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of a preexisting neuropathy. The acute onset of symptoms upon initiation of treatment and reversibility of symptoms when the phenylacetate was discontinued suggest a drug effect. [See Animal Toxicology and/or Pharmacology (13.2)]

5.6 Hyperventilation And Metabolic Acidosis

Due to structural similarities between phenylacetate and benzoate to salicylate, Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% may cause side effects typically associated with salicylate overdose, such as hyperventilation and metabolic acidosis. Monitoring of blood chemistry profiles, blood pH and should be performed.

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%).Caption: 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, thrombocytopeniaCARDIAC DISORDERS: atrial rupture, bradycardia, cardiac or cardiopulmonary arrest/failure, cardiogenic shock, cardiomyopathy, pericardial effusion EYE DISORDERS: blindness GASTROINTESTINAL DISORDERS: abdominal distension, gastrointestinal hemorrhageGENERAL 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, pCO2 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

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.

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%. It is not known whether Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Thus, Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

It is not known whether sodium phenylacetate, sodium benzoate, or their conjugation products are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% is administered to a nursing woman.

8.4 Pediatric Use

Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% 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 10% / 10% 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 10% / 10% 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 10% / 10% 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 10% / 10% to patients with hepatic insufficiency.

8.8 Renal Impairment

The drug metabolites of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% (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 10% / 10%.

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).

11 Description

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 white to off-white powder. It is soluble in water. Sodium benzoate is a white and odorless, crystalline powder that is readily soluble in water.Figure 1Sodium phenylacetate has a molecular weight of 158.13 and the molecular formula C8H7NaO2. Sodium benzoate has a molecular weight of 144.11 and the molecular formula C7H5NaO2. 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)].

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 2CPS              = carbamyl phosphate synthetase; OTC             = ornithine transcarbamylase; ASS              = argininosuccinate synthetase; ASL              = argininosuccinate lyase;ARG             = arginase;NAGS          = N-acetylglutamate synthetase

12.2 Pharmacodynamics

In patients with hyperammonemia due to deficiencies in enzymes of the urea cycle, Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% has been shown to decrease elevated plasma ammonia levels. These effects are considered to be the result of reduction in nitrogen overload through glutamine and glycine scavenging by Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% in combination with appropriate dietary and other supportive measures.

12.3 Pharmacokinetics

The pharmacokinetics of intravenously administered Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% was characterized in healthy adult volunteers. Both benzoate and phenylacetate exhibited nonlinear kinetics. Following 90 minute intravenous infusion mean AUClast for benzoate was 20.3, 114.9, 564.6, 562.8, and 1599.1 mcg/mL following doses of 1, 2, 3.75, 4, and 5.5 g/m2, respectively. The total clearance decreased from 5.19 to 3.62 L/h/m2at the 3.75 and 5.5 g/m2doses, respectively. Similarly, phenylacetate exhibited nonlinear kinetics following the priming dose regimens. AUClast was 175.6, 713.8, 2040.6, 2181.6, and 3829.2 mcg⋅h/mL following doses of 1, 2, 3.75, 4, and 5.5 g/m2, respectively. The total clearance decreased from 1.82 to 0.89 mcg⋅h/mL with increasing dose (3.75 and 4 g/m2, respectively). During the sequence of 90 minute priming infusion followed by a 24 hour maintenance infusion, phenylacetate was detected in the plasma at the end of infusion (Tmax of 2 hr at 3.75 g/m2) whereas, benzoate concentrations declined rapidly (Tmax of 1.5 hr at 3.75 g/m2) and were undetectable at 14 and 26 hours following the 3.75 and 4 g/m2dose, respectively. A difference in the metabolic rates for phenylacetate and benzoate was noted. The formation of hippurate from benzoate occurred more rapidly than that of phenylacetylglutamine from phenylacetate, and the rate of elimination for hippurate appeared to be more rapid than that for phenylacetylglutamine. Pharmacokinetic observations have also been reported from twelve episodes of hyperammonemic encephalopathy in seven children diagnosed (age 3 to 26 months) with urea cycle disorders who had been administered Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% intravenously. These data showed peak plasma levels of phenylacetate and benzoate at approximately the same times as were observed in healthy adults. As in healthy adults, the plasma levels of phenylacetate were higher than benzoate and were present for a longer time. The pharmacokinetics of intravenous phenylacetate have been reported following administration to adult patients with advanced solid tumors. The decline in serum phenylacetate concentrations following a loading infusion of 150 mg/kg was consistent with saturable enzyme kinetics. Ninety-nine percent of administered phenylacetate was excreted as phenylacetylglutamine [2,3].

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%. Studies to evaluate the possible impairment of fertility or mutagenic potential of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% have not been performed. Results indicate that sodium benzoate is not mutagenic or carcinogenic, and does not impair fertility.

13.2 Animal Toxicology And/Or Pharmacology

In animal studies, subcutaneous administration to rat pups of 190–474 mg/kg of phenylacetate caused decreased proliferation and increased loss of neurons, and reduced central nervous system (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. Pregnant rats were given phenylacetate at 3.5 μmol/g/day subcutaneously from gestation day 7 through normal delivery. Prenatal exposure of rat pups to phenylacetate produced lesions in layer 5 cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number.

14 Clinical Studies

The efficacy of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% in improving patient survival of acute hyperammonemic episodes was demonstrated in an analysis of 316 patients (1045 episodes of hospitalization) treated between 1981 and 2003. The demographic characteristics and diagnoses of the patient population are shown in Table 3. Table 3 Baseline Characteristics and Diagnoses of Study Population OTC = ornithine transcarbamylase deficiency; ASS = argininosuccinate synthetase deficiency; CPS = carbamyl phosphate synthetase deficiency; ASL = argininosuccinate lyase deficiency;ARG = arginase deficiency;THN = transient hyperammonemia of the newborn PatientsFor the summary at the patient level, data obtained at first episode used. N=316 Gender Male 158 (51%) Female 150 (49%) Age (years) N 310 Mean (SD) 6.2 (8.54) Min–Max 0.0–53.0 Age groups 0–30 days 104 (34%) 31 days–2 years 55 (18%) > 2–12 years 90 (29%) > 12–16 years 30 (10%) > 16 years 31 (10%) Enzyme deficiency OTC 146 (46%) ASS 71 (22%) CPS 38 (12%) ASL 7 (2%) ARG 2 (< 1%) THN 2 (< 1%) OtherDiagnosis unknown or pending (33 episodes), acidemia (14 episodes), HHH syndrome (6 episodes), carnitine translocase deficiency (4 episodes), liver disease (3 episodes), HMG CoA lyase deficiency (1 episode), non-ketotic hyperglycinemia (1 episode), suspected fatty acid oxidation deficiency (1 episode), and valproic-acid-induced hyperammonemia (1 episode). 56 (18%)On admission to the hospital, patients with hyperammonemia and a suspected or confirmed urea cycle disorder (UCD) diagnosis were treated with a bolus dose of 0.25 g/kg (or 5.5 g/m2) sodium phenylacetate + 0.25 g/kg (or 5.5 g/m2) sodium benzoate over a period of 90 minutes to 6 hours, depending on the specific UCD. Infusions also contained arginine; the dose of arginine depended on the specific UCD. After completion of the bolus dose, maintenance infusions of the same dose over 24 hours were continued until the patient was no longer hyperammonemic or oral therapy could be tolerated. The mean (SD) duration of treatment was 4.6 (6.45) days per episode, and ranged from 1 to 72 days. Survival was substantially improved after Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% treatment compared with historical values (estimated 14% 1-year survival rate with dietary therapy alone) and with dialysis (estimated 43% survival of acute hyperammonemia). Eighty percent of patients (252 of 316) survived their last episode. Of the 64 patients who died, 53 (83%) died during their first hyperammonemic episode. Of the 104 neonates (< 30d) treated with Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%, 34 (33%) died during the first hyperammonemic episode. Ammonia levels decreased from very high levels (> 4 times the upper limit of normal [ULN]) to lower levels in 91% of episodes after treatment. In patients responding to therapy, mean ammonia concentrations decreased from 200.9 umol/L at hour zero to 101.6 umol/L within four hours of initiation of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% therapy and were maintained. Hemodialysis is recommended for those patients who's plasma ammonia levels fail to fall below 150 umol/L or by more than 40% within 4 to 8 hours after receiving Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%. A shift from high (≤ 4 times ULN) to very high (> 4 times ULN) levels was observed in only 4% of the episodes. Overall, investigators rated neurological status as improved, much improved, or the same in 93% of episodes, and overall status in response to treatment as improved, much improved, or the same in 97% of episodes. Recovery from coma was observed in 97% of episodes where coma was present at admission (111 of 114 episodes).

16 How Supplied/Storage And Handling

Sodium Phenylacetate and Sodium Benzoate Injection 10% per 10% is supplied in a single dose glass vial. NDC 68475-001-50 single dose vial containing 50 mL of sodium phenylacetate and sodium benzoate injection 10% per 10%. Storage: Store at 25°C (77°F), excursions permitted to 15° - 30°C (59° to 86°F).

17 Patient Counseling Information

  • Physicians should advise patients and caregivers about the following for safe use of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%: When plasma ammonia levels have normalized, dietary protein intake can usually be increased with the goal of unrestricted protein intake.Caution should be exercised when Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% is administered to a nursing womanThe most common adverse reactions are vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment.Generally BUPHENYL is stopped during the time Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% is used.Distributed by:Navinta LLCEwing, NJ 08618 Revised: 04/201930011218 R0

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