Introduction

Fixed combination of 2 ammonia detoxicants.

Uses for Sodium Phenylacetate and Sodium Benzoate

Acute Hyperammonemia

Adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in patients with urea cycle disorders (e.g., deficiency in carbamyl phosphate synthetase [CPS], ornithine transcarbamylase [OTC], argininosuccinate synthetase [ASS], or argininosuccinate lyase [ASL]); designated an orphan drug by FDA for this use.

Treat any episode of acute symptomatic hyperammonemia as a life-threatening emergency; prompt use of all necessary therapies (e.g., dialysis [preferably hemodialysis], caloric supplementation, protein restriction) to reduce ammonia concentrations is essential.

Hemodialysis is the preferred therapy for acute neonatal hyperammonemic coma, moderate to severe episodes of hyperammonemic encephalopathy, and episodes of hyperammonemia that fail to respond to an initial course of sodium phenylacetate and sodium benzoate therapy. In such patients, administration of sodium phenylacetate and sodium benzoate helps prevent reaccumulation of ammonia by increasing waste nitrogen excretion.

Concomitant therapy with IV arginine hydrochloride is required in patients with CPS, OTC, ASS, or ASL deficiency; however, IV arginine hydrochloride is contraindicated in patients with arginase deficiency. Pending specific diagnosis, also give IV arginine hydrochloride to hyperammonemic infants with suspected urea cycle disorders.

If a urea cycle disorder is suspected based on family history, document hyperammonemia before administering sodium phenylacetate and sodium benzoate.

Sodium Phenylacetate and Sodium Benzoate Dosage and Administration

General

• Initiate therapy immediately following the diagnosis of hyperammonemia.

• Prior to infusion, discontinue analogous oral agents (e.g., sodium phenylbutyrate).

• May administer an antiemetic during the infusion for management of possible nausea and vomiting.

• Start or resume oral therapy (e.g., sodium phenylbutyrate), dietary management, and protein restriction when ammonia concentrations reduced to the normal range.

• Dialysis is recommended for those patients who do not have a significant reduction in plasma ammonia levels within 4–8 hours after receiving sodium phenylacetate and sodium benzoate.

• Concomitant therapy with arginine hydrochloride may be required. Consult the prescribing information for arginine hydrochloride for complete dosing and other information.

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion through a central venous line only; administration through a peripheral line may cause burns.

Vials are for single use only.

Dilution

Mustbe diluted in 10% dextrose injection prior to administration.

Always use the Millex Durapore GV 33-mm sterile syringe filter (0.22 µm) provided by the manufacturer when diluting sodium phenylacetate and sodium benzoate injection regardless of whether particulate matter is visible in the vial. Particulate matter has been reported but may notbe readily observed on visual inspection; removal of these particulates by this filter has been confirmed. (See Detection of Particulate Matter in Commercial Preparations under Cautions.)

Prepare IV infusion in glass or PVC container.

Determine the volume of diluent based on the patient’s weight (neonates, infants, and children weighing ≤20 kg) or BSA (children weighing >20 kg, adolescents, and adults). Dilute each loading or maintenance dose of injection concentrate in ≥25 mL/kg of body weight of 10% dextrose injection.

Rate of Administration

Administer loading dose over 90–120 minutes.

Administer maintenance dose over 24 hours.

Dosage

Available as sodium phenylacetate and sodium benzoate; dosage expressed in terms of the salts.

Base dosages in neonates, infants, and children weighing ≤20 kg on body weight; base dosages in pediatric patients weighing >20 kg and in adults on body surface area.

Pediatric Patients

Acute Hyperammonemia

IV

Pediatric patients weighing ≤20 kg: Loading dose of 250 mg/kg sodium phenylacetate in fixed combination with 250 mg/kg sodium benzoate infused over 90–120 minutes. Maintenance dose of 250 mg/kg of sodium phenylacetate and 250 mg/kg sodium benzoate infused over 24 hours.

Pediatric patients weighing >20 kg: Loading dose of 5.5 g/m² sodium phenylacetate and 5.5 g/m² sodium benzoate infused over 90–120 minutes. Maintenance dose of 5.5 g/m² sodium phenylacetate and 5.5 g/m² of sodium benzoate infused over 24 hours.

Continue maintenance infusions until elevated plasma ammonia concentrations decrease to normal levels or until patient can tolerate oral nutrition and drug therapy.

Repeat Loading Doses

Manufacturer states do not repeat loading doses; however, some experts state that a repeat loading dose within 24 hours should be considered only in neonates with severe disorders and/or those receiving dialysis; space loading doses ≥6 hours apart. (See Laboratory Monitoring and also see Repeat Loading Doses under Cautions.)

Adults

Acute Hyperammonemia

IV

Loading dose: 5.5 g/m² sodium phenylacetate and 5.5 g/m² sodium benzoate infused over 90–120 minutes. Manufacturer states do not repeat loading doses.

Maintenance dose: 5.5 g/m² sodium phenylacetate and 5.5 g/m² sodium benzoate infused over 24 hours.

Continue maintenance infusions until elevated plasma ammonia concentrations decrease to normal levels or until patient can tolerate oral nutrition and drug therapy.

Special Populations

No special population dosage recommendations at this time. (See Hepatic Impairment and see Renal Impairment under Cautions and also see Special Populations under Pharmacokinetics.)

Contraindications

• Known hypersensitivity to sodium phenylacetate or sodium benzoate or any ingredient in the formulation.

Warnings/Precautions

Warnings

Emergency Treatment of Hyperammonemia

Risk of rapid brain damage or death if acute symptomatic hyperammonemia is left uncontrolled; treat as a life-threatening emergency. Prompt use of all therapies to reduce serum ammonia concentrations (e.g., dialysis [preferably hemodialysis]) is essential. (See Acute Hyperammonemia under Uses.)

Manage hyperammonemia due to inborn errors of metabolism in coordination with medical personnel familiar with such conditions; usually requires health-care facilities able to provide multidisciplinary treatment (e.g., hemodialysis, nutritional management, medical support).

Laboratory Monitoring

Closely monitor plasma ammonia concentrations, neurologic status, laboratory tests, and clinical response during treatment.

Monitor serum electrolyte concentrations; maintain within the normal range.

Urinary loss of potassium is enhanced by excretion of nonabsorbable anions phenylacetylglutamine and hippurate; carefully monitor plasma potassium concentrations and provide replacement therapy, when necessary.

Perform blood chemistry profiles and frequent blood pH and blood gases (e.g., pCO₂) evaluations to check for salicylate-like toxicity. (See Salicylate-like Toxicity under Cautions.)

The Urea Cycle Disorders Conference Group and some experts recommend monitoring plasma concentrations of ammonia scavenging drugs (e.g., sodium phenylacetate and sodium benzoate) to avoid toxicity. Weigh the risk of overdosage against potential benefits of repeating a loading dose in the absence of facilities for drug concentration monitoring. (See Repeat Loading Doses under Dosage and Administration and also see Repeat Loading Doses under Cautions.)

Possible Prescribing Errors

Experts recommend double-checking the accuracy of prescription orders to avoid possible overdosage.

Detection of Particulate Matter in Commercial Preparations

Particulate matter has been detected in sodium phenylacetate and sodium benzoate injections. Particulates may notbe readily observed on visual inspection. Because these particulates could potentially affect injection safety, always use the Millex Durapore GV 33-mm sterile syringe filter (0.22 µm) provided by the manufacturer when diluting the injection (see Dilution under Dosage and Administration). Removal of these particulates by this filter has been confirmed.

Report any quality problems or suspected adverse effects to the manufacturer (800-900-6389) or the FDA MedWatch program.

For addditional information, see [Web] or [Web].

Extravasation

Do not administer injection concentrate undiluted; only administer via a central line. Peripheral venous administration may cause burns.

Extravasation into perivenous tissue may lead to skin necrosis. Carefully monitor the infusion site during infusion. If extravasation is suspected, discontinue the infusion and resume at a different site, if necessary. Treatment for extravasation may include aspiration of residual drug from the catheter, limb elevation, and intermittent cooling with cold packs.

Sodium Content

Each g of sodium phenylacetate provides 6.3 mEq (145 mg) of sodium, and each g of sodium benzoate provides 7 mEq (160 mg) of sodium; each mL of injection concentrate labeled as containing 100 mg each of sodium phenylacetate and sodium benzoate provides 1.33 mEq (30.5 mg) of sodium.

Consider sodium content and use with caution, if at all, in patients with CHF, severe renal impairment, or sodium retention with edema. If adverse effects associated with increased sodium concentrations occur, discontinue the drug, promptly evaluate the patient, and take appropriate measures.

Salicylate-like Toxicity

Structurally similar to salicylate; possibility of adverse effects (e.g., hyperventilation, metabolic acidosis) typically associated with acute salicylate toxicity. (See Laboratory Monitoring under Cautions.)

Major Toxicities

Neurotoxicity

Adverse neurotoxic effects (e.g., somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, exacerbation of existing neuropathy) reported in cancer patients receiving IV phenylacetate. Acute onset (mainly mild) occurred upon initiation of therapy; reversible upon discontinuance of the drug.

General Precautions

Repeat Loading Doses

The manufacturer states that, because plasma concentrations of phenylacetate are prolonged, do not repeat loading doses. However, some experts state that a repeat loading dose within 24 hours should be considered only in neonates with severe disorders and/or those receiving dialysis; space loading doses at least 6 hours apart. (See Repeat Loading Doses under Dosage and Administration and see Laboratory Monitoring under Cautions.)

Hyperbilirubinemia

Risk of indirect hyperbilirubinemia. Use with caution in neonates with hyperbilirubinemia. In infants at risk, reduce serum bilirubin concentrations to normal range before initiating therapy with sodium phenylacetate and sodium benzoate.

Dialysis

Manufacturer states drug is complementary with dialysis (e.g., standard hemodialysis, peritoneal dialysis, arteriovenous hemofiltration).

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether sodium phenylacetate or sodium benzoate or their conjugated metabolites are distributed into milk. Use with caution in nursing women.

Pediatric Use

Efficacy is established for treatment of hyperammonemia in pediatric patients 0–16 years of age, including neonates (0–30 days of age) and infants (31 days–2 years of age).

Use with caution in neonates with hyperbilirubinemia. (See Hyperbilirubinemia under Cautions.)

Hepatic Impairment

Use with caution in patients with hepatic impairment. (See Metabolism under Pharmacokinetics.)

Renal Impairment

Use with caution and carefully monitor patients with renal impairment. (See Elimination under Pharmacokinetics.)

Common Adverse Effects

Vomiting, hyperglycemia, hypokalemia, seizures, mental impairment.

General

• Initiate therapy immediately following the diagnosis of hyperammonemia.

• Prior to infusion, discontinue analogous oral agents (e.g., sodium phenylbutyrate).

• May administer an antiemetic during the infusion for management of possible nausea and vomiting.

• Start or resume oral therapy (e.g., sodium phenylbutyrate), dietary management, and protein restriction when ammonia concentrations reduced to the normal range.

• Dialysis is recommended for those patients who do not have a significant reduction in plasma ammonia levels within 4–8 hours after receiving sodium phenylacetate and sodium benzoate.

• Concomitant therapy with arginine hydrochloride may be required. Consult the prescribing information for arginine hydrochloride for complete dosing and other information.

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion through a central venous line only; administration through a peripheral line may cause burns.

Vials are for single use only.

Dilution

Mustbe diluted in 10% dextrose injection prior to administration.

Always use the Millex Durapore GV 33-mm sterile syringe filter (0.22 µm) provided by the manufacturer when diluting sodium phenylacetate and sodium benzoate injection regardless of whether particulate matter is visible in the vial. Particulate matter has been reported but may notbe readily observed on visual inspection; removal of these particulates by this filter has been confirmed. (See Detection of Particulate Matter in Commercial Preparations under Cautions.)

Prepare IV infusion in glass or PVC container.

Determine the volume of diluent based on the patient’s weight (neonates, infants, and children weighing ≤20 kg) or BSA (children weighing >20 kg, adolescents, and adults). Dilute each loading or maintenance dose of injection concentrate in ≥25 mL/kg of body weight of 10% dextrose injection.

Rate of Administration

Administer loading dose over 90–120 minutes.

Administer maintenance dose over 24 hours.

Dosage

Available as sodium phenylacetate and sodium benzoate; dosage expressed in terms of the salts.

Base dosages in neonates, infants, and children weighing ≤20 kg on body weight; base dosages in pediatric patients weighing >20 kg and in adults on body surface area.

Pediatric Patients

Acute Hyperammonemia

IV

Pediatric patients weighing ≤20 kg: Loading dose of 250 mg/kg sodium phenylacetate in fixed combination with 250 mg/kg sodium benzoate infused over 90–120 minutes. Maintenance dose of 250 mg/kg of sodium phenylacetate and 250 mg/kg sodium benzoate infused over 24 hours.

Pediatric patients weighing >20 kg: Loading dose of 5.5 g/m² sodium phenylacetate and 5.5 g/m² sodium benzoate infused over 90–120 minutes. Maintenance dose of 5.5 g/m² sodium phenylacetate and 5.5 g/m² of sodium benzoate infused over 24 hours.

Continue maintenance infusions until elevated plasma ammonia concentrations decrease to normal levels or until patient can tolerate oral nutrition and drug therapy.

Repeat Loading Doses

Manufacturer states do not repeat loading doses; however, some experts state that a repeat loading dose within 24 hours should be considered only in neonates with severe disorders and/or those receiving dialysis; space loading doses ≥6 hours apart. (See Laboratory Monitoring and also see Repeat Loading Doses under Cautions.)

Adults

Acute Hyperammonemia

IV

Loading dose: 5.5 g/m² sodium phenylacetate and 5.5 g/m² sodium benzoate infused over 90–120 minutes. Manufacturer states do not repeat loading doses.

Maintenance dose: 5.5 g/m² sodium phenylacetate and 5.5 g/m² sodium benzoate infused over 24 hours.

Continue maintenance infusions until elevated plasma ammonia concentrations decrease to normal levels or until patient can tolerate oral nutrition and drug therapy.

Special Populations

No special population dosage recommendations at this time. (See Hepatic Impairment and see Renal Impairment under Cautions and also see Special Populations under Pharmacokinetics.)

No formal drug interaction studies to date.

Specific Drugs