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Sodium Phenylacetate and Sodium Benzoate

Class: Ammonia Detoxicants
Chemical Name: Benzeneacetic acid, sodium salt
Molecular Formula: C8H7NaO2C7H5NaO2
CAS Number: 114-70-5
Brands: Ammonul

Introduction

Fixed combination of 2 ammonia detoxicants.1

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]);1 2 3 4 5 7 designated an orphan drug by FDA for this use.5

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.1 3 4 7

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.1 3 4 In such patients, administration of sodium phenylacetate and sodium benzoate helps prevent reaccumulation of ammonia by increasing waste nitrogen excretion.1 3 4

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.1 2 3 4 6 7 Pending specific diagnosis, also give IV arginine hydrochloride to hyperammonemic infants with suspected urea cycle disorders.1 3 7

If a urea cycle disorder is suspected based on family history, document hyperammonemia before administering sodium phenylacetate and sodium benzoate.1

Sodium Phenylacetate and Sodium Benzoate Dosage and Administration

General

  • Initiate therapy immediately following the diagnosis of hyperammonemia.1 7

  • Prior to infusion, discontinue analogous oral agents (e.g., sodium phenylbutyrate).1

  • May administer an antiemetic during the infusion for management of possible nausea and vomiting.1 6

  • Start or resume oral therapy (e.g., sodium phenylbutyrate), dietary management, and protein restriction when ammonia concentrations reduced to the normal range.1 7

  • 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.1

  • Concomitant therapy with arginine hydrochloride may be required.1 3 4 7 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.1

Vials are for single use only.1

Dilution

Mustbe diluted in 10% dextrose injection prior to administration.1 3 4 7

Always use the Millex Durapore GV 33-mm sterile syringe filter (0.22 mcm) provided by the manufacturer when diluting sodium phenylacetate and sodium benzoate injection regardless of whether particulate matter is visible in the vial.9 Particulate matter has been reported but may notbe readily observed on visual inspection; removal of these particulates by this filter has been confirmed.9 (See Detection of Particulate Matter in Commercial Preparations under Cautions.)

Prepare IV infusion in glass or PVC container. 1

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).1 Dilute each loading or maintenance dose of injection concentrate in ≥25 mL/kg of body weight of 10% dextrose injection.1 3

Rate of Administration

Administer loading dose over 90–120 minutes.1 3 7

Administer maintenance dose over 24 hours.1 3 7

Dosage

Available as sodium phenylacetate and sodium benzoate; dosage expressed in terms of the salts.1

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.1 3 7

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.1 3 7 Maintenance dose of 250 mg/kg of sodium phenylacetate and 250 mg/kg sodium benzoate infused over 24 hours.1 3 7

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.1 3 Maintenance dose of 5.5 g/m2 sodium phenylacetate and 5.5 g/m2 of sodium benzoate infused over 24 hours.1 3

Continue maintenance infusions until elevated plasma ammonia concentrations decrease to normal levels or until patient can tolerate oral nutrition and drug therapy.1 3 7

Repeat Loading Doses
IV

Manufacturer states do not repeat loading doses;1 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.3 4 (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.1 3 Manufacturer states do not repeat loading doses.1

Maintenance dose: 5.5 g/m2 sodium phenylacetate and 5.5 g/m2 sodium benzoate infused over 24 hours.1 3

Continue maintenance infusions until elevated plasma ammonia concentrations decrease to normal levels or until patient can tolerate oral nutrition and drug therapy.1 3 7

Special Populations

No special population dosage recommendations at this time.1 (See Hepatic Impairment and see Renal Impairment under Cautions and also see Special Populations under Pharmacokinetics.)

Cautions for Sodium Phenylacetate and Sodium Benzoate

Contraindications

  • Known hypersensitivity to sodium phenylacetate or sodium benzoate or any ingredient in the formulation.1

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.1 7 Prompt use of all therapies to reduce serum ammonia concentrations (e.g., dialysis [preferably hemodialysis]) is essential.1 3 4 6 7 (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).1 3

Laboratory Monitoring

Closely monitor plasma ammonia concentrations, neurologic status, laboratory tests, and clinical response during treatment.1

Monitor serum electrolyte concentrations; maintain within the normal range.1

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.1 6

Perform blood chemistry profiles and frequent blood pH and blood gases (e.g., pCO2) evaluations to check for salicylate-like toxicity.1 (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.6 Weigh the risk of overdosage against potential benefits of repeating a loading dose in the absence of facilities for drug concentration monitoring.4 (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.4

Detection of Particulate Matter in Commercial Preparations

Particulate matter has been detected in sodium phenylacetate and sodium benzoate injections.9 Particulates may notbe readily observed on visual inspection.9 Because these particulates could potentially affect injection safety, always use the Millex Durapore GV 33-mm sterile syringe filter (0.22 mcm) provided by the manufacturer when diluting the injection (see Dilution under Dosage and Administration).9 Removal of these particulates by this filter has been confirmed.9

Report any quality problems or suspected adverse effects to the manufacturer (800-900-6389) or the FDA MedWatch program.9

For addditional information, see or .9

Extravasation

Do not administer injection concentrate undiluted; only administer via a central line.1 Peripheral venous administration may cause burns.1

Extravasation into perivenous tissue may lead to skin necrosis.1 Carefully monitor the infusion site during infusion.1 If extravasation is suspected, discontinue the infusion and resume at a different site, if necessary.1 Treatment for extravasation may include aspiration of residual drug from the catheter, limb elevation, and intermittent cooling with cold packs.1

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.1 7

Consider sodium content and use with caution, if at all, in patients with CHF, severe renal impairment, or sodium retention with edema.1 If adverse effects associated with increased sodium concentrations occur, discontinue the drug, promptly evaluate the patient, and take appropriate measures.1

Salicylate-like Toxicity

Structurally similar to salicylate; possibility of adverse effects (e.g., hyperventilation, metabolic acidosis) typically associated with acute salicylate toxicity.1 2 (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.1 Acute onset (mainly mild) occurred upon initiation of therapy; reversible upon discontinuance of the drug.1

General Precautions

Repeat Loading Doses

The manufacturer states that, because plasma concentrations of phenylacetate are prolonged, do not repeat loading doses.1 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.3 4 (See Repeat Loading Doses under Dosage and Administration and see Laboratory Monitoring under Cautions.)

Hyperbilirubinemia

Risk of indirect hyperbilirubinemia.7 Use with caution in neonates with hyperbilirubinemia.7 In infants at risk, reduce serum bilirubin concentrations to normal range before initiating therapy with sodium phenylacetate and sodium benzoate.7

Dialysis

Manufacturer states drug is complementary with dialysis (e.g., standard hemodialysis, peritoneal dialysis, arteriovenous hemofiltration).1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether sodium phenylacetate or sodium benzoate or their conjugated metabolites are distributed into milk.1 Use with caution in nursing women.1

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).1

Use with caution in neonates with hyperbilirubinemia.7 (See Hyperbilirubinemia under Cautions.)

Hepatic Impairment

Use with caution in patients with hepatic impairment.1 (See Metabolism under Pharmacokinetics.)

Renal Impairment

Use with caution and carefully monitor patients with renal impairment.1 (See Elimination under Pharmacokinetics.)

Common Adverse Effects

Vomiting, hyperglycemia, hypokalemia, seizures, mental impairment.1

Interactions for Sodium Phenylacetate and Sodium Benzoate

No formal drug interaction studies to date.1

Specific Drugs

Drug

Interaction

Anti-infective agents (e.g., penicillin)

Some anti-infective agents may compete with phenylacetylglutamine and hippurate for active renal tubular secretion, affecting drug disposition1

Corticosteroids

Corticosteroids may increase plasma ammonia concentrations by causing protein catabolism1

Probenecid

Probenecid inhibits renal transport of organic compounds (including aminohippuric acid)1

Probenecid may affect renal excretion of phenylacetylglutamine and hippurate1

Valproic acid

Valproic acid may induce hyperammonemia via inhibition of N-acetylglutamate, a co-factor for carbamyl phosphate synthetase1

Concomitant use may exacerbate urea cycle disorders and antagonize plasma ammonia-lowering effects of the ammonia detoxicant1

Sodium Phenylacetate and Sodium Benzoate Pharmacokinetics

Absorption

Onset

Mean ammonia concentrations decrease significantly within 4 hours in patients responding to therapy.1

Distribution

Extent

Not known whether sodium phenylacetate or sodium benzoate or their conjugated metabolites are distributed into milk.1

Elimination

Metabolism

Sodium phenylacetate is metabolized in the liver and kidneys to phenylacetylglutamine.1

Sodium benzoate is metabolized in the liver and kidneys to hippuric acid.1

Elimination Route

Phenylacetylglutamine and hippuric acid are principally excreted in urine via glomerular filtration and tubular secretion.1

Special Populations

Sodium phenylacetate and sodium benzoate are metabolized in the liver; limited information available in impaired hepatic function.1

Sodium phenylacetate and sodium benzoate are metabolized and excreted by the kidneys; renal clearance of drug metabolites and ammonia is required.1

Stability

Storage

Parenteral

Injection Concentrate

25°C (may be exposed to 15–30°C).1 Diluted solutions are stable for up to 24 hours at room temperature and room lighting conditions.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Dextrose 10% in water1

Do not admix with other infusion solutions.1

Drug Compatibility
Admixture Compatibility

Compatible

Arginine HCl 10%

Do not admix with other drugs.1

Actions

  • Sodium phenylacetate and sodium benzoate decrease ammonia concentrations by serving as alternatives to urea for nitrogen waste excretion.1 3 7

  • Nitrogen content of phenylacetylglutamine is identical to urea (i.e., 2 moles of nitrogen).1

  • Two moles of nitrogen are removed per mole of phenylacetate conjugated with glutamine; one mole of nitrogen is removed per mole of benzoate conjugated with glycine.1 7

  • Glutamine and glycine used in these reactions are replaced by synthesis, reducing the nitrogen pool and attenuating the risk of ammonia and glutamine-induced neurotoxicity.1 3 7

Advice to Patients

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Manufacturer has notified health-care professionals that particular matter was detected in sodium phenylacetate and sodium benzoate injections.9 Use the syringe filter provided by the manufacturer when diluting the injection.9 Report any quality problems or suspected adverse effects to the manufacturer (800-900-6389) or the FDA MedWatch program.9 (See Detection of Particulate Matter in Commercial Preparations uunder Cautions.)

Sodium Phenylacetate and Sodium Benzoate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection concentrate, for IV use only

100 mg/mL (of sodium phenylacetate) and 100 mg/mL (of sodium benzoate)

Ammonul 10%/10%

Ucyclyd

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: March 01, 2009
Last reviewed: April 01, 2010
Date modified: February 08, 2016

References

1. Medicis Pharma. Ammonul (sodium phenylacetate and sodium benzoate injection 10%/10%) prescribing information. Scottsdale, AZ; 2005 Oct.

2. Summar M, Tuchman M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr. 2001; 138: S6-10.

3. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr. 2001; 138: S30-9.

4. The Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. J Pediatr. 2001; 138: S1-5.

5. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA website. Accessed 2005 Mar 21.

6. Batshaw ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr. 2001; 138: S46-55.

7. Rezvani I. Urea cycle and hyperammonemia (arginine, citrulline, ornithine). In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. Philadelphia: Saunders; 2004:424-9.

8. Ucyclyd Pharma, Scottsdale, AZ: Personal communication.

9. Dear health care provider letter regarding important safety information concerning particular matter detected in Ammonul (sodium phenylacetate and sodium benzoate) injections 10%/10%. Scottsdale, AZ: Ucyclyd; 2008 Sep 15.

a. AHFS drug information 2008. McEvoy GK, ed. Sodium phenylacetate and sodium benzoate. Bethesda, MD: American Society of Health-System Pharmacists; 2008:2719–20.

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