Sodium Phenylacetate and Sodium Benzoate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution [concentrate]:

Ammonul: Sodium phenylacetate 100 mg and sodium benzoate 100 mg per 1 mL (50 mL)

Generic: Sodium phenylacetate 100 mg and sodium benzoate 100 mg per 1 mL (50 mL)

Pharmacology

Mechanism of Action

Sodium phenylacetate and sodium benzoate provide alternate pathways for the removal of ammonia through the formation of their metabolites. One mole of sodium phenylacetate removes two moles of nitrogen; one mole of sodium benzoate removes one mole of nitrogen.

Pharmacokinetics/Pharmacodynamics

Metabolism

Hepatic and renal; sodium phenylacetate conjugates with glutamine, forming the active metabolite, phenylacetylglutamine (PAG); sodium benzoate combines with glycine to form the active metabolite hippuric acid (HIP)

Excretion

Primarily urine

Use in Specific Populations

Special Populations: Gender

Bioavailability of phenylacetate and benzoate was slightly higher in women than men; however, conclusion cannot be drawn because of the small number of subjects in the study.

Use: Labeled Indications

Hyperammonemia: Adjunct to treatment of acute hyperammonemia and associated encephalopathy in patients with urea cycle enzyme deficiencies

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Dosage and Administration

Dosing: Adult

Note: Administer as a loading dose over 90 to 120 minutes, followed by an equivalent maintenance infusion given over 24 hours. Initiate therapy as soon as the diagnosis of hyperammonemia is made; hyperammonemic coma in neonates should be aggressively treated while the diagnosis is pursued. Dosage is based on weight for neonates, infants, and young children and body surface area for older children, adolescents, and adults. Therapy should continue until ammonia levels are in normal range or patient can tolerate oral nutrition and medications. Repeat loading doses are not recommended due to neurotoxicity associated with prolonged plasma levels of phenylacetate. Antiemetics may be administered during infusion to aid control of infusion-associated nausea and vomiting.

Hyperammonemia, acute (urea cycle disorders): IV: 55 mL/m² (provides sodium phenylacetate 5.5 g/m² and sodium benzoate 5.5 g/m²) coadministered with arginine; consider conjunctive use of hemodialysis in patients with severe hyperammonemia or refractory to sodium phenylacetate/sodium benzoate.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Administer as a loading dose over 90 to 120 minutes, followed by an equivalent dose as a maintenance infusion over 24 hours. Dosage is based on weight for infants and young children and body surface area for older children and adolescents. Initiate therapy as soon as the diagnosis of hyperammonemia is made; therapy should continue until ammonia levels are in normal range or patient can tolerate oral nutrition and medications. Antiemetics may be administered during infusion to aid control of infusion-associated nausea and vomiting.

Hyperammonemia, acute (urea cycle disorders [UCD]): Note: Administer concomitantly with arginine; arginine dose varies based on type of UCD. Ammonul: IV:

Infants and Children ≤20 kg:

Loading dose: 2.5 mL/kg (provides sodium phenylacetate 250 mg/kg and sodium benzoate 250 mg/kg) followed by maintenance infusion of 2.5 mL/kg/24 hours (provides sodium phenylacetate 250 mg/kg and sodium benzoate 250 mg/kg per 24 hours)

Children and Adolescents >20 kg:

Loading dose: 55 mL/m² (provides sodium phenylacetate 5.5 g/m² and sodium benzoate 5.5 g/m²) followed by maintenance infusion of 55 mL/m²/24 hours (provides sodium phenylacetate 5.5 g/m² and sodium benzoate 5.5 g/m² per 24 hours)

Reconstitution

Must dilute in D₁₀W at ≥25 mL/kg prior to administration.

Administration

IV: Must be diluted prior to administration. Infuse via central line ONLY (administration via peripheral line may cause burning). If extravasation is suspected discontinue infusion and resume at a different infusion site (if necessary). Infuse loading dose over 90 to 120 minutes; maintenance dose is administered over 24 hours. May be an irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation (may cause necrosis).

Dietary Considerations

Contains 30.5 mg of sodium per mL of undiluted product. Caloric supplementation and dietary protein restriction should be part of treatment. Caloric intake of >80 cal/kg/day should be attempted.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Following dilution, solution for infusion may be stored at room temperature for up to 24 hours.

Drug Interactions

Probenecid: May increase the serum concentration of Sodium Phenylacetate. Specifically, probenecid may inhibit the renal transport of the phenylacetylglutamine metabolite of sodium phenylacetate. Monitor therapy

Probenecid: May increase the serum concentration of Sodium Benzoate. Specifically, probenecid may inhibit the renal transport of the hippuric acid metabolite of sodium benzoate. Monitor therapy

Adverse Reactions

>10%: Infection: Infection (12%)

1% to 10%:

Cardiovascular: Hypotension (4%; more common in neonates), bradycardia, cardiac failure, cardiogenic shock, cardiomyopathy, chest pain, edema, flushing, hepatic artery stenosis, hypertension, low cardiac output, myocardial rupture (atria), pericardial effusion, septic shock, subdural hematoma, thrombosis, venous thrombosis

Central nervous system: Decreased mental acuity (6%), seizure (6%), cerebral edema (5%), agitation (3%), coma (3%), absent reflexes, acute psychosis, aggressive behavior, ataxia, brain disease, cerebral atrophy, cerebral hemorrhage, cerebral herniation, cerebral infarction, clonus, confusion, hallucination, impaired consciousness, increased intracranial pressure, paralysis (nerve)

Dermatologic: Alopecia, maculopapular rash, pruritus, skin rash, urticaria

Endocrine & metabolic: Hyperglycemia (7%), hypokalemia (7%), hyperammonemia (5%), metabolic acidosis (4%), acidosis (3%), hypocalcemia (3%), alkalosis, dehydration, fluid retention, hyperkalemia, hypernatremia, hypervolemia, respiratory acidosis

Gastrointestinal: Vomiting (9%; more common in infants), diarrhea (3%; more common in infants), nausea (3%; more common in infants), abdominal distention, cholestasis, gastrointestinal hemorrhage

Genitourinary: Urinary tract infection (3%), anuria, urinary retention

Hematologic & oncologic: Anemia (4%), disseminated intravascular coagulation (DIC; 3%), altered serum glucose, blood coagulation disorder, hemangioma, hemorrhage, increased serum pH, pancytopenia, pulmonary hemorrhage, thrombocytopenia

Hepatic: Hepatic failure, hepatotoxicity, jaundice

Infection: Sepsis

Local: Injection site reaction (3%; includes extravasation, hemorrhage at injection site, injection site blister formation)

Neuromuscular & skeletal: Tetany, tremor, weakness

Ophthalmic: Blindness

Renal: Renal failure

Respiratory: Respiratory distress (3%), acute respiratory distress, aspiration pneumonia, dyspnea, hypercapnia, hyperventilation, Kussmaul’s respiration, pneumothorax, pulmonary edema, respiratory alkalosis, respiratory insufficiency, tachypnea

Miscellaneous: Fever (5%), multi-organ failure

Warnings/Precautions

Concerns related to adverse effects:

• Acute hyperammonemia: Uncontrolled hyperammonemia can result in brain death. Immediate use of all additional therapies to decrease ammonia levels is essential including hemodialysis, caloric supplementation, and dietary protein restriction. Nonprotein calories should be supplied primarily as glucose (8 to 10 mg/kg/minute) with the addition of IV fat emulsion; attempts should be made to maintain a caloric intake of >80 cal/kg/day.
• Extravasation: Infuse via central line ONLY; peripheral administration may cause burning. May be an irritant with vesicant-like properties; avoid extravasation. If extravasation is suspected discontinue infusion and resume at a different infusion site (if necessary).
• Fluid overload: Use with caution, if at all, in patients at risk for fluid overload (eg, heart failure, severe renal impairment) or sodium retention edema; contains a significant amount of sodium. Discontinue use if patient experiences clinically significant fluid overload.
• Gastrointestinal effects: Nausea and vomiting may occur; premedication with antiemetics may be administered.
• Hypokalemia: May occur; monitor plasma potassium and initiate appropriate treatment as necessary.
• Metabolic acidosis/hyperventilation: Use may cause hyperventilation and metabolic acidosis; phenylacetate and benzoate are structurally similar to salicylate, therefore, adverse effects typically associated with salicylate overdose may occur with sodium phenylacetate/sodium benzoate use.
• Neurotoxicity: Phenylacetate may result in neurotoxicity (fatigue, lightheadedness, somnolence); symptoms were observed upon initiation of treatment and were reversible with discontinuation.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; metabolism of sodium phenylacetate/sodium benzoate may be impaired.
• Renal impairment: Use with caution in patients with renal impairment; excretion of drug metabolites (phenylacetylglutamine and hippurate) and ammonia may be reduced since primarily excreted by the kidneys; use may also predispose to fluid overload.

Special populations:

• Neonates: Hyperammonemic coma, regardless of the cause, should be treated aggressively until a specific diagnosis is made. Hemodialysis should be initiated immediately in all neonates and may be repeated until plasma ammonia level is stable at normal or near normal levels; a blood flow rate of 150 mL/minute/m² should be targeted.

Dosage form specific issues:

• Sodium benzoate: Contains sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin.

Other warnings/precautions:

• Appropriate use: Initiate therapy as soon as hyperammonemia is diagnosed. Must be diluted prior to administration. Administer through a central line; peripheral administration may result in burning. Repeat loading doses should not be administered (may result in prolonged phenylacetate plasma levels). Arginine supplementation is an essential part of therapy for patients with carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) deficiency.
• Experienced personnel: Patients should be managed by medical personnel experienced in the treatment of metabolic disorders.

Monitoring Parameters

Neurologic status, Glasgow Coma Scale, tachypnea, CT or MRI scan or fundoscopic evidence of cerebral edema, and/or of gray matter and white matter damage; plasma ammonia, plasma glutamine, plasma amino acids; blood chemistry, blood glucose, AST, ALT, blood pH and pCO₂, clinical response, serum electrolytes (potassium, chloride, or bicarbonate), infusion site

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea or vomiting. Have patient report immediately to prescriber signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of acidosis (confusion, fast breathing, fast heartbeat, arrhythmia, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or feeling very tired or weak), severe dizziness, passing out, headache, confusion, seizures, change in taste, trouble hearing, trouble with memory, burning or numbness feeling, muscle pain, muscle cramps, or severe injection site pain, burning, edema, blisters, or irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.