Note: Initiate therapy as soon as urea cycle disorder is suspected to reduce risk of irreversible neurological sequelae from hyperammonemia/encephalopathy.
Hyperammonemia, acute (in patients with known or suspected urea cycle disorders) (adjunctive therapy): Note: Use in conjunction with other therapies depending on the specific urea cycle disorder, including arginine (essential component for most urea cycle disorders), caloric supplementation, dietary protein restriction, hemodialysis, and other ammonia lowering therapies (Enns 2007). Antiemetics may be needed to prevent or treat infusion-associated nausea and vomiting (Enns 2007).
Loading dose: IV: 55 mL/m2 (provides sodium phenylacetate 5.5 g/m2 and sodium benzoate 5.5 g/m2) administered over 90 to 120 minutes. Note: Repeat loading doses are not recommended due to neurotoxicity associated with prolonged plasma levels of phenylacetate.
Maintenance dose: IV: 55 mL/m2 administered as a maintenance infusion over 24 hours until patient no longer has hyperammonemia and oral therapy can be tolerated.
There are no dosage adjustments provided in the manufacturer’s labeling; however, since the conjugates formed from treatment (phenylacetylglutamine and hippurate) are excreted by the kidneys, adequate kidney function is needed (Häberle 2012; Husson 2016).
There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution as metabolic conjugation of sodium benzoate and sodium phenylacetate takes place in the liver and kidneys.
Refer to adult dosing.
(For additional information see "Sodium phenylacetate and sodium benzoate: Pediatric drug information")
Note: Initiate therapy as soon as urea cycle disorder is suspected to reduce risk of irreversible neurological sequelae from hyperammonemia/encephalopathy. Sodium phenylacetate and sodium benzoate should be used. Dosing is based on weight (mL/kg) and body surface area (mL/m2) depending on patient weight; use caution to ensure appropriate dosing units.
Hyperammonemia, acute (urea cycle disorders [UCD]): Note: Use in conjunction with other therapies depending on the specific UCD, including arginine (essential component for most UCDs), caloric supplementation, dietary protein restriction, hemodialysis and other ammonia lowering therapies. Antiemetics may be used to prevent or treat infusion-associated nausea and vomiting (BIMDG 2017; Enns 2007; Häberle 2019; manufacturer's labeling).
Infants and Children ≤20 kg: Ammonul:
Loading dose: IV: 2.5 mL/kg (provides sodium phenylacetate 250 mg/kg and sodium benzoate 250 mg/kg) administered over 90 to 120 minutes. Note: Repeat loading doses are not recommended due to neurotoxicity associated with prolonged plasma levels of phenylacetate.
Maintenance dose: Continuous IV infusion: 2.5 mL/kg administered as a maintenance infusion over 24 hours (provides sodium phenylacetate 250 mg/kg and sodium benzoate 250 mg/kg per 24 hours); continue until patient no longer has hyperammonemia and oral therapy can be tolerated.
Children and Adolescents >20 kg: Ammonul:
Loading dose: IV: 55 mL/m2 (provides sodium phenylacetate 5.5 g/m2 and sodium benzoate 5.5 g/m2) administered over 90 to 120 minutes. Note: Repeat loading doses are not recommended due to neurotoxicity associated with prolonged plasma levels of phenylacetate.
Maintenance dose: Continuous IV infusion: 55 mL/m2 administered as a maintenance infusion over 24 hours (provides sodium phenylacetate 5.5 g/m2 and sodium benzoate 5.5 g/m2 per 24 hours); continue until patient no longer has hyperammonemia and oral therapy can be tolerated.
There are no dosage adjustments provided in the manufacturer's labeling; however, the drug metabolites and ammonia are excreted by the kidneys. Use with caution; monitor closely.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution, metabolism of sodium phenylacetate/sodium benzoate may be impaired in liver impairment.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults and pediatrics treated for on-label and off-label indications.
>10%: Infection: Infection (12%)
1% to 10%:
Cardiovascular: Bradycardia (<3%), cardiogenic shock (<3%), cardiomyopathy (<3%), chest pain (<3%), edema (<3%), flushing (<3%), heart failure (<3%), hypertension (<3%), hypotension (4%; more common in neonates), low cardiac output (<3%), myocardial rupture (atria) (<3%), pericardial effusion (<3%), thrombosis (<3%), venous thrombosis (<3%)
Dermatologic: Alopecia (<3%), pruritus (<3%), skin blister (<3%), skin rash (<3%), urticaria (<3%)
Endocrine & metabolic: Acidosis (3%), alkalosis (<3%), dehydration (<3%), fluid retention (<3%), hyperammonemia (5%), hyperglycemia (7%), hyperkalemia (<3%), hypernatremia (<3%), hypervolemia (<3%), hypocalcemia (3%), hypoglycemia (<3%), hypokalemia (7%), increased serum pH (<3%), metabolic acidosis (4%), respiratory acidosis (<3%), respiratory alkalosis (<3%)
Gastrointestinal: Abdominal distention (<3%), cholestasis (<3%), diarrhea (3%), gastrointestinal hemorrhage (<3%), nausea (3%), vomiting (9%)
Genitourinary: Anuria (<3%), urinary retention (<3%), urinary tract infection (3%)
Hematologic & oncologic: Anemia (4%), disorder of hemostatic components of blood (<3%), disseminated intravascular coagulation (3%), hemangioma (<3%), hemorrhage (<3%), pancytopenia (<3%), thrombocytopenia (<3%)
Hepatic: Hepatic artery stenosis (<3%), hepatic failure (<3%), hepatotoxicity (<3%), jaundice (<3%)
Infection: Sepsis (<3%), septic shock (<3%)
Local: Injection-site reaction (3%)
Nervous system: Absent reflexes (<3%), acute psychosis (<3%), aggressive behavior (<3%), agitation (3%), asthenia (<3%), ataxia (<3%), brain edema (5%), cerebral atrophy (<3%), cerebral hemorrhage (<3%), cerebral herniation (<3%), cerebral infarction (<3%), clonus (<3%), coma (3%), confusion (<3%), decreased mental acuity (6%), encephalopathy (<3%), hallucination (<3%), impaired consciousness (<3%), increased intracranial pressure (<3%), paralysis (nerve) (<3%), seizure (6%), subdural hematoma (<3%), tremor (<3%)
Neuromuscular & skeletal: Tetany (<3%)
Ophthalmic: Blindness (<3%)
Renal: Kidney failure (<3%)
Respiratory: Aspiration pneumonia (<3%), dyspnea (<3%), hypercapnia (<3%), hyperventilation (<3%), Kussmaul respiration (<3%), pneumothorax (<3%), pulmonary edema (<3%), pulmonary hemorrhage (<3%), respiratory distress (3%, including acute respiratory distress), respiratory failure (<3%), tachypnea (<3%), variations in blood CO2 concentration (<3%, including partial pressure CO2)
Miscellaneous: Fever (5%), multi-organ failure (<3%)
There are no contraindications listed in the manufacturer’s labeling.
Concerns related to adverse effects:
• Extravasation: Infuse via central line ONLY; peripheral administration may cause burning. May be an irritant with vesicant-like properties; avoid extravasation. Monitor infusion site closely during administration. 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. Avoid repeat loading doses due to potential for neurotoxicity associated with prolonged plasma levels of phenylacetate.
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.
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.
Enhanced potassium excretion may occur with treatment of hyperammonemia; monitor serum potassium concentration closely. Repeat loading doses of drug are not indicated due to prolonged plasma levels noted in pharmacokinetic studies. Maintain caloric intake of >80 cal/kg/day.
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)
Yes
Solution (Ammonul Intravenous)
10-10% (per mL): $1,095.86
Solution (Sod Benz-Sod Phenylacet Intravenous)
10-10% (per mL): $120.00 - $876.00
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IV: Must be diluted with 10% dextrose (D10W) 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, followed by a maintenance dose administered over 24 hours. May be an irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and monitor site during infusion; avoid extravasation (may cause necrosis).
Parenteral: IV: Must dilute prior to administration; may administer in combination with arginine. Infuse via central line ONLY (administration via peripheral line may cause burns). Infuse loading dose over 90 to 120 minutes; maintenance dose is a continuous infusion infused over 24 hours. Antiemetics may be needed to decrease nausea during infusion. May be an irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation (may cause necrosis). If extravasation is suspected discontinue infusion and resume at a different infusion site (if necessary).
Hyperammonemia, acute (in patients with suspected/known urea cycle disorders): Adjunct treatment of acute hyperammonemia and associated encephalopathy in patients with urea cycle enzyme deficiencies.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Corticosteroids (Systemic): May diminish the therapeutic effect of Sodium Benzoate. Risk C: Monitor therapy
Penicillins: May diminish the therapeutic effect of Sodium Benzoate. Risk C: Monitor therapy
Probenecid: May diminish the therapeutic effect of Sodium Benzoate. Risk C: Monitor therapy
Valproate Products: May diminish the therapeutic effect of Sodium Benzoate. Risk C: Monitor therapy
Phenylacetate and benzoate can be detected in umbilical cord and newborn blood following sodium phenylacetate/sodium benzoate infusion during labor (Wilnai 2018).
Also refer to the Sodium Benzoate monograph for additional information.
It is not known if sodium phenylacetate/sodium benzoate are present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother
Also refer to the Sodium Benzoate monograph for additional information.
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.
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 amino acids (including plasma glutamine); blood chemistry, blood glucose, AST, ALT, blood pH and pCO2, clinical response, serum electrolytes (sodium, potassium, chloride, or bicarbonate), monitor infusion site closely for potential extravasation during drug administration.
Long-term target levels (may not be appropriate for every patient):
Plasma ammonia: <40 micromole/L
Plasma glutamine: <1,000 micromole/L
Sodium phenylacetate and sodium benzoate provide alternate pathways for the removal of ammonia in patients with decreased or deficient enzymes in the urea cycle, which when functioning properly, forms water-soluble conjugation products that can be excreted in the urine. Sodium phenylacetate conjugates with glutamine in the liver and kidneys to form phenylacetylglutamine, while sodium benzoate conjugates with glycine to form hippuric acid and is excreted by the kidneys. One mole of phenylacetate removes 2 moles of nitrogen and 1 mole of benzoate removes 1 mole of nitrogen (Häberle 2012; Husson 2016).
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
Sex: 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.
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