Note: Administer as a loading dose over 90 to 120 minutes, followed by an equivalent dose as a maintenance infusion over 24 hours. 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: 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)
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)
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.
Dialysis: Commonly used in conjunction with dialysis. Ammonia clearance is ~10 times greater with hemodialysis than by peritoneal dialysis or hemofiltration. Exchange transfusion is ineffective.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
(For additional information see "Sodium phenylacetate and sodium benzoate: Drug information")
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.
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
IV: Must dilute prior to administration; may administer in combination with arginine. Must be administered via central line; 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).
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).
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.
Adjunct to treatment of acute hyperammonemia and encephalopathy in patients with urea cycle disorders (FDA approved in all ages)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>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
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.
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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
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 Lexicomp drug interactions program
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
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.
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.
Plasma ammonia, plasma amino acid (quantitative) and glutamine concentrations, blood glucose, serum electrolytes, hepatic and renal function tests, blood gases, neurologic status, physical signs/symptoms of hyperammonemia (ie, lethargy, ataxia, confusion, vomiting, seizures, and memory impairment); infusion site
Long-term target levels (may not be appropriate for every patient) (Berry 2001):
Plasma ammonia: <40 μmol/L
Plasma glutamine: <1000 μmol/L
Normal plasma levels of alanine, glycine, lysine, arginine (except in arginase deficiency); no subnormal concentrations of essential amino acids (eg, leucine, isoleucine, valine)
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.
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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