Sodium phenylacetate/Sodium benzoate

Uses and Indications

Sodium Phenylacetate and Sodium Benzoate Injection is indicated as adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in pediatric and adult patients with deficiencies in enzymes of the urea cycle.

Limitations of Use: There are no teratogenic or nonteratogenic effects associated with this drug as per the available data.

Dosage and Administration

Sodium Phenylacetate and Sodium Benzoate Injection must be diluted with sterile 10% Dextrose Injection (D10W) prior to administration. It is essential that the injection is administered through a central venous catheter, as administration via a peripheral line may result in burns.

The initial loading dose should be infused intravenously over a period of 90 to 120 minutes. Following the loading dose, an equivalent maintenance dose should be administered as a continuous infusion over a duration of 24 hours.

For complete dosing recommendations, healthcare professionals are advised to refer to the Full Prescribing Information.

Contraindications

There are no contraindications associated with the use of this product. It is not classified as a controlled substance, and there are no identified risks of abuse, misuse, or dependence.

Warnings and Precautions

Plasma potassium levels should be carefully monitored in patients receiving Sodium Phenylacetate and Sodium Benzoate Injection, with appropriate treatment administered as necessary to address any decreases (5.1).

Caution is advised when administering Sodium Phenylacetate and Sodium Benzoate Injection to patients with conditions associated with fluid overload, such as congestive heart failure or severe renal insufficiency, as the product contains 30.5 mg of sodium per mL of undiluted solution. This is particularly important for patients with conditions that may lead to sodium retention and edema (5.2).

Extravasation of Sodium Phenylacetate and Sodium Benzoate Injection into perivenous tissues during high flow bolus infusion poses a risk of skin necrosis, especially in infants. Therefore, the infusion site must be monitored closely for signs of tissue infiltration throughout the administration of the drug (5.3).

Due to the prolonged plasma levels of phenylacetate observed in pharmacokinetic studies, repeat loading doses should be avoided. Additionally, neurotoxicity associated with phenylacetate has been reported in cancer patients; thus, it is essential to monitor these patients for symptoms indicative of acute neurotoxicity (5.4).

Sodium Phenylacetate and Sodium Benzoate Injection may induce side effects similar to those seen in salicylate overdose, including hyperventilation and metabolic acidosis. Regular monitoring of patient blood chemistry profiles is recommended, along with frequent assessments of blood pH and pCO2 levels to ensure patient safety (5.5).

Side Effects

Most frequently reported adverse reactions in patients receiving Sodium Phenylacetate and Sodium Benzoate Injection include vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment, with an incidence of 6% or greater.

In clinical trials, less common adverse reactions characterized as severe, occurring in less than 3% of patients, encompass a range of serious conditions across various systems. Notable blood and lymphatic system disorders include coagulopathy, pancytopenia, and thrombocytopenia. Cardiac disorders may manifest as atrial rupture, bradycardia, cardiac or cardiopulmonary arrest/failure, cardiogenic shock, cardiomyopathy, and pericardial effusion. Eye disorders such as blindness have also been reported.

Gastrointestinal disorders may present as abdominal distension and gastrointestinal hemorrhage. General disorders and administration-site conditions include asthenia, brain death, chest pain, multiorgan failure, and edema. Hepatobiliary disorders can involve cholestasis, hepatic artery stenosis, hepatic failure/hepatotoxicity, and jaundice. Infections and infestations, particularly sepsis or septic shock, have been observed.

Injury, poisoning, and procedural complications may lead to brain herniation, subdural hematoma, and overdose. Investigations may reveal changes in blood carbon dioxide, blood glucose, blood pH, cardiac output, pCO2, and respiratory rate. Metabolism and nutrition disorders include alkalosis, dehydration, fluid overload/retention, hypoglycemia, hyperkalemia, hypernatremia, and tetany.

Neoplasms such as acquired hemangioma have been noted, alongside nervous system disorders like areflexia, ataxia, brain infarction, brain hemorrhage, cerebral atrophy, clonus, depressed level of consciousness, encephalopathy, nerve paralysis, increased intracranial pressure, and tremor. Psychiatric disorders may present as acute psychosis, aggression, confusional state, and hallucinations. Renal and urinary disorders include anuria, renal failure, and urinary retention.

Respiratory, thoracic, and mediastinal disorders may manifest as acute respiratory distress syndrome, dyspnea, hypercapnia, hyperventilation, Kussmaul respiration, aspiration pneumonia, pneumothorax, pulmonary hemorrhage, pulmonary edema, and respiratory acidosis or alkalosis, including respiratory arrest/failure. Skin and subcutaneous tissue disorders may involve alopecia, blistering, generalized pruritus, rash, and urticaria. Vascular disorders can include flushing, hemorrhage, hypertension, and phlebothrombosis/thrombosis.

It is important to monitor plasma potassium levels closely and provide appropriate treatment as necessary. Caution is advised when administering Sodium Phenylacetate and Sodium Benzoate Injection to patients with congestive heart failure, severe renal insufficiency, or conditions associated with sodium retention and edema due to the risk of fluid overload. Extravasation of the injection into perivenous tissues during high flow bolus infusion may lead to skin necrosis, particularly in infants.

Patients should be monitored for symptoms of acute neurotoxicity associated with phenylacetate. The injection may also cause side effects typically associated with salicylate overdose, such as hyperventilation and metabolic acidosis; therefore, regular monitoring of blood chemistry profiles, blood pH, and pCO2 levels is recommended.

In cases of overdosage, signs of intoxication may include obtundation (in the absence of hyperammonemia), hyperventilation, severe compensated metabolic acidosis, large anion gap, hypernatremia, hyperosmolarity, progressive encephalopathy, cardiovascular collapse, and potentially death.

Drug Interactions

Some antibiotics, particularly penicillin, may influence the overall disposition of the infused drug, potentially altering its therapeutic effects.

Probenecid has been shown to impact the renal excretion of phenylacetylglutamine and hippurate, which may necessitate monitoring of these metabolites in patients receiving both agents.

In patients with urea cycle disorders, the administration of valproic acid may exacerbate their condition. This is due to its potential to antagonize the efficacy of Sodium Phenylacetate and Sodium Benzoate Injection by inhibiting the synthesis of N-acetylglutamate, a critical co-factor for carbamyl phosphate synthetase. Close monitoring of ammonia levels and clinical status is advised in these patients.

Corticosteroids may lead to the breakdown of body protein, which can result in increased plasma ammonia levels in individuals with a compromised ability to form urea. It is recommended that patients receiving corticosteroids be monitored for signs of hyperammonemia, particularly if they have underlying urea cycle disorders.

Packaging & NDC

The table below lists all NDC Code configurations of Sodium Phenylacetate and Sodium Benzoate, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Sodium Phenylacetate and Sodium Benzoate Injection has been utilized for the treatment of acute hyperammonemia in pediatric patients, including those in the early neonatal period. Clinical experience supports its use in this population, although specific dosage adjustments may be necessary based on the age and clinical condition of the patient. Healthcare professionals should exercise caution and closely monitor these patients due to the potential for varying responses and the need for individualized treatment plans.

Geriatric Use

Clinical studies of Sodium Phenylacetate and Sodium Benzoate Injection did not include any patients aged 65 and over, thus it remains unclear whether elderly patients respond differently from younger patients. Urea cycle disorders, for which this medication is indicated, predominantly affect pediatric and younger adult populations.

No pharmacokinetic studies have been conducted specifically in geriatric patients. Therefore, healthcare providers should exercise caution when prescribing Sodium Phenylacetate and Sodium Benzoate Injection to elderly patients. It is advisable to initiate treatment at the lower end of the dosing range, taking into account the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the potential for concomitant diseases or other drug therapies in this demographic. Regular monitoring of these patients is recommended to ensure safety and efficacy.

Pregnancy

Available data on the combination use of sodium phenylacetate and sodium benzoate in pregnant patients are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with Sodium Phenylacetate and Sodium Benzoate Injection, limiting the understanding of potential risks in human pregnancies.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown; however, it is important to note that all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2 to 5% and 15 to 20%, respectively. Healthcare professionals should consider these factors when counseling women of childbearing potential regarding the use of this medication during pregnancy.

Lactation

There are no data on the presence of sodium phenylacetate or sodium benzoate in either human or animal milk, nor are there any known effects on breastfed infants or on milk production.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for Sodium Phenylacetate and Sodium Benzoate Injection. Additionally, potential adverse effects on the breastfed infant from Sodium Phenylacetate and Sodium Benzoate Injection, as well as from the underlying maternal condition, should be considered.

Renal Impairment

Patients with impaired renal function should be closely monitored when receiving Sodium Phenylacetate and Sodium Benzoate Injection, as the drug metabolites, including phenylacetylglutamine and hippurate, as well as ammonia, are primarily excreted by the kidneys. Caution is advised in this population, particularly for those with severe renal insufficiency or congestive heart failure, as these conditions may exacerbate sodium retention and edema. Adjustments to dosing and careful observation of renal function are recommended to mitigate potential risks associated with reduced kidney function.

Hepatic Impairment

Limited information is available regarding the metabolism and excretion of sodium phenylacetate and sodium benzoate in patients with impaired hepatic function. Given that the metabolic conjugation of these compounds occurs primarily in the liver and kidney, caution is advised when administering Sodium Phenylacetate and Sodium Benzoate Injection to patients with hepatic insufficiency.

Due to the potential for altered pharmacokinetics in this population, it is recommended that healthcare providers closely monitor patients with compromised liver function for any adverse effects or changes in therapeutic response. Specific dosage adjustments have not been established; therefore, careful consideration of the patient's overall clinical status and liver function is essential when determining the appropriate dosing regimen.

Overdosage

Overdosage has been documented in patients receiving Sodium Phenylacetate and Sodium Benzoate Injection, particularly among those with urea cycle deficiencies. In an uncontrolled open-label study, all participants were intended to receive a uniform dosage of the injection; however, some individuals inadvertently received doses exceeding the protocol specifications.

In a review of clinical outcomes, it was noted that 16 out of 64 fatalities involved patients who had received a confirmed overdose of Sodium Phenylacetate and Sodium Benzoate Injection. The causes of death in these cases were varied and included cardiorespiratory failure or arrest (6 patients), hyperammonemia (3 patients), increased intracranial pressure (2 patients), and other complications such as pneumonitis with septic shock and coagulopathy (1 patient), error in dialysis procedure (1 patient), respiratory failure (1 patient), intractable hypotension with probable sepsis (1 patient), and one case with an unknown cause.

Signs of intoxication may manifest as obtundation (notably in the absence of hyperammonemia), hyperventilation, severe compensated metabolic acidosis potentially accompanied by a respiratory component, a large anion gap, hypernatremia, hyperosmolarity, progressive encephalopathy, cardiovascular collapse, and ultimately, death.

In the event of an overdose, it is imperative to discontinue the administration of Sodium Phenylacetate and Sodium Benzoate Injection immediately. Healthcare professionals should initiate appropriate emergency medical monitoring and interventions. In severe cases, the preferred management strategy is hemodialysis; however, peritoneal dialysis may be considered if hemodialysis is not available.

Nonclinical Toxicology

Long-term studies in animals have not been conducted to assess the carcinogenic potential of Sodium Phenylacetate and Sodium Benzoate Injection. However, available data indicate that sodium benzoate is not mutagenic or carcinogenic and does not impair fertility.

Studies evaluating the potential impairment of fertility or mutagenic effects of Sodium Phenylacetate and Sodium Benzoate Injection have not been performed. In animal studies, subcutaneous administration of phenylacetate to rat pups at doses ranging from 190 to 474 mg/kg resulted in decreased proliferation and increased loss of neurons, as well as reduced myelination in the central nervous system (CNS). Additionally, cerebral synapse maturation was delayed, and the number of functioning nerve terminals in the cerebrum was diminished, leading to impaired brain growth.

In a separate study, pregnant rats received subcutaneous doses of phenylacetate at 3.5 µmol/g/day from gestation day 7 until normal delivery. Prenatal exposure to phenylacetate resulted in lesions in layer 5 cortical pyramidal cells of rat pups, characterized by longer and thinner dendritic spines than normal, along with a reduced number of these spines.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions reported voluntarily or through surveillance programs. The most frequently observed adverse reactions include vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment. These events have been documented in the context of postmarketing surveillance, contributing to the overall understanding of the product's safety profile.

Patient Counseling

Healthcare providers should advise patients and caregivers regarding the safe use of Sodium Phenylacetate and Sodium Benzoate Injection. It is important to inform them that once plasma ammonia levels have normalized, dietary protein intake can typically be increased, with the ultimate goal of achieving unrestricted protein intake.

Providers should also discuss the potential adverse reactions associated with this treatment. The most common adverse reactions include vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment. Patients should be made aware of these risks and instructed to report any concerning symptoms promptly.

Additionally, healthcare providers should clarify that BUPHENYL is generally discontinued during the administration of Sodium Phenylacetate and Sodium Benzoate Injection. This information is crucial for ensuring the safe and effective use of the medication.

Storage and Handling

The product is supplied in a sterile, non-pyrogenic, single-dose glass vial. It should be stored at a temperature range of 20°C to 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F). Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

When plasma ammonia levels have normalized, patients may typically increase dietary protein intake with the aim of achieving unrestricted protein consumption. Clinicians should be aware that the most common adverse reactions associated with treatment include vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment. It is also noted that BUPHENYL is generally discontinued during the administration of Sodium Phenylacetate and Sodium Benzoate Injection.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Sodium Phenylacetate and Sodium Benzoate as submitted by MAIA PHARMACEUTICALS. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)