Sodium phenylacetate/Sodium benzoate

Description

Sodium phenylacetate and sodium benzoate injection is a sterile, concentrated aqueous solution containing 10% sodium phenylacetate and 10% sodium benzoate, intended for intravenous administration via a central venous catheter only after dilution. The pH of the solution ranges from 6 to 8.

Sodium phenylacetate is presented as a crystalline, white to off-white powder with a strong, offensive odor and is soluble in water. It has a molecular weight of 158.14 and a molecular formula of C8H7NaO2. Sodium benzoate, in contrast, is a white to off-white, odorless crystalline powder that is also readily soluble in water, with a molecular weight of 144.10 and a molecular formula of C7H5NaO2.

Each milliliter of the injection contains 100 mg of sodium phenylacetate and 100 mg of sodium benzoate, along with Water for Injection. Sodium hydroxide and/or hydrochloric acid may be utilized for pH adjustment.

Uses and Indications

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

This drug does not have any reported teratogenic or nonteratogenic effects.

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 administration occurs exclusively through a central venous catheter, as administration via a peripheral line may result in burns.

The initial loading dose should be administered intravenously as an infusion over a period of 90 to 120 minutes. Following the loading dose, an equivalent maintenance dose should be infused over a duration of 24 hours. Careful monitoring of the infusion process is recommended to ensure patient safety and efficacy of the treatment.

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. Therefore, no specific instructions regarding avoidance or non-use are necessary.

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.

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. In patients with conditions that lead to sodium retention and edema, careful consideration of the risks is essential.

Extravasation of sodium phenylacetate and sodium benzoate injection into perivenous tissues during high flow bolus infusion poses a risk of skin necrosis, particularly in infants. Therefore, the infusion site must be monitored closely for signs of tissue infiltration throughout the administration of the drug.

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

Sodium phenylacetate and sodium benzoate injection may induce side effects similar to those seen in salicylate overdose, including hyperventilation and metabolic acidosis.

Healthcare professionals are advised to monitor patient blood chemistry profiles regularly, including plasma potassium levels, and to perform frequent assessments of blood pH and pCO2 to ensure patient safety during treatment.

Side Effects

Common adverse reactions observed in patients receiving sodium phenylacetate and sodium benzoate injection include vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment, with an incidence of 6% or greater.

Serious adverse reactions may arise from the use of this injection. Decreased potassium levels should be carefully monitored, and appropriate treatment should be administered when necessary. Patients with conditions associated with fluid overload, such as congestive heart failure or severe renal insufficiency, should be treated with caution due to the sodium content of the injection, which contains 30.5 mg of sodium per mL of undiluted product.

Extravasation of the injection into perivenous tissues during high flow bolus infusion can lead to skin necrosis, particularly in infants. Therefore, it is essential to monitor the infusion site closely for any signs of tissue infiltration during administration.

Neurotoxicity related to phenylacetate has been reported, particularly in cancer patients, necessitating careful monitoring for symptoms of acute neurotoxicity. Due to the prolonged plasma levels achieved by phenylacetate, repeat loading doses should not be administered.

Additionally, sodium phenylacetate and sodium benzoate injection may induce side effects typically associated with salicylate overdose, such as hyperventilation and metabolic acidosis. Regular monitoring of patient blood chemistry profiles, including frequent blood pH and pCO2 measurements, is recommended.

Overdosage has been reported in urea cycle-deficient patients, leading to severe outcomes including cardiorespiratory failure/arrest, hyperammonemia, increased intracranial pressure, and other critical conditions. 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 death.

Drug Interactions

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

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.

The use of corticosteroids may lead to the breakdown of body protein, which can result in increased plasma ammonia levels, particularly in individuals with a compromised ability to form urea. Monitoring of ammonia levels is recommended in patients receiving corticosteroids who 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, and therefore, it is not known whether elderly patients respond differently from younger patients. Urea cycle disorders primarily affect pediatric and younger adult populations, and no pharmacokinetic studies have been conducted specifically in geriatric patients.

In general, dose selection for elderly patients should be approached with caution. It is advisable to start at the low end of the dosing range, taking into account the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in this demographic. Careful monitoring is recommended to ensure safety and efficacy in this population.

Pregnancy

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

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 4% and 15 to 20%, respectively. Given the lack of specific data, healthcare professionals should consider these background risks when counseling women of childbearing potential regarding the use of sodium phenylacetate and sodium benzoate injection 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 the injection or from the underlying maternal condition should be considered.

Renal Impairment

Caution should be exercised when administering sodium phenylacetate and sodium benzoate injection to patients with severe renal insufficiency. Monitoring of renal function is recommended in this population to ensure safety and efficacy. Dosing adjustments may be necessary based on the degree of renal impairment to mitigate potential risks associated with reduced kidney function.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdosage has been documented in patients receiving sodium phenylacetate and sodium benzoate injection, particularly among those with urea cycle disorders. In an uncontrolled open-label study, all participants were intended to receive a uniform dosage; 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 were associated with known overdoses 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), errors in dialysis procedures (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. Appropriate emergency medical monitoring and interventions should be initiated. In severe cases, hemodialysis is the preferred method of management; however, peritoneal dialysis may be considered if hemodialysis is not available.

Nonclinical Toxicology

Available data regarding the use of sodium phenylacetate and sodium benzoate injection in pregnant women are insufficient to determine 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, and long-term studies in animals have not been performed to evaluate the carcinogenic potential of this injection.

Studies aimed at assessing the possible impairment of fertility or the mutagenic potential of sodium phenylacetate and sodium benzoate injection have not been conducted. However, results indicate that sodium benzoate is not mutagenic or carcinogenic and does not impair fertility.

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 central nervous system (CNS) myelin. Additionally, cerebral synapse maturation was retarded, and the number of functioning nerve terminals in the cerebrum was diminished, leading to impaired brain growth.

Pregnant rats received phenylacetate at a dose of 3.5 μmol/g/day subcutaneously from gestation day 7 until normal delivery. Prenatal exposure of rat pups to phenylacetate resulted in lesions in layer 5 cortical pyramidal cells, 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

Sodium phenylacetate and sodium benzoate injection 10%/10% is supplied in a sterile, non-pyrogenic, single-dose glass vial. It should be stored at a temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F). Care should be taken to ensure that the storage conditions remain within these specified temperature ranges to maintain the integrity of the product.

Additional Clinical Information

Plasma potassium levels should be carefully monitored in patients, along with blood chemistry profiles, blood pH, and pCO2. Administration of the product must be conducted through a central venous catheter, and it is important to avoid administering the undiluted product.

In postmarketing experience, neurotoxicity has been reported in cancer patients receiving intravenous phenylacetate. Symptoms associated with this neurotoxicity include somnolence, fatigue, lightheadedness, headaches, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of pre-existing neuropathy.

FDA Insert (PDF)

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

View full prescribing information (PDF)