Sodium phenylacetate/Sodium benzoate

Description

Sodium phenylacetate and sodium benzoate injection is a sterile, concentrated, aqueous solution containing sodium phenylacetate and 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 appears as a white to off-white powder and is soluble in water, with a molecular weight of 158.14 and a molecular formula of C₈H₇NaO₂. Sodium benzoate, also a white to off-white powder, is readily soluble in water, possessing 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.

There are no teratogenic or nonteratogenic effects associated with this drug.

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. Therefore, the product can be used without specific restrictions related to contraindications.

Warnings and Precautions

Plasma potassium levels should be carefully monitored, and appropriate treatment should be administered when necessary. Caution is advised when administering sodium phenylacetate and sodium benzoate injection to patients with congestive heart failure, severe renal insufficiency, or conditions characterized by sodium retention with edema.

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

Due to the prolonged plasma levels of phenylacetate observed in pharmacokinetic studies, repeat loading doses should not be given. 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.

Sodium phenylacetate and sodium benzoate injection may induce side effects commonly associated with 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.

Side Effects

Most frequently reported adverse reactions occurring 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 closely monitored, and appropriate treatment should be administered as necessary. Patients with congestive heart failure, severe renal insufficiency, or conditions associated with sodium retention and edema 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 signs of tissue infiltration during administration. Additionally, neurotoxicity related to phenylacetate has been reported in cancer patients, necessitating careful monitoring for symptoms of acute neurotoxicity, especially given the prolonged plasma levels achieved by phenylacetate in pharmacokinetic studies. Repeat loading doses should be avoided.

Patients may also experience hyperventilation and metabolic acidosis, which are side effects typically associated with salicylate overdose. Regular monitoring of blood chemistry profiles, along with frequent measurements of blood pH and pCO2, is recommended.

Overdosage of sodium phenylacetate and sodium benzoate injection has been reported in urea cycle-deficient patients, leading to severe outcomes. Causes of death in these patients included cardiorespiratory failure or arrest (6 patients), hyperammonemia (3 patients), increased intracranial pressure (2 patients), and other serious conditions such as pneumonitis with septic shock and coagulopathy, respiratory failure, and intractable hypotension. Signs of intoxication may manifest as 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.

The use of 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. Monitoring of ammonia levels is recommended for patients receiving corticosteroids, especially those with pre-existing 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 in pediatric patients for the treatment of acute hyperammonemia, including those in the early neonatal period. The safety and efficacy of this treatment in children have been established, although specific dosage adjustments may be necessary based on the patient's age and clinical condition. Healthcare professionals should exercise caution when administering this therapy to ensure appropriate dosing and monitoring in this vulnerable population.

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 there are no pharmacokinetic studies available for sodium phenylacetate and sodium benzoate injection specifically in geriatric patients.

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

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 in clinically recognized pregnancies is between 2 to 4%, while the risk of miscarriage is estimated to be between 15 to 20%. 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

Sodium phenylacetate and sodium benzoate injection should be used with caution in patients with severe renal insufficiency. Healthcare professionals should consider the potential for sodium retention and edema when administering this injection to patients with reduced kidney function. Monitoring for these conditions is advised to ensure patient safety and effective management.

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 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 cases, it was noted that 16 out of 64 fatalities involved patients who had experienced a confirmed overdose of sodium phenylacetate and sodium benzoate injection. The causes of death in these instances were varied, including 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

Prenatal exposure of rat pups to phenylacetate resulted in lesions in layer 5 cortical pyramidal cells, characterized by longer and thinner dendritic spines that were reduced in number. In animal studies, subcutaneous administration of phenylacetate at doses ranging from 190 to 474 mg/kg led to decreased neuronal proliferation, increased neuronal loss, and reduced central nervous system myelin. Additionally, the maturation of cerebral synapses was delayed, and there was a reduction in the number of functioning nerve terminals in the cerebrum, ultimately impairing brain growth. Pregnant rats received phenylacetate subcutaneously at a dosage of 3.5 μmol/g/day from gestation day 7 until normal delivery.

Sodium benzoate has been shown not to exhibit mutagenic or carcinogenic properties and does not impair fertility. However, long-term studies in animals have not been conducted to assess the carcinogenic potential of sodium phenylacetate and sodium benzoate injection. Furthermore, studies to evaluate the potential impairment of fertility or mutagenic effects of sodium phenylacetate and sodium benzoate injection have not been performed.

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 dosing of BUPHENYL in the context of specific conditions, including HHH syndrome (6 episodes), carnitine translocase deficiency (4 episodes), liver disease (3 episodes), HMG CoA lyase deficiency (1 episode), non-ketotic hyperglycinemia (1 episode), suspected fatty acid oxidation deficiency (1 episode), and valproic-acid-induced hyperammonemia (1 episode).

It is important to inform patients that once plasma ammonia levels have normalized, dietary protein intake can typically be increased, with the ultimate goal of achieving unrestricted protein intake.

Patients should be made aware of the most common adverse reactions associated with BUPHENYL, which include vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment.

Additionally, healthcare providers should explain that BUPHENYL is generally discontinued during the administration of sodium phenylacetate and sodium benzoate injection to ensure optimal treatment outcomes.

Storage and Handling

The product is supplied in a sterile, non-pyrogenic, single-use 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 product integrity.

Additional Clinical Information

Plasma potassium levels should be carefully monitored in patients receiving treatment, along with blood chemistry profiles, blood pH, and pCO2. Administration of the product must be conducted through a central venous catheter, and it is critical not to administer the undiluted product.

In postmarketing experience, neurotoxicity has been reported in cancer patients treated with intravenous phenylacetate at doses of 250–300 mg/kg/day for 14 days, with treatments repeated at 4-week intervals. Symptoms observed included somnolence, fatigue, lightheadedness, headaches, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of pre-existing neuropathy. The acute onset of these symptoms upon treatment initiation and their reversibility upon discontinuation of phenylacetate indicate a potential drug effect.

FDA Insert (PDF)

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

View full prescribing information (PDF)