Sodium phenylacetate/Sodium benzoate

Description

Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%, is a sterile, concentrated, aqueous solution containing sodium phenylacetate and sodium benzoate as active ingredients. The solution has a pH range of 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, with a molecular weight of 158.13 and a molecular formula of C8H7NaO2. Sodium benzoate appears as a white, odorless crystalline powder that is also readily soluble in water, possessing a molecular weight of 144.11 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. pH adjustment may be achieved using sodium hydroxide and/or hydrochloric acid. This injection is intended for intravenous administration via a central line only after appropriate dilution.

Uses and Indications

Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% 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, 10%/10% must be diluted with sterile 10% Dextrose Injection (D10W) prior to administration. It is essential that this medication is administered exclusively 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.

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

Management of acute hyperammonemia requires vigilant monitoring of plasma ammonia levels throughout treatment. Prolonged exposure to elevated plasma ammonia can lead to severe neurological injury or death. Therefore, it is imperative to initiate all necessary therapies promptly to reduce plasma ammonia levels.

Careful monitoring of plasma potassium levels is essential, and appropriate treatment should be administered as needed to address any deficiencies.

Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% contains 30.5 mg of sodium per mL of undiluted product. Caution is advised when administering this injection to patients with congestive heart failure, severe renal insufficiency, or any conditions associated with sodium retention and edema, due to the risk of fluid overload.

Extravasation of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% into perivenous tissues during high flow bolus infusion may result in skin necrosis, particularly in infants. It is crucial to closely monitor the infusion site for signs of tissue infiltration during drug administration.

Due to the potential for prolonged plasma levels of phenylacetate, repeat loading doses should be avoided. Neurotoxicity associated with phenylacetate has been documented in cancer patients; therefore, healthcare professionals should monitor these patients for symptoms indicative of acute neurotoxicity.

Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% may induce side effects similar to those observed in salicylate overdose, including hyperventilation and metabolic acidosis. Regular monitoring of patient blood chemistry profiles, along with frequent assessments of blood pH and pCO2 levels, is recommended to ensure patient safety.

Side Effects

Most frequently reported adverse reactions associated with Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%, occurring in 6% or more of patients include vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment.

Serious adverse reactions may arise from prolonged exposure to elevated plasma ammonia levels, which can lead to rapid brain injury or death. Therefore, management of acute hyperammonemia is critical. Plasma potassium levels should be carefully monitored, and appropriate treatment should be administered when necessary to address decreased potassium levels.

Caution is advised when administering Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% to patients with congestive heart failure, severe renal insufficiency, or conditions associated with sodium retention and edema, as these conditions may be exacerbated by fluid overload.

Extravasation of the injection into perivenous tissues during high flow bolus infusion may result in skin necrosis, particularly in infants. Additionally, neurotoxicity related to phenylacetate has been reported in cancer patients, necessitating close monitoring for symptoms of acute neurotoxicity.

Patients may also experience hyperventilation and metabolic acidosis, which are side effects typically associated with salicylate overdose.

Overdosage has been reported in urea cycle-deficient patients receiving Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%. Causes of death in these cases included cardiorespiratory failure or arrest, hyperammonemia, increased intracranial pressure, pneumonitis with septic shock and coagulopathy, errors in dialysis procedures, respiratory failure, intractable hypotension with probable sepsis, and unknown causes. Signs of intoxication may manifest as obtundation (in the absence of hyperammonemia), hyperventilation, severe compensated metabolic acidosis, large anion gap, hypernatremia and hyperosmolarity, progressive encephalopathy, cardiovascular collapse, and death.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacodynamic and pharmacokinetic effects:

Pharmacokinetic Interactions:

• Certain antibiotics, including penicillin, may influence the overall disposition of the infused drug. Clinicians should monitor for potential alterations in drug efficacy or safety when these antibiotics are co-administered.

• Probenecid has the potential to affect the renal excretion of phenylacetylglutamine and hippurate. It is advisable to consider dosage adjustments or enhanced monitoring of these metabolites when probenecid is used concurrently.

Pharmacodynamic Interactions:

• Valproic acid, when administered to patients with urea cycle disorders, may exacerbate their condition. It can antagonize the efficacy of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% by inhibiting the synthesis of N-acetylglutamate, which is a critical co-factor for carbamyl phosphate synthetase. Close monitoring of ammonia levels and clinical status is recommended in these patients.

• The use of corticosteroids may lead to the breakdown of body protein, potentially increasing plasma ammonia levels in patients with a compromised ability to form urea. Monitoring of ammonia levels and clinical symptoms is advised in such cases to prevent complications.

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, 10%/10%, 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, 10%/10% did not include any patients aged 65 and over, thus it remains unclear whether elderly patients respond differently compared to younger individuals. Given that urea cycle disorders predominantly affect pediatric and younger adult populations, there is limited clinical experience with this medication in geriatric patients.

No pharmacokinetic studies have been conducted specifically in elderly patients, which further complicates the understanding of its safety and efficacy in this demographic. Therefore, when considering dose selection for elderly patients, it is advisable to proceed with caution. Typically, dosing should begin at the lower end of the recommended range to account for the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the potential for concomitant diseases or other drug therapies that may be present in this population.

Healthcare providers should closely monitor geriatric patients for any adverse effects and adjust the dosage as necessary to ensure safety and therapeutic effectiveness.

Pregnancy

Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% is classified as Pregnancy Category C. Animal reproduction studies have not been conducted with this formulation, and it is not known whether it can cause fetal harm or affect reproductive capacity when administered to pregnant patients. Therefore, Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% should be administered to pregnant women only if clearly needed, weighing the potential benefits against any possible risks to the fetus.

Lactation

It is not known whether sodium phenylacetate, sodium benzoate, or their conjugation products are excreted in human milk.

Due to the potential for many drugs to be excreted in human milk, caution should be exercised when administering Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% to lactating mothers.

Renal Impairment

Caution should be exercised when administering Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%, 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.

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, 10%/10%, 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, 16 out of 64 fatalities were associated with known overdoses of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%. The causes of death in these cases 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 Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% immediately. Appropriate emergency medical monitoring and interventions should be initiated. In severe cases, hemodialysis is the preferred treatment option; however, peritoneal dialysis may be considered if hemodialysis is not available.

Nonclinical Toxicology

Pregnancy Category C indicates that animal reproduction studies have not been conducted with Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%. Therefore, it is unknown whether this injection can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. Consequently, Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% should be administered to pregnant women only if clearly needed.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%. Additionally, studies to assess the possible impairment of fertility or mutagenic potential of this 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. The maturation of cerebral synapses 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 dosage 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, which were also reduced in number.

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 routine pharmacovigilance activities.

Patient Counseling

Healthcare providers should advise patients and caregivers regarding the safe use of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%. It is important to inform patients that once plasma ammonia levels have normalized, they may typically increase dietary protein intake with the aim of achieving unrestricted protein consumption.

Caution is warranted when administering Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% to nursing women, and healthcare providers should discuss the potential risks involved. Patients should be made aware of the most common adverse reactions associated with this treatment, which include vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment.

Additionally, healthcare providers should explain that BUPHENYL is generally discontinued during the period when Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% is being used. It is essential for patients to understand these points to ensure safe and effective treatment.

Storage and Handling

Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%, is supplied in a single-dose glass vial.

This product should be stored at a temperature of 25°C (77°F), with permissible excursions between 15° and 30°C (59° and 86°F). Care should be taken to ensure that the storage conditions remain within these specified limits to maintain the integrity of the product.

Additional Clinical Information

Ongoing monitoring of plasma ammonia levels, neurological status, laboratory tests, and clinical response is essential for patients receiving Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%. This monitoring helps clinicians assess the effectiveness of the treatment.

Administration of the injection must occur through a central line, as peripheral line administration may result in burns. Bolus infusion flow rates are notably high, particularly in infants, and the product should not be administered undiluted. In cases of suspected extravasation, the infusion should be discontinued and, if necessary, resumed at a different site, with close monitoring for infiltration during administration.

Postmarketing experience has indicated that neurotoxicity can occur in cancer patients receiving intravenous phenylacetate at doses of 250–300 mg/kg/day for 14 days, with treatments repeated at 4-week intervals. Symptoms reported include somnolence, fatigue, and lightheadedness, along with less common effects such as 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 suggest a direct drug effect.

FDA Insert (PDF)

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

View full prescribing information (PDF)