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.

This drug is available in various forms, including injection, solution, and concentrate.

Limitations of Use

No teratogenic or nonteratogenic effects are mentioned in the provided information.

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 dosing regimen consists of an initial loading dose infusion administered intravenously over a period of 90 to 120 minutes, followed by an equivalent maintenance dose infusion that is administered continuously over 24 hours. For complete dosing recommendations, healthcare professionals should refer to the Full Prescribing Information.

Contraindications

There are no contraindications for the use of Sodium Phenylacetate and Sodium Benzoate in any form, including injection, solution, or concentrate.

Warnings and Precautions

Plasma potassium levels should be carefully monitored, and appropriate treatment should be administered when necessary. Sodium Phenylacetate and Sodium Benzoate Injection 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 conditions associated with sodium retention and edema.

Extravasation of Sodium Phenylacetate and Sodium Benzoate Injection into the perivenous tissues during high flow bolus infusion may lead to skin necrosis, particularly in infants. Therefore, the infusion site must be monitored closely for possible tissue infiltration during drug administration.

Due to the prolonged plasma levels achieved by phenylacetate in pharmacokinetic studies, repeat loading doses should not be administered. Neurotoxicity related to phenylacetate has been reported in cancer patients; thus, monitoring for symptoms of acute neurotoxicity is essential.

Sodium Phenylacetate and Sodium Benzoate Injection may also cause 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.

Monitoring Requirements

• Plasma potassium levels should be monitored.

• Monitor plasma ammonia levels during treatment for acute hyperammonemia, as prolonged exposure to elevated plasma ammonia can lead to severe brain injury or death.

• Regularly assess patient blood chemistry profiles and perform frequent blood pH and pCO2 measurements.

General Precautions

• Patients should be monitored for symptoms of acute neurotoxicity.

• Close observation of the infusion site is necessary to prevent complications from extravasation.

Side Effects

Most frequently reported adverse reactions (incidence ≥ 6%) associated with Sodium Phenylacetate and Sodium Benzoate include:

• Vomiting

• Hyperglycemia

• Hypokalemia

• Convulsions

• Mental impairment

Serious Adverse Reactions

• Neurotoxicity of Phenylacetate: Neurotoxicity related to phenylacetate has been reported in cancer patients. Patients should be monitored for symptoms of acute neurotoxicity.

• Overdosage: Overdosage has been reported during treatment in urea cycle-deficient patients. Causes of death in these patients included:

  • Cardiorespiratory failure/arrest (6 patients)

  • Hyperammonemia (3 patients)

  • Increased intracranial pressure (2 patients)

  • Pneumonitis with septic shock and coagulopathy (1 patient)

  • Error in dialysis procedure (1 patient)

  • Respiratory failure (1 patient)

  • Intractable hypotension and probable sepsis (1 patient)

  • Unknown causes (1 patient)

Signs of intoxication may include:

• Obtundation (in the absence of hyperammonemia)

• Hyperventilation

• Severe compensated metabolic acidosis, perhaps with a respiratory component

• Large anion gap

• Hypernatremia and hyperosmolarity

• Progressive encephalopathy

• Cardiovascular collapse

• Death

Additional Adverse Reactions or Important Notes

• Decreased Potassium Levels: Plasma potassium levels should be carefully monitored, and appropriate treatment should be given when necessary.

• Conditions Associated with Fluid Overload: Caution should be exercised 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.

• Extravasation: Extravasation of Sodium Phenylacetate and Sodium Benzoate Injection into the perivenous tissues during high flow bolus infusion may lead to skin necrosis, particularly in infants. The infusion site must be monitored closely for possible tissue infiltration during drug administration.

• Hyperventilation and Metabolic Acidosis: Sodium Phenylacetate and Sodium Benzoate Injection may cause side effects typically associated with salicylate overdose, such as hyperventilation and metabolic acidosis. Monitoring of patient blood chemistry profiles and frequent blood pH and pCO2 measurements is recommended.

Less Common Adverse Reactions (Incidence < 3%)

Severe adverse reactions characterized in clinical trials include:

• Blood and Lymphatic System Disorders: Coagulopathy, pancytopenia, thrombocytopenia

• Cardiac Disorders: Atrial rupture, bradycardia, cardiac or cardiopulmonary arrest/failure, cardiogenic shock, cardiomyopathy, pericardial effusion

• Eye Disorders: Blindness

• Gastrointestinal Disorders: Abdominal distension, gastrointestinal hemorrhage

• General Disorders and Administration-Site Conditions: Asthenia, brain death, chest pain, multiorgan failure, edema

• Hepatobiliary Disorders: Cholestasis, hepatic artery stenosis, hepatic failure/hepatotoxicity, jaundice

• Infections and Infestations: Sepsis/septic shock

• Injury, Poisoning and Procedural Complications: Brain herniation, subdural hematoma, overdose

• Investigations: Blood carbon dioxide changes, blood glucose changes, blood pH increased, cardiac output decreased, pCO2 changes, respiratory rate increased

• Metabolism and Nutrition Disorders: Alkalosis, dehydration, fluid overload/retention, hypoglycemia, hyperkalemia, hypernatremia, tetany

• Neoplasms Benign, Malignant and Unspecified: Hemangioma acquired

• Nervous System Disorders: Areflexia, ataxia, brain infarction, brain hemorrhage, cerebral atrophy, clonus, depressed level of consciousness, encephalopathy, nerve paralysis, increased intracranial pressure, subdural hematoma, tremor

• Psychiatric Disorders: Acute psychosis, aggression, confusional state, hallucinations

• Renal and Urinary Disorders: Anuria, renal failure, urinary retention

• Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, dyspnea, hypercapnia, hyperventilation, Kussmaul respiration, aspiration pneumonia, pneumothorax, pulmonary hemorrhage, pulmonary edema, respiratory acidosis or alkalosis, respiratory arrest/failure

• Skin and Subcutaneous Tissue Disorders: Alopecia, blister, generalized pruritus, rash, urticaria

• Vascular Disorders: Flushing, hemorrhage, hypertension, phlebothrombosis/thrombosis

Drug Interactions

Some antibiotics, particularly penicillin, may influence the overall disposition of Sodium Phenylacetate and Sodium Benzoate when infused. Additionally, probenecid has the potential to affect the renal excretion of phenylacetylglutamine and hippurate, which may alter the drug's effectiveness.

Valproic acid, when administered to patients with urea cycle disorders, can exacerbate their condition and antagonize the efficacy of Sodium Phenylacetate and Sodium Benzoate. This occurs through the inhibition of N-acetylglutamate synthesis, a crucial co-factor for carbamyl phosphate synthetase, thereby impairing the urea cycle.

The use of corticosteroids may lead to the breakdown of body protein, which can potentially increase plasma ammonia levels in patients who have a compromised ability to form urea. This effect may further complicate the management of patients receiving Sodium Phenylacetate and Sodium Benzoate.

Overall, careful monitoring is advised when these drugs are used in conjunction with the aforementioned agents to mitigate potential adverse effects and ensure therapeutic efficacy.

Pediatric Use

Sodium Phenylacetate and Sodium Benzoate Injection has been utilized as a treatment for acute hyperammonemia in pediatric patients, including those in the early neonatal period. The formulation is available in various forms, including injection, solution, and concentrate, with a specific concentration of 10%/10% noted in some instances.

The efficacy of Sodium Phenylacetate and Sodium Benzoate in managing acute hyperammonemia has been established in this population, demonstrating its importance in the clinical management of this condition in infants and children.

Geriatric Use

Clinical studies of Sodium Phenylacetate and Sodium Benzoate Injection did not include any patients aged 65 and over, and therefore, it is unknown whether geriatric patients respond differently from younger patients. Urea cycle disorders primarily affect pediatric and younger adult populations, and no pharmacokinetic studies have been conducted 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. Regular monitoring of these patients is advised to ensure safety and efficacy.

Pregnancy

Available data on the 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.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 5%, while the risk of miscarriage is estimated at 15 to 20%.

Sodium Phenylacetate and Sodium Benzoate are classified as Pregnancy Category C. It is not known whether this medication can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. Therefore, Sodium Phenylacetate and Sodium Benzoate should be given to pregnant patients only if clearly needed.

Lactation

There are currently no data available regarding the presence of sodium phenylacetate and sodium benzoate in human or animal milk, nor are there any known effects on breastfed infants or on milk production. Given the lack of information, caution is advised when administering Sodium Phenylacetate and Sodium Benzoate Injection to lactating mothers.

Healthcare providers should weigh the developmental and health benefits of breastfeeding against the mother's clinical need for sodium phenylacetate and sodium benzoate. Additionally, potential adverse effects on the breastfed infant from the injection or from the underlying maternal condition should be considered. Since many drugs can be excreted in human milk, careful monitoring is recommended when these medications are prescribed to nursing women.

Renal Impairment

Caution is advised when administering Sodium Phenylacetate and Sodium Benzoate Injection to patients with severe renal insufficiency. The metabolites of this drug, including phenylacetylglutamine and hippurate, as well as ammonia, are primarily excreted by the kidneys. Therefore, close monitoring of patients with impaired renal function is essential to avoid potential complications.

In addition, special consideration should be given to patients with conditions that may lead to sodium retention and edema, such as congestive heart failure. The risk of adverse effects may be heightened in these populations, necessitating careful assessment and potential adjustments in therapy.

Overall, healthcare providers should exercise caution and ensure appropriate monitoring when treating patients with renal impairment with Sodium Phenylacetate and Sodium Benzoate Injection.

Hepatic Impairment

Limited information is available regarding the metabolism and excretion of Sodium Phenylacetate and Sodium Benzoate in patients with impaired hepatic function. The metabolic conjugation of these compounds occurs primarily in the liver and kidney. Therefore, caution should be exercised when administering Sodium Phenylacetate and Sodium Benzoate Injection to patients with hepatic insufficiency.

Currently, there are no specific dosage adjustments, special monitoring requirements, or additional precautions outlined for patients with hepatic impairment.

Overdosage

Overdosage has been reported during the administration of Sodium Phenylacetate and Sodium Benzoate Injection in patients with urea cycle deficiencies. In an uncontrolled open-label study, all patients were intended to receive the same dosage; however, some patients received doses exceeding the protocol specifications. Notably, 16 out of 64 deaths were associated with known overdoses of Sodium Phenylacetate and Sodium Benzoate Injection.

The causes of death in these overdose cases included cardiorespiratory failure or arrest (6 patients), hyperammonemia (3 patients), increased intracranial pressure (2 patients), pneumonitis with septic shock and coagulopathy (1 patient), error in dialysis procedure (1 patient), respiratory failure (1 patient), intractable hypotension and probable sepsis (1 patient), and unknown causes (1 patient).

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

In the event of an overdose, it is imperative to discontinue the drug immediately and initiate appropriate emergency medical monitoring and interventions. In severe cases, hemodialysis is the preferred procedure; however, peritoneal dialysis may be considered if hemodialysis is not available.

Nonclinical Toxicology

Teratogenic Effects

Sodium Phenylacetate and Sodium Benzoate Injection is classified as Pregnancy Category C. Animal reproduction studies have not been conducted, and it is unknown whether this injection can cause fetal harm or affect reproductive capacity when administered to a pregnant woman. Therefore, it should be given to pregnant women only if clearly needed. Prenatal exposure of rat pups to phenylacetate has been shown to produce lesions in layer 5 cortical pyramidal cells, with dendritic spines that are longer and thinner than normal and reduced in number.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Animal Toxicology

In animal studies, subcutaneous administration of phenylacetate at doses ranging from 190 to 474 mg/kg to rat pups resulted in decreased proliferation and increased loss of neurons, as well as reduced central nervous system (CNS) myelin. Cerebral synapse maturation was retarded, and the number of functioning nerve terminals in the cerebrum was reduced, leading to impaired brain growth. Pregnant rats received phenylacetate at a dosage of 3.5 µmol/g/day subcutaneously from gestation day 7 through normal delivery.

Storage and Handling

Sodium Phenylacetate and Sodium Benzoate is supplied in a sterile, non-pyrogenic, single-dose glass vial. The product is available in the following forms: Injection, Solution, and Concentrate.

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). For certain formulations, storage can also be maintained within a range of 20°C to 25°C (68°F to 77°F), allowing for similar temperature excursions.