pharmacopeia

Phenylacetate

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Mechanism of action

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Urea cycle disorders can result from decreased activity of any of the following enzymes: N -acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), argininosuccinate lyase (ASL), or arginase (ARG). Sodium phenylacetate and sodium benzoate are metabolically active compounds that can serve as alternatives to urea for the excretion of waste nitrogen.

Indications

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  • Sodium Phenylacetate and Sodium Benzoate Injection is a nitrogen binding agent indicated as adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in paediatric and adult patients with deficiencies in enzymes of the urea cycle. ( 1 ) Sodium Phenylacetate and Sodium Benzoate Injection is indicated as adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle.

Contraindications

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  • None ( 4 ) None.contraindicated

Dosage & administration

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Sodium Phenylacetate and Sodium Benzoate Injection must be diluted with sterile 10% Dextrose Injection (D10W) before administration. Administration must be through a central venous catheter. Administration through a peripheral line may cause burns. ( 2 ) Sodium Phenylacetate and Sodium Benzoate Injection is administered intravenously as a loading dose infusion administered over 90 to 120 minutes, followed by an equivalent maintenance dose infusion administered over 24 hours. ( 2 ) See Full Prescribing Information for complete dosing recommendations. 2.1 Recommended Dosage Sodium Phenylacetate and Sodium Benzoate Injection must be diluted with sterile 10% Dextrose Injection (D10W) before administration. The dilution and dosage of Sodium Phenylacetate and Sodium Benzoate Injection are determined by weight for neonates, infants and young children, and by body surface area for larger patients, including older children, adolescents, and adults (Table 1). Table 1: Dosage and Administration Abbreviations: CPS - carbamyl phosphate synthetase; OTC - ornithine transcarbamylase; ASS - argininosuccinate synthetase; ASL - argininosuccinate lyase Patient Population Components of Infusion Solution Sodium Phenylacetate and Sodium Benzoate Injection must be diluted with sterile 10% Dextrose Injection at ≥ 25 mL/Kg before administration.

Warnings & precautions

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Decreased Potassium Levels: Plasma potassium levels should be carefully monitored and appropriate treatment given when necessary. ( 5.1 ) Conditions Associated with Fluid Overload: Sodium Phenylacetate and Sodium Benzoate Injection contains 30.5 mg of sodium per mL of undiluted product. Caution should be used if Sodium Phenylacetate and Sodium Benzoate Injection is administered to patients with congestive heart failure, severe renal insufficiency, or with conditions in which there is sodium retention with edema. ( 5.2 ) Extravasation: Extravasation of Sodium Phenylacetate and Sodium Benzoate Injection into the perivenous tissues during high flow bolus infusion may lead to skin necrosis, especially in infants. The infusion site must be monitored closely for possible tissue infiltration during drug administration. ( 5.3 ) Neurotoxicity of Phenylacetate: Because of prolonged plasma levels achieved by phenylacetate in pharmacokinetic studies, repeat loading doses should not be administered. Additionally, neurotoxicity related to phenylacetate has been reported in cancer patients. Monitor patients for symptoms of acute neurotoxicity.( 5.4 ) 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. Monitor patient blood chemistry profiles and perform frequent blood pH and pCO 2 measurements.

Adverse reactions

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The most frequently reported adverse reactions (incidence ≥ 6%) are vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc. Pennington, NJ 08534 at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data were obtained from 316 patients who received Sodium Phenylacetate and Sodium Benzoate Injection as emergency (rescue) or prospective treatment for hyperammonemia as part of an uncontrolled, open-label study. The study population included patients between the ages of 0 to 53 years with a mean (SD) of 6.2 (8.54) years; 51% were male and 49% were female who had the following diagnoses: OTC (46%), ASS (22%), CPS (12%), ASL (2%), ARG (<1%), THN (<1%), and other (18%). Adverse reactions were reported with similar frequency in patients with OTC, ASS, CPS, and diagnoses categorized as "other." Nervous system disorders were more frequent in patients with OTC and CPS, compared with patients with ASS and patients with "other" diagnoses. Convulsions and mental impairment were reported in patients with OTC and CPS.

Use in specific populations

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8.1 Pregnancy Risk Summary Available data on the combination use of Sodium Phenylacetate and Sodium Benzoate in pregnant women 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. All pregnancies have a background risk of birth defect, 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 2 to 4% and 15 to 20%, respectively. 8.2 Lactation Risk Summary There are no data on the presence of sodium phenylacetate, sodium benzoate in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sodium Phenylacetate and Sodium Benzoate Injection and any potential adverse effects on the breastfed infant from Sodium Phenylacetate and Sodium Benzoate Injection or from the underlying maternal condition.

Pharmacokinetics

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Metabolism
The pharmacokinetics of intravenously administered Sodium Phenylacetate and Sodium Benzoate Injection was characterized in healthy adult volunteers. Both benzoate and phenylacetate exhibited nonlinear kinetics.

Overdosage

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Overdosage has been reported during Sodium Phenylacetate and Sodium Benzoate Injection treatment in urea cycle-deficient patients. All patients in the uncontrolled open-label study were to be treated with the same dose of Sodium Phenylacetate and Sodium Benzoate Injection. However, some patients received more than the dose level specified in the protocol. In 16 of the 64 deaths, the patient received a known overdose of Sodium Phenylacetate and Sodium Benzoate Injection. 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), and unknown (1 patient). Additionally, other signs of intoxication may include obtundation (in the absence of hyperammonemia), hyperventilation, a severe compensated metabolic acidosis, perhaps with a respiratory component, large anion gap, hypernatremia and hyperosmolarity, progressive encephalopathy, cardiovascular collapse, and death.

Approval history

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  • Feb 24, 2016ANDAANDA207096Ailex Pharms Llc
  • Aug 4, 2016ANDAANDA205880Navinta Llc
  • May 8, 2017ANDAANDA208521Maia Pharms Inc
  • Jun 10, 2021NDANDA215025Maia Pharms Inc
  • Jul 14, 2023ANDAANDA217526Navinta Llc

FAERS reports

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Reference statistics only. FAERS reports are voluntarily submitted and are not incidence rates, safety signals, or causal evidence. Counts reflect reporting volume — how often a reaction was reported, not how often it occurs. For decision-grade use, consult openFDA and the FAERS Public Dashboard directly.
9 total reports matchedLatest report Share = reports listing the reaction ÷ total matched reports. Rows can sum to >100% because a single report often lists multiple reactions.
  1. 1Drug Ineffective556%
  2. 2Hyperglycaemia222%
  3. 3Ammonia Decreased111%
  4. 4Anion Gap Increased111%
  5. 5Blood Lactic Acid Increased111%
  6. 6Brain Oedema111%
  7. 7Cerebral Infarction111%
  8. 8Drug Ineffective For Unapproved Indication111%
  9. 9Maternal Exposure During Pregnancy111%
  10. 10Mycoplasma Test Positive111%
  11. 11Off Label Use111%
  12. 12Therapy Non-responder111%

Literature

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Recent PubMed references pinned to Phenylacetate as a MeSH major topic. Citations link to pubmed.ncbi.nlm.nih.gov.

Clinical trials

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The 10 most recently updated of 793 ClinicalTrials.gov registrations naming Phenylacetate as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

Frequently asked questions

How does Phenylacetate work?
Urea cycle disorders can result from decreased activity of any of the following enzymes: N -acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), argininosuccinate lyase (ASL), or arginase (ARG). Sodium phenylacetate and sodium benzoate are metabolically active compounds that can serve as alternatives to urea for the excretion of waste nitrogen.
What is Phenylacetate used for?
According to FDA labeling, Phenylacetate carries indications including: Sodium Phenylacetate and Sodium Benzoate Injection is a nitrogen binding agent indicated as adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in paediatric and adult patients with deficiencies in enzymes of the urea cycle. ( 1 ) Sodium Phenylacetate and Sodium Benzoate Injection is indicated as adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.
What are the brand names for Phenylacetate?
Phenylacetate is marketed under brand names including Ammonul.
What are the contraindications for Phenylacetate?
Phenylacetate labeling lists contraindications including: None ( 4 ) None.. Always consult the full prescribing information and a clinician.
Note. Data for phenylacetate is illustrative MVP content compiled from public sources. pharmacopeia is for educational and informational use only and is not a substitute for professional medical advice.

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