Sodium Phenylacetate / Sodium Benzoate

Pronunciation: SO-dee-uhm FEN-ill-ASS-eh-tate/SO-dee-uhm BEN-zoe-ate
Class: Metabolic agent

Trade Names

Ammonul
- Injection sodium benzoate 100 mg/sodium phenylacetate 100 mg

Pharmacology

Sodium phenylacetate and sodium benzoate are metabolically active compounds that can serve as alternatives to urea for the excretion of waste nitrogen. Phenylacetate conjugates with glutamine in the liver to form phenylacetylglutamine (renally excreted), and benzoate conjugates with glycine to form hippuric acid (renally excreted). This results in reduction of waste nitrogen levels in patients with deficiencies of urea cycle enzymes, thus attenuating ammonia and glutamine-induced neurotoxicity.

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Pharmacokinetics

Absorption

Sodium phenylacetate and sodium benzoate follow nonlinear pharmacokinetics after IV infusion. Following a 90 min IV infusion of sodium phenylacetate, the AUC for doses of 1 and 5.5 g/m ² were 175.6 and 3,829.2 mcg•h/mL, respectively. Following a 90 min IV infusion of sodium benzoate, the AUC for doses of 1 and 5.5 g/m ² were 20.3 and 1,599.1 mcg•h/mL, respectively.

Elimination

The total Cl for sodium phenylacetate decreased from 1.82 to 0.89 mcg•h/mL, with increasing doses of 3.75 and 4 g/m ² , respectively. The total Cl for sodium benzoate decreased from 5.19 to 3.62 L/h/m ² , with increasing doses of 3.75 and 5.5 g/m ² , respectively.

Special Populations

For effective sodium phenylacetate and sodium benzoate therapy, renal Cl of the drug metabolites, and subsequently ammonia, is required. Closely monitor patients with impaired renal function.

Limited data are available; however, because the liver is one of the organs in which the metabolic conjugation of sodium phenylacetate and sodium benzoate is known to occur, administer with care to patients with hepatic function impairment.

Bioavailability of phenylacetate and benzoate was slightly higher in women than men; however, conclusion cannot be drawn because of the small number of subjects in the study.

Indications and Usage

Adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzyme of the urea cycle.

Contraindications

Standard considerations.

Dosage and Administration

IV Loading and maintenance doses: 2.5 mL/kg of sodium phenylacetate and sodium benzoate, and 2 mL/kg of arginine 10% injection.

IV Loading and maintenance doses: 55 mL/m ² of sodium phenylacetate and sodium benzoate, and 2 mL/kg of arginine 10% injection.

IV Loading and maintenance doses: 2.5 mL/kg of sodium phenylacetate and sodium benzoate, and 6 mL/kg of arginine 10% injection.

IV Loading and maintenance doses: 55 mL/m ² of sodium phenylacetate and sodium benzoate, and 6 mL/kg of arginine 10% injection.

IV Patients suspected of having ASS should be infused with sodium phenylacetate and sodium benzoate injection and 600 mg/kg of arginine as a loading dose over a 6-h infusion period. If patient is confirmed with ASS, then the loading dose infusion is administered over 90 min.

General Advice

• For IV infusion only. Not for intradermal, subcutaneous, IM, IV bolus, or intra-arterial administration.
• Administer only through a central line; administration via a peripheral line may cause burns.
• Discontinue any analogous oral drugs (eg, sodium phenylbutyrate) prior to infusion of sodium benzoate and sodium phenylacetate.
• Administer loading dose by infusion over 90 to 120 min, followed by maintenance dose infusion over 24 h. Maintenance infusions may be continued until plasma ammonia levels have been normalized or the patient can tolerate oral nutrition and medications.
• Do not use undiluted. Must be diluted with 10% dextrose in water before infusion. Withdraw required amount of injection concentrate and dilute in 10% dextrose in water to volume of at least 25 mL/kg.
• Diluted solutions may be prepared in glass or PVC containers.
• Arginine 10% injection may be added to diluted sodium phenylacetate and sodium benzoate solution. Do not administer with any other drug products or infusion solutions.
• Do not administer if solution is discolored, cloudy, or contains particulate matter.
• Discard any unused solution in vial. Do not save for future use.

Storage/Stability

Store vials of injection concentrate at controlled room temperature (59° to 86°F). Diluted solutions are stable for up to 24 h at room temperature and room lighting conditions.

Drug Interactions

May compete with phenylacetylglutamine and hippurate for active renal tubular secretion.

May compete with phenylacetylglutamine and hippurate for renal excretion.

May exacerbate urea cycle disorders and antagonize the efficacy of sodium phenylacetate/sodium benzoate.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Cardiac disorder (9%); vascular disorder (6%); hypotension (4%).

CNS

CNS disorders (22%); convulsions, mental impairment (6%); brain edema, psychiatric disorder, pyrexia (5%); agitation, coma (3%).

Dermatologic

Skin and subcutaneous disorders (6%).

GI

GI disorders (13%); vomiting (12%); diarrhea, nausea (3%).

Genitourinary

Renal and urinary disorders (4%); UTI (3%).

Hematologic-Lymphatic

Anemia (4%); disseminated intravascular coagulation (3%).

Metabolic-Nutritional

Metabolism and nutrition disorders (21%); hyperglycemia, hypokalemia (7%); hyperammonemia (5%); metabolic acidosis (4%); acidosis, hypocalcemia (3%).

Respiratory

Mediastinal, respiratory, and thoracic disorders (15%); respiratory distress (3%).

Miscellaneous

Administration-site conditions, general disorders (14%); infections (12%); injury, poisoning, procedural complications (4%); injection-site reactions (3%).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Has been used in children, including patients in the early neonatal period.

Renal Function

Use with caution.

Hepatic Function

Use with caution.

Acute symptomatic hyperammonemia

Uncontrolled hyperammonemia can rapidly result in brain damage or death and should be treated as a life-threatening emergency, using all therapies necessary to reduce ammonia levels.

Arginine coadministration

High-dose arginine administration may result in hyperchloremic acidosis. Monitor plasma chloride and bicarbonate levels; administer bicarbonate, as appropriate, to maintain acid-base balance.

Caloric supplementation and protein restriction

Treatment of hyperammonemia also requires caloric supplementation and restriction of dietary protein.

Conversion to oral treatment

Once ammonia levels have been reduced to the normal range, start or reinitiate oral therapy such as sodium phenylbutyrate, dietary management, and protein restriction.

Extravasation

Extravasation may lead to skin necrosis. If extravasation occurs or is suspected, discontinue infusion and resume at a different infusion site. Treat extravasation by aspiration of residual drug from catheter, limb elevation, and intermittent cooling using cold packs.

Hypokalemia

May develop because urine potassium loss is enhanced during treatment; be prepared to treat appropriately.

Loading doses

Do not administer repeat loading doses because of prolonged phenylacetate plasma levels.

Nausea/Vomiting

May cause nausea and vomiting. Consider using antiemetic during infusion.

Neurotoxicity of phenylacetate

Neurotoxicity (disorientation, exacerbation of preexisting neuropathy, fatigue, headaches, impaired memory, light-headedness, somnolence) was reported in cancer patients receiving IV phenylacetate (250 to 300 mg/kg/day for 14 days every 4 wk).

Salicylate effects

Because of structural similarities of phenylacetate and benzoate to salicylate, adverse reactions typically associated with salicylate overdose (eg, hyperventilation, metabolic acidosis) may develop. Monitor blood pH and pCO ₂ frequently during infusion.

Sodium content

Contains sodium 30.5 mg/mL of undiluted product. Use with caution, if at all, in patients with heart failure, severe renal function impairment, or clinical states with sodium retention and edema.

Overdosage

Symptoms

Obtundation, hyperventilation, severe compensated metabolic acidosis, large anion gap, hypernatremia, hyperosmolarity, progressive encephalopathy, CV collapse, death caused by cardiorespiratory failure, hyperammonemia, increased intracranial pressure, pneumonitis with septic shock and coagulopathy, respiratory failure, intractable hypotension, and probable sepsis.

Patient Information

• Advise patient or caregiver that medication will be prepared and administered by health care providers in a closely monitored medical setting.

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