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Sodium Phenylacetate and Sodium Benzoate

Pronunciation

(SOW dee um fen il AS e tate & SOW dee um BENZ oh ate)

Index Terms

  • NAPA and NABZ
  • Sodium Benzoate and Sodium Phenylacetate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution [concentrate]:

Ammonul: Sodium phenylacetate 100 mg and sodium benzoate 100 mg per 1 mL (50 mL)

Generic: Sodium phenylacetate 100 mg and sodium benzoate 100 mg per 1 mL (50 mL)

Brand Names: U.S.

  • Ammonul

Pharmacologic Category

  • Antidote
  • Urea Cycle Disorder (UCD) Treatment Agent

Pharmacology

Sodium phenylacetate and sodium benzoate provide alternate pathways for the removal of ammonia through the formation of their metabolites. One mole of sodium phenylacetate removes two moles of nitrogen; one mole of sodium benzoate removes one mole of nitrogen.

Metabolism

Hepatic and renal; sodium phenylacetate conjugates with glutamine, forming the active metabolite, phenylacetylglutamine (PAG); sodium benzoate combines with glycine to form the active metabolite hippuric acid (HIP)

Excretion

Primarily urine

Special Populations: Gender

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.

Use: Labeled Indications

Hyperammonemia: Adjunct to treatment of acute hyperammonemia and associated encephalopathy in patients with urea cycle enzyme deficiencies

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Dosing: Adult

Note: Administer as a loading dose over 90 to 120 minutes, followed by an equivalent maintenance infusion given over 24 hours. Initiate therapy as soon as the diagnosis of hyperammonemia is made; hyperammonemic coma in neonates should be aggressively treated while the diagnosis is pursued. Dosage is based on weight for neonates, infants, and young children and body surface area for older children, adolescents, and adults. Therapy should continue until ammonia levels are in normal range or patient can tolerate oral nutrition and medications. Repeat loading doses are not recommended due to neurotoxicity associated with prolonged plasma levels of phenylacetate. Antiemetics may be administered during infusion to aid control of infusion-associated nausea and vomiting.

Hyperammonemia, acute (urea cycle disorders): IV: 55 mL/m2 (provides sodium phenylacetate 5.5 g/m2 and sodium benzoate 5.5 g/m2) coadministered with arginine; consider conjunctive use of hemodialysis in patients with severe hyperammonemia or refractory to sodium phenylacetate/sodium benzoate.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Administer as a loading dose over 90 to 120 minutes, followed by an equivalent maintenance infusion given over 24 hours. Initiate therapy as soon as the diagnosis of hyperammonemia is made; hyperammonemic coma in neonates should be aggressively treated while the diagnosis is pursued. Dosage is based on weight for neonates, infants, and young children and body surface area for older children, adolescents, and adults. Therapy should continue until ammonia levels are in normal range or patient can tolerate oral nutrition and medications. Repeat loading doses are not recommended due to neurotoxicity associated with prolonged plasma levels of phenylacetate. Antiemetics may be administered during infusion to aid control of infusion-associated nausea and vomiting.

Hyperammonemia, acute (urea cycle disorders):

Neonates, Infants, and Children ≤20 kg: IV: 2.5 mL/kg (provides sodium phenylacetate 250 mg/kg and sodium benzoate 250 mg/kg) coadministered with arginine; consider conjunctive use of hemodialysis in patients with severe hyperammonemia or refractory to sodium phenylacetate/sodium benzoate.

Children >20 kg and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; however, the drug metabolites and ammonia are excreted by the kidneys. Use with caution; monitor closely.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution.

Reconstitution

Must dilute in D10W at ≥25 mL/kg prior to administration.

Administration

Must be diluted prior to administration. Infuse via central line ONLY (administration via peripheral line may cause burning). If extravasation is suspected discontinue infusion and resume at a different infusion site (if necessary). Infuse loading dose over 90 to 120 minutes; maintenance dose is administered over 24 hours. May be an irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation (may cause necrosis).

Dietary Considerations

Contains 30.5 mg of sodium per mL of undiluted product. Caloric supplementation and dietary protein restriction should be part of treatment. Caloric intake of >80 cal/kg/day should be attempted.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Following dilution, solution for infusion may be stored at room temperature for up to 24 hours.

Drug Interactions

Probenecid: May increase the serum concentration of Sodium Phenylacetate. Specifically, probenecid may inhibit the renal transport of the phenylacetylglutamine metabolite of sodium phenylacetate. Monitor therapy

Probenecid: May increase the serum concentration of Sodium Benzoate. Specifically, probenecid may inhibit the renal transport of the hippuric acid metabolite of sodium benzoate. Monitor therapy

Adverse Reactions

Nonspecific adverse reactions include: Nervous system disorders (22%); metabolism and nutrition disorders (21%); respiratory, thoracic, and mediastinal disorders (15%); general disorders and injection site reactions (14%); gastrointestinal disorders (13%); blood and lymphatic system disorders (11%); cardiac disorders (9%); skin and subcutaneous tissue disorders (6%); vascular disorders (6%); psychiatric disorders (5%); injury, poisoning, and procedural complications (4%); renal and urinary disorders (4%)

More blood and lymphatic system, and vascular disorders were reported for patients ≤30 days of age; more gastrointestinal disorders were reported for patients >30 days.

>10%: Miscellaneous: Infections (12%)

3% to 10%:

Cardiovascular: Hypotension (4%)

Central nervous system: Mental impairment (6%), seizure (6%), brain edema (5%), fever (5%), agitation (3%), coma (3%)

Endocrine & metabolic: Hyperglycemia (7%), hypokalemia (7%), hyperammonemia (5%), metabolic acidosis (4%), acidosis (3%), hypocalcemia (3%)

Gastrointestinal: Vomiting (9%), diarrhea (3%), nausea (3%)

Genitourinary: Urinary tract infection (3%)

Hematologic: Anemia (4%), disseminated intravascular coagulation (DIC) (3%)

Local: Injection site reaction (3%)

Respiratory: Respiratory distress (3%)

<3% (Limited to important or life-threatening): Abdominal distention, acute psychosis, acute respiratory distress syndrome, aggression, alkalosis, alopecia, anuria, areflexia, ataxia, atrial rupture, blindness, blood carbon dioxide changes, blood glucose changes, blood pH increased, bradycardia, brain death, brain hemorrhage, brain herniation, brain infarction, cardiac arrest/failure, cardiac output decreased, cardiogenic shock, cardiomyopathy, cardiopulmonary arrest/failure, cerebral atrophy, chest pain, cholestasis, clonus, coagulopathy, confusion, consciousness depressed, dehydration, dyspnea, edema, encephalopathy, fluid overload/retention, flushing, gastrointestinal hemorrhage, hallucinations, hemangioma, hemorrhage, hepatic artery stenosis, hepatic failure, hepatotoxicity, hypercapnia, hyperkalemia, hypernatremia, hypertension, hyperventilation, injection site reaction (blistering, extravasation, hemorrhage), intracranial pressure increased, jaundice, Kussmaul respiration, maculopapular rash, multiorgan failure, nerve paralysis, pancytopenia, pCO2 changes, pericardial effusion, phlebothrombosis, pneumonia aspiration, pneumothorax, pruritus, pulmonary edema, pulmonary hemorrhage, rash, renal failure, respiratory alkalosis/acidosis, respiratory arrest/failure, respiratory rate increased, sepsis, septic shock, subdural hematoma, tetany, thrombocytopenia, thrombosis, tremor, urinary retention, urticaria, weakness

Warnings/Precautions

Concerns related to adverse effects:

• Extravasation: Infuse via central line ONLY; peripheral administration may cause burning. May be an irritant with vesicant-like properties; avoid extravasation. If extravasation is suspected discontinue infusion and resume at a different infusion site (if necessary).

• Fluid overload: Use with caution, if at all, in patients at risk for fluid overload (eg, heart failure, severe renal impairment) or sodium retention edema; contains a significant amount of sodium. Discontinue use if patient experiences clinically significant fluid overload.

• Gastrointestinal effects: Nausea and vomiting may occur; premedication with antiemetics may be administered.

• Hypokalemia: May occur; monitor plasma potassium and initiate appropriate treatment as necessary.

• Neurotoxicity: Phenylacetate may result in neurotoxicity (fatigue, lightheadedness, somnolence); symptoms were observed upon initiation of treatment and were reversible with discontinuation.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; metabolism of sodium phenylacetate/sodium benzoate may be impaired.

• Renal impairment: Use with caution in patients with renal impairment; excretion of drug metabolites (phenylacetylglutamine and hippurate) and ammonia may be reduced since primarily excreted by the kidneys; use may also predispose to fluid overload.

Special populations:

• Neonates: Hyperammonemic coma, regardless of the cause, should be treated aggressively until a specific diagnosis is made. Hemodialysis should be initiated immediately in all neonates and may be repeated until plasma ammonia level is stable at normal or near normal levels; a blood flow rate of 150 mL/minute/m2 should be targeted.

Dosage form specific issues:

• Sodium benzoate: Contains sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin.

Other warnings/precautions:

• Appropriate use: Initiate therapy as soon as hyperammonemia is diagnosed. Must be diluted prior to administration. Administer through a central line; peripheral administration may result in burning. Repeat loading doses should not be administered (may result in prolonged phenylacetate plasma levels). Arginine supplementation is an essential part of therapy for patients with carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) deficiency.

• Experienced personnel: Patients should be managed by medical personnel experienced in the treatment of metabolic disorders.

• Nonpharmacologic support: Uncontrolled hyperammonemia can result in brain death and immediate use of all additional therapies to decrease ammonia levels is essential including hemodialysis, caloric supplementation, and dietary protein restriction. Nonprotein calories should be supplied primarily as glucose (8 to 10 mg/kg/minute) with the addition of IV fat emulsion; attempts should be made to maintain a caloric intake of >80 cal/kg/day.

Monitoring Parameters

Neurologic status, Glasgow Coma Scale, tachypnea, CT or MRI scan or fundoscopic evidence of cerebral edema, and/or of gray matter and white matter damage; plasma ammonia, plasma glutamine, plasma amino acids; blood chemistry, blood glucose, AST, ALT, blood pH and pCO2, clinical response, serum electrolytes (potassium, chloride, or bicarbonate), infusion site

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea or vomiting. Have patient report immediately to prescriber signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of acidosis (confusion, fast breathing, tachycardia, arrhythmia, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or feeling very tired or weak), severe dizziness, passing out, headache, confusion, seizures, change in taste, hearing impairment, memory impairment, burning or numbness feeling, muscle pain, muscle cramps, or severe injection site pain, burning, edema, blisters, or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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