SODIUM PHENYLACET-SOD BENZOATE (Generic for AMMONUL)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Dilution
-Ammonul is supplied as a 10% sodium benzoate; 10% sodium phenylacetate solution. Thus, each mL provides 100 mg of sodium benzoate and 100 mg of sodium phenylacetate.
-Using the provided MilIex Durapore GV 33 mm sterile syringe filter (0.22 micrometer), withdraw the needed amount for the dosage and mix with at least 25 mL of 10% sterile dextrose injection per kilogram of the patient's weight. Dilution must be done in a glass or PVC container.
-The presence of particulate matter may impact the safe use of sodium benzoate; sodium phenylacetate. Since particulate matter may not be readily seen on visual inspection, a filter must be employed in all cases regardless of whether particulate matter is seen in the vial.
-Arginine HCl 10% injection can be mixed in the same container with diluted sodium benzoate; sodium phenylacetate. No other compatibility data are available.
-Storage: Sodium benzoate; sodium phenylacetate does not contain preservatives. The solution is physically and chemically stable for 24 hours at room temperature and lighting conditions once it has been reconstituted. Discard any unused product; do no store for reuse.

Intravenous Injection
-Do not administer undiluted product.
-Sodium benzoate; sodium phenylacetate is administered as an intravenous infusion through a central line only. Peripheral infusion may cause burns.
-If visibly opaque particles, discoloration, or other foreign particles are observed, the solution should not be used.
-Sodium benzoate; sodium phenylacetate should be infused through a different line than the one used for the infusion of other solutions or medications. If use of a separate line is not possible, the line should be flushed with at least 15 mL of saline solution before and after infusion with sodium benzoate; sodium phenylacetate.
-The loading dose should be infused over 90 minutes.

Continuous Intravenous Infusion
-Infuse the maintenance dose over 24 hours immediately following the loading dose. Closely monitor the infusion site for possible drug extravasation.
-Sodium benzoate; sodium phenylacetate is indicated for the adjunctive treatment of hyperammonemia. Caloric supplementation (ideally, more than 80 cal/kg/day) and dietary protein restriction are needed concurrently. Non-protein calories should be given as glucose 8 to 10 mg/kg/day with intravenous fat emulsion added. Also, all infants with hyperammonemic coma regardless of the cause need prompt hemodialysis. Further, concurrent hemodialysis may be advisable for moderate to severe hyperammonemic encephalopathy, for patients with a large ammonia burden, and for failure to respond within 4 to 8 hours of sodium benzoate; sodium phenylacetate initiation.
-Continually assess the patient's neurological status, ammonia concentrations, and serum electrolyte concentrations until hyperammonemia has resolved, and the patient is able to tolerate oral therapy.

In a clinical trial of 316 patients receiving sodium benzoate; sodium phenylacetate, 7% developed hypokalemia and < 3% developed hyperkalemia. Urine potassium loss is enhanced by the excretion of phenylacetylglutamine and hippuric acid, which are non-reabsorbable anions. Also, high-dose glucose administration, which is recommended when administering sodium benzoate; sodium phenylacetate, can drive potassium intracellularly. Monitoring of serum potassium concentrations is recommended; supplementation may be needed.

Adverse effects observed in clinical trials may be due to the underlying disease, the patient's restricted diet, intercurrent illness, or sodium benzoate; sodium phenylacetate administration. Of 316 patients, 6% developed seizures or impaired cognition, 5% had cerebral edema or hyperammonemia, 3% developed a coma, agitation, or irritability, and < 3% had acute psychosis, brain herniation, brain death, aggression, confusion, encephalopathy, or hallucinations. Serum ammonia concentrations rose in 4% of 1045 hyperammonemic episodes treated with sodium benzoate; sodium phenylacetate. Dialysis is recommended for patients who either have an increase or an absence of a significant plasma ammonia concentration decrease within 4-8 hours of sodium benzoate; sodium phenylacetate initiation. Some of these adverse reactions are signs and symptoms of toxicity; patients should be monitored for toxicity if these signs or symptoms occur. If an overdose is suspected, stop the infusion and administer medical monitoring and any needed emergency procedures such as dialysis.

In a clinical trial of 316 patients receiving sodium benzoate; sodium phenylacetate, hypocalcemia occurred in 3%, and hypernatremia, edema, fluid retention, dehydration, tetany, or hypertension occurred in < 3% of patients. The undiluted sodium benzoate; sodium phenylacetate product contains 30.5 mg of sodium per ml. Electrolyte concentrations and fluid status should be monitored closely in patients receiving sodium benzoate; sodium phenylacetate.

Phenylacetate and benzoate are structurally similar to salicylate and may cause similar adverse effects such as hyperventilation and metabolic acidosis. Metabolic acidosis occurred in 13 of 316 patients and was serious enough to warrant sodium benzoate; sodium phenylacetate discontinuation in 2 patients. Patients with argininosuccinate synthetase (ASS) or argininosuccinate lyase (ALS) deficiency may develop a hyperchloremic acidosis after high-dose arginine hydrochloride administration. Hyperventilation is also associated with hyperammonemia and may cause a respiratory alkalosis. Changes in blood carbon dioxide, increased blood pH, tachypnea, acute respiratory distress syndrome (ARDS), dyspnea, hypercapnia, respiratory acidosis or alkalosis, pneumonia aspiration, pneumothorax, pulmonary hemorrhage, pulmonary edema, or respiratory failure have been reported in < 3% of patients. Closely monitor blood chemistry including plasma chloride and bicarbonate concentrations, pH, and pCO2 for abnormalities requiring prompt attention; bicarbonate administration may be needed. Some of these adverse reactions are signs and symptoms of toxicity; patients should be monitored for toxicity if these signs or symptoms occur. If an overdose is suspected, stop the infusion and administer medical monitoring and any needed emergency procedures such as dialysis.

In a clinical trial of 316 patients on sodium benzoate; sodium phenylacetate therapy, 3% had injection site reactions. An injection site reaction led to drug discontinuation in 2 patients. Alopecia, pruritus, rash (unspecified), flushing, urticaria, or hemangioma occurred in < 3% of patients.

Adverse effects observed in clinical trials may be due to the underlying disease, the patient's restricted diet, intercurrent illness, or sodium benzoate; sodium phenylacetate administration. Nausea and vomiting are commonly associated with hyperammonemia; an antiemetic may be given if needed. In a clinical trial of 316 patients, 3% had nausea, 9% had vomiting, 7% had hyperglycemia, 5% had fever, 4% had anemia or hypotension, 3% had disseminated intravascular coagulation (DIC) or diarrhea, and < 3% had hypoglycemia, visual impairment (blindness), asthenia, decreased cardiac output, sepsis/septic shock, or multiorgan failure. As compared with older patients, more patients 30 days old or younger experienced anemia, DIC, or hypotension. In contrast, more older patients had nausea/vomiting or diarrhea. Hypotension may be caused by arginine administration, as arginine is a precursor of nitrous oxide. Hyperglycemia needs to be controlled to prevent exacerbation of any cerebral edema that may be present.

In a clinical trial of 316 patients receiving sodium benzoate; sodium phenylacetate, <3% had cholestasis, hepatic failure, jaundice, hepatic artery stenosis, bleeding, GI bleeding, abdominal distension, coagulopathy, thrombocytopenia, pancytopenia, or thrombosis. The liver is one of the primary sites of sodium benzoate; sodium phenylacetate conjugation. Patients should be closely monitored for any signs or symptoms of impaired hepatic function including coagulation parameter values.

If sodium benzoate; sodium phenylacetate escapes the vein, skin necrosis can result. If signs or symptoms of extravasation are noted, immediately discontinue injection and begin at a different central site. Treatment in the event of extravasation may include aspiration from the catheter, limb elevation, and intermittent cooling. The clinician should pay careful attention to the possibility of extravasation of sodium benzoate; sodium phenylacetate.

In a clinical trial of 316 patients, <3% had anuria, renal failure (unspecified), or urinary retention. A urinary tract infection occurred in 3% of patients. The kidneys are a site of conjugation and excretion of sodium benzoate; sodium phenylacetate. Monitor renal function and urine output during sodium benzoate; sodium phenylacetate administration.

Areflexia (profound hyporeflexia), ataxia, brain infarction, intracranial bleeding, cerebral degeneration (atrophy), nerve paralysis, increased intracranial pressure, subdural hematoma, or tremor occurred in < 3% of 316 patients who received sodium benzoate; sodium phenylacetate in clinical trials. The adverse effects may be due to the underlying disorder and not from sodium benzoate; sodium phenylacetate. People with enzymatic deficiencies earlier in the urea cycle tend to have more serious complications. Patients deficient in ornithine transcarbamylase or carbamyl phosphate synthetase are at increased risk for neurologic problems such as convulsions and mental impairment. Both ornithine transcarbamylase and carbamyl phosphate synthetase are enzymes that occur early in the urea cycle.

Adverse effects observed in clinical trials may be due to the underlying disease, the patient's restricted diet, intercurrent illness, or sodium benzoate; sodium phenylacetate administration. Cardiovascular adverse reactions reported in < 3% of patients during clinical trials include trial rupture, bradycardia, chest pain (unspecified), cardiac arrest, cardiogenic shock, cardiomyopathy, and pericardial effusion.

Sodium benzoate; sodium phenylacetate should only be infused through a central intravenous line. Do not give sodium benzoate; sodium phenylacetate by any other route including intraarterial administration or intramuscular administration. The infusion site should be monitored closely for signs of infiltration. The infusion should be stopped immediately and begun at a different central site if extravasation is suspected, as necrosis may occur. Treatment in the event of extravasation may include aspiration of residual drug from the catheter, limb elevation, and intermittent cooling.

Adequate renal function is necessary for the removal of hippurate and phenylacetylglutamine, and the undiluted injection contains 30.5 mg of sodium per ml. Therefore, patients with a history of heart failure, severe renal impairment, renal failure, hypertension, or any other condition in which hypernatremia or edema are of concern might be at particular risk for adverse events. Patients with sodium restriction requirements should also be given a risk-benefit analysis before beginning therapy. Monitor the patient's hydration status to help preserve renal function and perfusion of other tissues. Avoid overhydration, as most patients with acute hyperammonemia have cerebral swelling.

Phenylacetylglutamine and hippurate excretion enhance potassium loss in the kidneys. As a result, monitor patients closely for signs and symptoms of hypokalemia, and give supplementation accordingly. Monitor electrolyte concentrations closely in patients receiving sodium benzoate; sodium phenylacetate.

Assess patients with hepatic disease closely to ensure efficacy is being achieved with sodium benzoate; sodium phenylacetate administration since hepatic conjugation is a key step in the drug's mechanism of action. Monitor plasma ammonia and glutamine concentrations routinely.

Patients with a history of seizures need to be carefully monitored during sodium benzoate; sodium phenylacetate administration. Seizures may be an adverse effect of sodium benzoate; sodium phenylacetate, although comparative placebo data are unavailable, and hyperammonemia can cause seizures.

Hyperglycemia may be an adverse effect of sodium benzoate; sodium phenylacetate. Patients with diabetes mellitus should be monitored closely for glucose control during treatment.

Description: Sodium benzoate and sodium phenylacetate are used together in an injectable preparation as an adjunctive treatment of acute hyperammonemia. They are given in combination with arginine hydrochloride. Sodium benzoate; sodium phenylacetate provide an alternative pathway for waste nitrogen excretion in patients with disorders of the urea cycle. Breakdown of amino acids creates nitrogenous waste in the form of ammonia. As the urea cycle normally metabolizes ammonia, enzyme deficiencies in the cycle often result in hyperammonemia. Subsequent damage to CNS neurons from ammonia and glutamine can be fatal if left untreated. Patients with a deficiency in one of the earlier enzymes of the urea cycle are at high risk of hyperammonemic crisis and often become symptomatic in early childhood. Neonatal patients in hyperammonemic crisis may present with lethargy, seizures, poor feeding, neurologic changes, edema, or respiratory distress. Less severe urea cycle deficiencies may not manifest until late adolescence or early adulthood during a viral illness, high protein diet, stress, or trauma. Through conjugation with amino acids, sodium phenylacetate and sodium benzoate form nitrogenous compounds that are readily excreted. Dialysis removes ammonia from the blood faster, but sodium benzoate; sodium phenylacetate also help prevent ammonia reaccumulation. Only one loading dose of sodium benzoate; sodium phenylacetate should be given due to the long half-life and risk of toxicity with high doses. Sodium benzoate; sodium phenylacetate is approved in pediatric patients, as young as neonates.

General dosing information:
-Uncontrolled elevated ammonia concentrations can rapidly cause brain damage or death and should be treated immediately, especially in neonates presenting with coma, regardless of whether the specific causative enzyme deficiency has been identified. If the enzyme deficiency is unknown, administer 600 mg/kg of arginine HCl over 90 minutes and an equivalent dose over 24 hours to all hyperammonemic infants with suspected urea cycle deficiency.
-Do not give more than one loading dose due to prolonged phenylacetate plasma concentrations and toxicity. In a trial, the mean treatment duration per episode was 4.6 days (range, 1 to 72 days).

For the adjunctive treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle:
-for patients with carbamyl phosphate synthetase (CPS) or ornithine transcarbamylase (OTC) deficiency:
Intravenous infusion dosage:
Neonates: 2.5 mL/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) IV loading dose through a central line over 90 to 120 minutes, then give a maintenance dose of 2.5 mL/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) IV through a central line over 24 hours. Administer each dose with 2 mL/kg (provides 200 mg/kg) arginine HCl IV. Maintenance infusions may be given daily, each over 24 hours, until plasma ammonia concentrations normalize or until the patient can tolerate oral nutrition and medications.
Infants and Children weighing 20 kg or less: 2.5 mL/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) IV loading dose through a central line over 90 to 120 minutes, then give a maintenance dose of 2.5 mL/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) IV through a central line over 24 hours. Administer each dose with 2 mL/kg (provides 200 mg/kg) arginine HCl IV. Maintenance infusions may be given daily, each over 24 hours, until plasma ammonia concentrations normalize or until the patient can tolerate oral nutrition and medications.
Children and Adolescents weighing more than 20 kg: 55 mL/m2 (provides 5.5 g/m2 of sodium phenylacetate and 5.5 g/m2 of sodium benzoate) IV loading dose through a central line over 90 to 120 minutes, then give a maintenance dose of 55 mL/m2 (provides 5.5 g/m2 of sodium phenylacetate and 5.5 g/m2 of sodium benzoate) IV through a central line over 24 hours. Administer each dose with 2 mL/kg (provides 200 mg/kg) arginine HCl IV. Maintenance infusions may be given daily, each over 24 hours, until plasma ammonia concentrations normalize or until the patient can tolerate oral nutrition and medications.
-for patients with argininosuccinate lyase (ASL) or argininosuccinate synthetase (ASS) deficiency:
Intravenous infusion dosage:
Neonates: 2.5 mL/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) IV loading dose through a central line over 90 to 120 minutes, then give a maintenance dose of 2.5 mL/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) IV through a central line over 24 hours. Administer each dose with 6 mL/kg (provides 600 mg/kg) arginine HCl IV. Maintenance infusions may be given daily, each over 24 hours, until plasma ammonia concentrations normalize or until the patient can tolerate oral nutrition and medications.
Infants and Children weighing 20 kg or less: 2.5 mL/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) IV loading dose through a central line over 90 to 120 minutes, then give a maintenance dose of 2.5 mL/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) IV through a central line over 24 hours. Administer each dose with 6 mL/kg (provides 600 mg/kg) arginine HCl IV. Maintenance infusions may be given daily, each over 24 hours, until plasma ammonia concentrations normalize or until the patient can tolerate oral nutrition and medications.
Children and Adolescents weighing more than 20 kg: 55 mL/m2 (provides 5.5 g/m2 of sodium phenylacetate and 5.5 g/m2 of sodium benzoate) IV loading dose through a central line over 90 to 120 minutes, then give a maintenance dose of 55 mL/m2 (provides 5.5 g/m2 of sodium phenylacetate and 5.5 g/m2 of sodium benzoate) IV through a central line over 24 hours. Administer each dose with 6 mL/kg (provides 600 mg/kg) arginine HCl IV. Maintenance infusions may be given daily, each over 24 hours, until plasma ammonia concentrations normalize or until the patient can tolerate oral nutrition and medications.

Maximum Dosage Limits:
-Neonates
2.5 ml/kg IV as a loading dose (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) and a maintenance dose of 2.5 ml/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate), both administered on day 1. Subsequent days, only the maintenance dose is given; do not give more than 1 loading dose.
-Infants
2.5 ml/kg IV as a loading dose (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) and a maintenance dose of 2.5 ml/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate), both administered on day 1. Subsequent days, only the maintenance dose is given; do not give more than 1 loading dose.
-Children
< 20 kg: 2.5 ml/kg IV as a loading dose (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate) and a maintenance dose of 2.5 ml/kg (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate), both administered on day 1. Subsequent days, only the maintenance dose is given; do not give more than 1 loading dose.
> 20 kg: 55 ml/m2 IV as a loading dose (provides 5.5 g/m2 of sodium phenylacetate and 5.5 g/m2 of sodium benzoate) and maintenance dose of 55 ml/m2 IV as a loading dose (provides 5.5 g/m2 of sodium phenylacetate and 5.5 g/m2 of sodium benzoate), both administered on day 1. Subsequent days, only the maintenance dose is given; do not give more than 1 loading dose.
-Adolescents
55 ml/m2 IV as a loading dose (provides 5.5 g/m2 of sodium phenylacetate and 5.5 g/m2 of sodium benzoate) and maintenance dose of 55 ml/m2 IV as a loading dose (provides 5.5 g/m2 of sodium phenylacetate and 5.5 g/m2 of sodium benzoate), both administered on day 1. Subsequent days, only the maintenance dose is given; do not give more than 1 loading dose.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; however, care should be taken in patients with hepatic impairment, as the liver is one of the primary sites of conjugation of phenylacetylglutamine and hippuric acid.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; close monitoring for renal clearance of drug metabolites and ammonia is necessary for clinical assessment.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Sodium benzoate; sodium phenylacetate help to reduce serum ammonia and glutamine concentrations. Patients with high ammonia and glutamine concentrations are at particular risk for encephalopathies and neurotoxicity. The urea cycle is normally responsible for maintaining low blood concentrations of ammonia and glutamine from protein breakdown. The normal urea cycle requires numerous enzyme-catalyzed steps to form nitrogenous waste such as urea. Hyperammonemia may occur when there is a deficiency in one or more urea cycle enzymes or a cofactor: N-acetylglutamate synthetase, carbamyl phosphate synthetase, argininosuccinate synthetase, ornithine transcarbamylase, or argininosuccinate lyase. Arginine becomes an essential amino acid when carbamyl phosphate synthetase, argininosuccinate synthetase, ornithine transcarbamylase, or argininosuccinate lyase is deficient. If essential amino acids are not available, protein catabolism occurs, which increases ammonia concentrations.

Ammonia in the blood may be converted to glycine, glutamine, or carbamyl phosphate. In contrast to the normal urea cycle, only two steps are required to form nitrogenous molecules from sodium benzoate; sodium phenylacetate. Phenylacetate conjugates glutamine in the liver and kidneys to form glutamine phenylacetate, which is acetylated to form phenylacetylglutamine. Benzoate undergoes acylation and conjugates with glycine to form hippuric acid. These two nitrogenous waste products, phenylacetylglutamine and hippuric acid, are excreted by the kidneys through glomerular filtration and tubular secretion. The scavenged glutamine and glycine are regenerated, which reduces the serum ammonia concentration and reduces the nitrogen load once conversion to phenylacetylglutamine and hippuric acid occurs, and the products are excreted from the body. Thus, ammonia is eliminated indirectly from the blood. Similar to urea, two moles of nitrogen are removed per mole of phenylacetylglutamine. One mole of nitrogen is removed per mole of hippuric acid.

Pharmacokinetics: Sodium benzoate; sodium phenylacetate is administered by intravenous infusion through a central line only. Both benzoate and phenylacetate display nonlinear kinetics. Total clearance decreases and systemic exposure increases with increasing doses. As compared with benzoate, phenylacetate is cleared at a much slower rate. Phenylacetate conjugates glutamine in the liver and kidneys to form glutamine phenylacetate, which is acetylated to form phenylacetylglutamine. Benzoate undergoes acylation and conjugates with glycine to form hippuric acid. Hippuric acid formation from benzoate occurs faster than phenylacetylglutamine formation from phenylacetate. Both phenylacetylglutamine and hippuric acid undergo glomerular filtration and tubular secretion.

Most patients with hyperammonemia have sustained reductions in their mean ammonia concentration within 4 hours of sodium benzoate; sodium phenylacetate administration. Some patients may have an increase in plasma ammonia concentrations after sodium benzoate; sodium phenylacetate administration.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
After a 24-hour infusion of sodium benzoate; sodium phenylacetate, phenylacetate was detectable in plasma 24 hours after the end of the infusion with a Tmax of 2 hours; while benzoate was undetectable 14 hours after the infusion cessation with a Tmax of 1.5 hours.


-Special Populations
Pediatrics
Infants and Children
Limited pharmacokinetic data are available from children 3-26 months old. The times of peak plasma concentrations were similar to the values obtained from adults. Also similar to findings in adult populations, the plasma phenylacetate concentrations were higher and persisted longer as compared to the plasma benzoate concentrations.

Hepatic Impairment
Pharmacokinetic parameters of sodium benzoate; sodium phenylacetate in patients with hepatic insufficiency have not been formally studied. The manufacturer recommends that care be taken in these patients, as the liver is a primary site of conjugation.

Renal Impairment
Pharmacokinetic parameters of sodium benzoate; sodium phenylacetate in patients with renal insufficiency have not been formally studied. The manufacturer recommends that care be taken in these patients, as the kidneys are sites of drug excretion.