Sodium Benzoate and Sodium Phenylacetate (Systemic )


VA CLASSIFICATION
Primary: AD900

Commonly used brand name(s): Ucephan.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antihyperammonemic—

Indications

Accepted

Hyperammonemia (prophylaxis and treatment)—Sodium benzoate and sodium phenylacetate combination is indicated as adjunctive therapy in the prevention and treatment of hyperammonemia in patients with urea cycle enzymopathy (UCE) due to carbamylphosphate synthetase, ornithine transcarbamylase, or arginosuccinate synthetase deficiency. Sodium benzoate and sodium phenylacetate combination is used in conjunction with a low protein diet and amino acid supplementation. {01} {02} {04}
—Beneficial use of sodium benzoate and sodium phenylacetate combination in treating neonatal hyperammonemic coma has not been established. Treatment of choice for neonatal hyperammonemic coma is hemodialysis. {01}


Pharmacology/Pharmacokinetics

Mechanism of action/Effect:

Sodium benzoate and sodium phenylacetate combination decreases ammonia formation by conjugation reactions involving acylation of amino acids. Benzoate and phenylacetate activate conjugation pathways, which then substitute for or supplement the defective ureagenic pathway in patients with urea cycle enzymopathies. Benzoate conjugates with glycine to form hippurate, and phenylacetate conjugates with glutamine to form phenylacetylglutamine. {01} {02}

Biotransformation:

Hepatic and renal. {01}

Time to peak concentration:

Within 1 hour in normal adults. {01}

Elimination:
    Primarily renal; approximately 80 to 100% as the respective conjugation product, hippurate or phenylacetylglutamine, within 24 hours in normal adults. {01}


Precautions to Consider

Carcinogenicity/Mutagenicity

Sodium benzoate has been tested as a food preservative and results indicate that it is not carcinogenic or mutagenic. Carcinogenic or mutagenic studies of sodium phenylacetate have not been conducted. {01}

Pregnancy/Reproduction
Fertility—
Sodium benzoate has not been found to impair fertility. Fertility studies of sodium phenylacetate have not been conducted. {01}

Pregnancy—
Studies have not been done in humans. {01}

Studies have not been done in animals.

FDA Pregnancy Category C.

Breast-feeding

It is not known whether sodium benzoate or sodium phenylacetate combination is distributed into breast milk. {01}

Pediatrics

It is theorized that low birthweight infants with immature livers may not be capable of metabolizing benzoate and hippurate. Sodium benzoate and sodium phenylacetate combination should not be administered to low birthweight infants unless the benefits of treatment outweigh the risks. {01}


Geriatrics


No information is available on the relationship of age to the effects of sodium benzoate and sodium phenylacetate combination in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require careful monitoring in patients receiving sodium benzoate and sodium phenylacetate combination. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Penicillins    (concurrent use with sodium benzoate and sodium phenylacetate combination is not recommended because penicillins may compete with the conjugated products of sodium benzoate and sodium phenylacetate for active secretion by renal tubules {01})


Probenecid    (probenecid inhibits the renal transport of many organic compounds, including aminohippuric acid, and may affect renal excretion of the conjugated products of sodium benzoate and sodium phenylacetate {01})


Valproic acid    (hyperammonemia, reported to be induced by valproic acid, may exacerbate urea cycle enzymopathy deficiency and antagonize the efficacy of sodium benzoate and sodium phenylacetate combination {01} {03})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Edematous sodium-retaining conditions, such as:
» Congestive heart failure or
» Renal function impairment or
» Toxemia of pregnancy    (fluid retention may be increased due to the sodium content of sodium benzoate and sodium phenylacetate {01})


Hyperbilirubinemia, neonatal    (benzoate may compete for bilirubin binding sites on albumin {01})


Peptic ulcer    (the condition may be exacerbated by sodium benzoate and sodium phenylacetate combination because of structural similarities between benzoate and salicylates {01})


Sensitivity to sodium benzoate or sodium phenylacetate combination, or either component{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Ammonia concentrations, plasma{05}    (determinations recommended at frequent intervals during therapy to confirm efficacy of sodium benzoate and sodium phenylacetate combination; excessive ammonia concentrations may lead to hyperammonemic coma)




Side/Adverse Effects

Note: Because of structural similarities between benzoate and salicylates, sodium benzoate and sodium phenylacetate combination may have the potential to cause side effects associated with salicylates, such as exacerbation of peptic ulcers, mild hyperventilation, and mild respiratory alkalosis. {01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Nausea or vomiting





Overdose
For information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Circulatory collapse (feeling of faintness; rapid fall in blood pressure){01}
    
lethargy (unusual drowsiness){01}
    
metabolic acidosis (shortness of breath or troubled breathing){01}
    
respiratory alkalosis {05}
    
unusual irritability {01}
    
vomiting, persistent{01}
Note: Circulatory collapse, lethargy, and metabolic acidosis were reported after overdoses with intravenous sodium benzoate and sodium phenylacetate combination. {01}
All side/adverse effects of sodium benzoate and sodium phenylacetate combination may also be symptoms of the disease state; however, they may be increased if overdose occurs. {06}




Treatment of overdose
The medication should be discontinued. There is no known specific antidote for sodium benzoate and sodium phenylacetate combination overdose. Recommended treatment consists of the following

   • Supportive care—Supportive therapy for metabolic acidosis and circulatory collapse. Hemodialysis or peritoneal dialysis.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Sodium Benzoate and Sodium Phenylacetate (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to sodium benzoate and sodium phenylacetate combination, or either component





Use in children—Caution in low birthweight infants with immature livers

Other medicines, especially penicillins
Other medical problems, especially congestive heart failure, edema, renal function impairment, or toxemia of pregnancy

Proper use of this medication
Diluting medication in formula or milk before taking

Taking medication with meals

Importance of low protein diet

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during therapy


General Dosing Information
Sodium benzoate and sodium phenylacetate combination is a concentrated solution for oral use only. Each dose should be diluted in infant formula or milk before administration. If other beverages are used, particularly acidic beverages, precipitation of the medication may occur, depending on the pH and the final concentration. The mixture should be inspected for compatibility before administration. {01}

Since sodium benzoate and sodium phenylacetate combination is a concentrated solution, care should be taken in calculating the dose to avoid the possibility of an overdose. {01}

Since sodium phenylacetate has a lingering odor, caution should be used in mixing or administering the medication to minimize contact with skin and clothing. {01}

Diet/Nutrition
Sodium benzoate and sodium phenylacetate combination should be administered with meals.

Sodium benzoate and sodium phenylacetate combination should be combined with a low protein diet to reduce nitrogen intake and in some patients amino acid supplementation to provide a better tolerated type of dietary nitrogen. {01} {04}

Each dose of sodium benzoate and sodium phenylacetate combination must be diluted in 4 to 8 ounces of infant formula or milk before administration. {01}


Oral Dosage Forms

SODIUM BENZOATE AND SODIUM PHENYLACETATE ORAL SOLUTION

Usual adult and adolescent dose
Antihyperammonemic
Oral, 250 mg of sodium benzoate and 250 mg of sodium phenylacetate (2.5 mL) per kg of body weight a day, in three to six equally divided doses, not to exceed 100 mL (10 grams each of sodium benzoate and sodium phenylacetate) a day. {01}


Usual pediatric dose
See Usual adult and adolescent dose .

Note: Use in neonates with hyperammonemic coma has not been established. {01}


Strength(s) usually available
U.S.—


100 mg sodium benzoate and 100 mg sodium phenylacetate per mL (Rx) [Ucephan]

Canada—
Not commercially available.

Note: The concentrated sodium benzoate and sodium phenylacetate solution, before dilution, contains 130 mEq (262 milliosmoles) of sodium per 100 mL. {01}


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
Each dose of sodium benzoate and sodium phenylacetate combination must be diluted in 4 to 8 ounces of infant formula or milk before administration. {01}

Incompatibilities:
Mixing with acidic beverages or medications may cause precipitation of sodium benzoate and sodium phenylacetate, depending on the pH and final concentration of the diluted solution. {01}

Auxiliary labeling:
   • For oral use only.
   • Take mixed in infant formula or milk.



Revised: 07/15/1993



References
  1. Ucephan package insert (Kendall McGaw Labs—US) Rec 4/92, Rev 3/91.
  1. Msall M, Batshaw M, Suss R, Brusilow S, Mellits E. Neurologic outcome in children with inborn errors of urea synthesis. N Eng J Med 1984; 310(23): 1500-5.
  1. Watson A, Karp J, Walker W, Chambers T, Risch V, Brusilow S. Transient idiopathic hyperammonaemia in adults. Lancet 1985 Dec 7: 1271-4.
  1. Brunsilow S, Danney M, Waber L, et al. Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis. N Eng J Med 1984; 310(25): 1630-4.
  1. Panel comment, 1990 revision.
  1. Manufacturer comment, 1990.
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