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Ammonul (Sodium Phenylacetate / Sodium Benzoate) - Warnings and Precautions

 
 



WARNINGS

Any episode of acute symptomatic hyperammonemia should be treated as a life-threatening emergency. Treatment of hyperammonemia may require dialysis, preferably hemodialysis, to remove a large burden of ammonia. Uncontrolled hyperammonemia can rapidly result in brain damage or death, and prompt use of all therapies necessary to reduce ammonia levels is essential.

Management of hyperammonemia due to inborn errors of metabolism should be done in coordination with medical personnel familiar with these diseases. The severity of the disorder may necessitate the use of hemodialysis combined with nutritional management and medical support. The multidisciplinary nature of the treatment usually requires the facilities of a tertiary or quaternary care center.

Ongoing monitoring of plasma ammonia levels, neurological status, laboratory tests, and clinical response in patients receiving AMMONUL® is crucial to assess patient response to treatment. Because urine potassium loss is enhanced by the excretion of the non-reabsorbable anions, phenylacetylglutamine and hippurate, plasma potassium levels should be carefully monitored and appropriate treatment given when necessary. Serum electrolyte levels should be monitored and maintained within the normal range.

AMMONUL® contains 30.5 mg of sodium per mL of undiluted product. Thus, AMMONUL® should be used with great care, if at all, in patients with congestive heart failure or severe renal insufficiency, and in clinical states in which there is sodium retention with edema. If an adverse reaction does occur, discontinue administration of AMMONUL®, evaluate the patient, and institute appropriate therapeutic countermeasures.

Administration must be through a central line. Administration through a peripheral line may cause burns.

Bolus infusion flow rates are relatively high, especially for infants (see DOSAGE AND ADMINISTRATION). Extravasation of AMMONUL® into the perivenous tissues may lead to skin necrosis. If extravasation is suspected, discontinue the infusion and resume at a different infusion site, if necessary. Standard treatment for extravasation can include aspiration of residual drug from the catheter, limb elevation, and intermittent cooling using cold packs [14]. The infusion site must be monitored closely for possible infiltration during drug administration. Do not administer undiluted product.

Due to structural similarities between phenylacetate and benzoate to salicylate, AMMONUL® may cause side effects typically associated with salicylate overdose, such as hyperventilation and metabolic acidosis. The clinician is advised to perform blood chemistry profiles, and frequent blood pH and pCO2 monitoring.

PRECAUTIONS

General

AMMONUL® is a concentrated solution and must be diluted before administration via a central line. Because sodium phenylacetate and sodium benzoate are metabolized in the liver and kidney, and since phenylacetylglutamine and hippurate are primarily excreted by the kidney, use caution when administering AMMONUL® to patients with hepatic or renal insufficiency. AMMONUL® infusion has been associated with nausea and vomiting. An antiemetic may be administered during AMMONUL® infusion.

Because of prolonged plasma levels achieved by phenylacetate in pharmacokinetic studies, repeat loading doses of AMMONUL® should not be administered.

Use of corticosteroids may cause the breakdown of body protein and, thereby, potentially increase plasma ammonia levels in patients with impaired ability to form urea.

Neurotoxicity of Phenylacetate

Neurotoxicity was reported in cancer patients receiving intravenous phenylacetate, 250–300 mg/kg/day for 14 days, repeated at 4-week intervals. Manifestations were predominantly somnolence, fatigue, and lightheadedness, with less frequent headaches, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of a pre-existing neuropathy. These adverse events were mainly mild. The acute onset of symptoms upon initiation of treatment and reversibility of symptoms when the phenylacetate was discontinued suggest a drug effect [2,3].

In animal studies, subcutaneous administration to rat pups of 190–474 mg/kg of phenylacetate caused decreased proliferation and increased loss of neurons, and reduced central nervous system (CNS) myelin. Cerebral synapse maturation was retarded, and the number of functioning nerve terminals in the cerebrum was reduced, which resulted in impaired brain growth [15]. Pregnant rats were given phenylacetate at 3.5 µmol/g/day subcutaneous from gestation day 7 through normal delivery. Prenatal exposure of rat pups to phenylacetate produced lesions in layer 5 cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number [16].

Drug Interactions

Some antibiotics such as penicillin may compete with phenylacetylglutamine and hippurate for active secretion by renal tubules, which may affect the overall disposition of the infused drug.

Probenecid is known to inhibit the renal transport of many organic compounds, including aminohippuric acid, and may affect renal excretion of phenylacetylglutamine and hippurate [13].

There have been reports that valproic acid can induce hyperammonemia through inhibition of the synthesis of N-acetylglutamate, a co-factor for carbamyl phosphate synthetase [14]. Therefore, administration of valproic acid to patients with urea cycle disorders may exacerbate their condition and antagonize the efficacy of AMMONUL®  [15].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity and fertility studies of sodium phenylacetate have not been conducted. Sodium benzoate has been extensively tested as a food preservative. Results indicate that sodium benzoate is not mutagenic or carcinogenic, and does not impair fertility.

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with AMMONUL®. It is not known whether AMMONUL® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Thus, AMMONUL® should be given to a pregnant woman only if clearly needed.

Labor and Delivery

The effects of AMMONUL® on labor and delivery are unknown.

Nursing Mothers

It is not known whether sodium phenylacetate, sodium benzoate, or their conjugation products are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AMMONUL® is administered to a nursing woman.

Pediatric

AMMONUL® has been used as a treatment for acute hyperammonemia in pediatric patients including patients in the early neonatal period (see DOSAGE AND ADMINISTRATION).

Page last updated: 2007-04-17

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