WARNINGS AND PRECAUTIONS
Management of Acute Hyperammonemia
Any episode of acute symptomatic hyperammonemia should be treated as a life-threatening emergency. Uncontrolled hyperammonemia can rapidly result in brain damage or death, and prompt use of all therapies necessary, including hemodialysis, to reduce ammonia levels is essential.
Hyperammonemic coma (regardless of cause) in the newborn infant should be aggressively treated while the specific diagnosis is pursued. Hemodialysis should be promptly initiated in all newborn patients. A blood flow rate of 150 mL/min/m2 should be targeted (ammonia clearance [mL/min] is similar to the blood flow rate [mL/min] through the dialyzer). Clearance of ammonia is approximately ten times greater by hemodialysis than by peritoneal dialysis or hemofiltration. Exchange transfusion is ineffective in the management of hyperammonemia. Hemodialysis may be repeated until the plasma ammonia level is stable at normal or near normal levels.
Hyperammonemia due to urea cycle disorders should be managed in coordination with medical personnel experienced in metabolic disorders. 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.
Decreased Potassium Levels
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.
Conditions Associated with Fluid Overload
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. Discontinue administration of AMMONUL, evaluate the patient, and institute appropriate therapeutic countermeasures if an adverse event occurs.
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 (2)
]. 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. The infusion site must be monitored closely for possible infiltration during drug administration. Do not administer undiluted product.
Neurotoxicity of Phenylacetate
Because of prolonged plasma levels achieved by phenylacetate in pharmacokinetic studies, repeat loading doses of AMMONUL should not be administered. Additionally, 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. The acute onset of symptoms upon initiation of treatment and reversibility of symptoms when the phenylacetate was discontinued suggest a drug effect. [See Animal Toxicology and/or Pharmacology]
Hyperventilation and Metabolic Acidosis
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. Monitoring of blood chemistry profiles, blood pH and pCO2 should be performed.
USE IN SPECIFIC POPULATIONS
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.
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.
AMMONUL has been used as a treatment for acute hyperammonemia in pediatric patients including patients in the early neonatal period [see Dosage and Administration (2)
Clinical studies of AMMONUL did not include any patients aged 65 and over to determine whether they respond differently from younger patients. Urea cycle disorders are presently diseases of the pediatric and younger adult populations. No pharmacokinetic studies of AMMONUL have been performed in geriatric patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy in this patient population.
Pharmacokinetic parameters of AMMONUL were compared in healthy males and females. Bioavailability of both benzoate and phenylacetate was slightly higher in females than in males. However, conclusions cannot be drawn due to the limited number of subjects in this study.
Limited information is available on the metabolism and excretion of sodium phenylacetate and sodium benzoate in patients with impaired hepatic function. However, metabolic conjugation of sodium phenylacetate and sodium benzoate is known to take place in the liver and kidney. Therefore, caution should be used in administering AMMONUL to patients with hepatic insufficiency.
The drug metabolites of AMMONUL (phenylacetylglutamine and hippurate) and subsequently ammonia are primarily excreted by the kidney. Therefore, use caution and closely monitor patients with impaired renal function who receive AMMONUL.