warnings and cautions
5 WARNINGS AND PRECAUTIONS Management of Acute Hyperammonemia : Monitor plasma ammonia levels during treatment. Prolonged exposure to elevated plasma ammonia levels can rapidly result in injury to the brain or death. Prompt use of all therapies necessary to reduce plasma ammonia levels is essential. ( 5.1 ) Decreased Potassium Levels : Plasma potassium levels should be carefully monitored and appropriate treatment given when necessary. ( 5.2 ) Conditions Associated with Fluid Overload : Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% contains 30.5 mg of sodium per mL of undiluted product. Caution should be used if Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% is administered to patients with congestive heart failure, severe renal insufficiency, or with conditions in which there is sodium retention with edema. ( 5.3 ) Extravasation : Extravasation of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% into the perivenous tissues during high flow bolus infusion may lead to skin necrosis, especially in infants. The infusion site must be monitored closely for possible tissue infiltration during drug administration. ( 5.4 ) Neurotoxicity of Phenylacetate: Because of prolonged plasma levels achieved by phenylacetate in pharmacokinetic studies, repeat loading doses should not be administered. Additionally, neurotoxicity related to phenylacetate has been reported in cancer patients. Monitor patients for symptoms of acute neurotoxicity. ( 5.5 ) Hyperventilation and Metabolic Acidosis: Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% may cause side effects typically associated with salicylate overdose, such as hyperventilation and metabolic acidosis. Monitor patient blood chemistry profiles and perform frequent blood pH and pCO 2 measurements. ( 5.6 ) 5.1 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/m 2 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 Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% is crucial to assess patient response to treatment. 5.2 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. 5.3 Conditions Associated with Fluid Overload Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% contains 30.5 mg of sodium per mL of undiluted product. Thus, Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% 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 Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10%, evaluate the patient, and institute appropriate therapeutic countermeasures if an adverse event occurs. 5.4 Extravasation 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 Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% 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. 5.5 Neurotoxicity of Phenylacetate Because of prolonged plasma levels achieved by phenylacetate in pharmacokinetic studies, repeat loading doses of Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% 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 (13.2) ] . 5.6 Hyperventilation and Metabolic Acidosis Due to structural similarities between phenylacetate and benzoate to salicylate, Sodium Phenylacetate and Sodium Benzoate Injection, 10%/10% may cause side effects typically associated with salicylate overdose, such as hyperventilation and metabolic acidosis. Monitoring of blood chemistry profiles, blood pH and pCO 2 should be performed.