Sodium Phenylacetate and Sodium Benzoate (Page 2 of 5)
Arginine Administration
Intravenous arginine is an essential component of therapy for patients with carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) deficiency. Because hyperchloremic acidosis may develop after high-dose arginine hydrochloride administration, chloride and bicarbonate levels should be monitored and appropriate amounts of bicarbonate administered.
In hyperammonemic infants with suspected, but unconfirmed urea cycle disorders, intravenous arginine should be given (6 mL/kg of Arginine HCl Injection 10%, over 90 minutes followed by the same dose given as a maintenance infusion over 24 hours). If deficiencies of ASS or ASL are excluded as diagnostic possibilities, the intravenous dose of Arginine HCl should be reduced to 2 mL/kg/day Arginine HCl Injection 10%.
Converting to Oral Treatment
Once elevated ammonia levels have been reduced to the normal range, oral therapy, such as sodium phenylbutyrate, dietary management and maintenance protein restrictions should be started or reinitiated.
3 DOSAGE FORMS AND STRENGTHS
Sodium Phenylacetate and Sodium Benzoate Injection, 10% per 10%, for intravenous use, is a sterile, concentrated, aqueous solution of sodium phenylacetate and sodium benzoate.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 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.
5.2 Conditions Associated with Fluid Overload
Sodium phenylacetate and sodium benzoate injection contains 30.5 mg of sodium per mL of undiluted product. Thus, sodium phenylacetate and sodium benzoate injection 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, evaluate the patient, and institute appropriate therapeutic countermeasures if an adverse event occurs.
5.3 Extravasation
Administration must be through a central venous catheter. 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 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.
5.4 Neurotoxicity of Phenylacetate
Because of prolonged plasma levels achieved by phenylacetate in pharmacokinetic studies, repeat loading doses of sodium phenylacetate and sodium benzoate injection 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 [s ee Animal Toxicology and/or Pharmacology (13.2) ].
5.5 Hyperventilation and Metabolic Acidosis
Due to structural similarities between phenylacetate and benzoate to salicylate, sodium phenylacetate and sodium benzoate injection 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.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety data were obtained from 316 patients who received sodium phenylacetate and sodium benzoate injection as emergency (rescue) or prospective treatment for hyperammonemia as part of an uncontrolled, open-label study. The study population included patients between the ages of 0 to 53 years with a mean (SD) of 6.2 (8.54) years; 51% were male and 49% were female who had the following diagnoses: OTC (46%), ASS (22%), CPS (12%), ASL (2%), ARG (< 1%), THN (< 1%), and other (18%).
Adverse reactions were reported with similar frequency in patients with OTC, ASS, CPS, and diagnoses categorized as “other.” Nervous system disorders were more frequent in patients with OTC and CPS, compared with patients with ASS and patients with “other” diagnoses. Convulsions and mental impairment were reported in patients with OTC and CPS. These observations are consistent with literature reports that patients with enzyme deficiencies occurring earlier in the urea cycle (i.e., OTC and CPS) tend to be more severely affected.
Adverse reactions profiles differed by age group. Patients ≤ 30 days of age had more blood and lymphatic system disorders and vascular disorders (specifically hypotension), while patients > 30 days of age had more gastrointestinal disorders (specifically nausea, vomiting and diarrhea).
Less common adverse reactions (< 3% of patients) that are characterized as severe are listed below by body system.
Blood and Lymphatic System Disorders: coagulopathy, pancytopenia, thrombocytopenia
Cardiac Disorders: atrial rupture, bradycardia, cardiac or cardiopulmonary arrest/failure, cardiogenic shock, cardiomyopathy, pericardial effusion
Eye Disorders: blindness
Gastrointestinal Disorders: abdominal distension, gastrointestinal hemorrhage
General Disorders and Administration-Site Conditions: asthenia, brain death, chest pain, multiorgan failure, edema
Hepatobiliary Disorders: cholestasis, hepatic artery stenosis, hepatic failure/hepatotoxicity, jaundice
Infections and Infestations: sepsis/septic shock
Injury, Poisoning and Procedural Complications: brain herniation, subdural hematoma, overdose
Investigations: blood carbon dioxide changes, blood glucose changes, blood pH increased, cardiac output decreased, pCO 2 changes, respiratory rate increased
Metabolism and Nutrition Disorders: alkalosis, dehydration, fluid overload/retention, hypoglycemia, hyperkalemia, hypernatremia, alkalosis, tetany
Neoplasms Benign, Malignant and Unspecified: hemangioma acquired
Nervous System Disorders: areflexia, ataxia, brain infarction, brain hemorrhage, cerebral atrophy, clonus, depressed level of consciousness, encephalopathy, nerve paralysis, intracranial pressure increased, subdural hematoma, tremor
Psychiatric Disorders: acute psychosis, aggression, confusional state, hallucinations
Renal and Urinary Disorders: anuria, renal failure, urinary retention
Respiratory, Thoracic and Mediastinal Disorders: acute respiratory distress syndrome, dyspnea, hypercapnia, hyperventilation, Kussmaul respiration, pneumonia aspiration, pneumothorax, pulmonary hemorrhage, pulmonary edema, respiratory acidosis or alkalosis, respiratory arrest/failure
Skin and Subcutaneous Tissue Disorders: alopecia, blister, pruritus generalized, rash, urticaria
Vascular Disorders: flushing, hemorrhage, hypertension, phlebothrombosis/thrombosis
Patients N = 316 | |
Number of patients with any adverse event | 163 (52%) |
Blood and lymphatic system disorders | 35 (11%) |
Anemia | 12 (4%) |
Disseminated intravascular coagulation | 11 (3%) |
Cardiac disorders | 28 (9%) |
Gastrointestinal disorders | 42 (13%) |
Diarrhea | 10 (3%) |
Nausea | 9 (3%) |
Vomiting | 29 (9%) |
General disorders and administration-site conditions | 45 (14%) |
Injection-site reaction | 11 (3%) |
Pyrexia | 17 (5%) |
Infections | 39 (12%) |
Urinary tract infection | 9 (3%) |
Injury, poisoning and procedural complications | 12 (4%) |
Investigations | 32 (10%) |
Metabolism and nutrition disorders | 67 (21%) |
Acidosis | 8 (3%) |
Hyperammonemia | 17 (5%) |
Hyperglycemia | 22 (7%) |
Hypocalcemia | 8 (3%) |
Hypokalemia | 23 (7%) |
Metabolic acidosis | 13 (4%) |
Nervous system disorders | 71 (22%) |
Brain edema | 17 (5%) |
Coma | 10 (3%) |
Convulsions | 19 (6%) |
Mental impairment | 18 (6%) |
Psychiatric disorders | 16 (5%) |
Agitation | 8 (3%) |
Renal and urinary disorders | 14 (4%) |
Respiratory, thoracic and mediastinal disorders | 47 (15%) |
Respiratory distress | 9 (3%) |
Skin and subcutaneous tissue disorders | 19 (6%) |
Vascular disorders | 19 (6%) |
Hypotension | 14 (4%) |
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.
https://medlibrary.org/lib/rx/meds/sodium-phenylacetate-and-sodium-benzoate-8/page/2/