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

Table 2: Adverse Reactions Occurring in ≥ 3% of Patients Treated with Sodium Phenylacetate and Sodium Benzoate Injection

	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%)