Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% is indicated as adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle. During acute hyperammonemic episodes, arginine supplementation, caloric supplementation, dietary protein restriction, hemodialysis, and other ammonia lowering therapies should be considered. 

Posology

Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% must be diluted with sterile 10%

Dextrose Injection (D10W) before administration. The dilution and dosage of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% are determined by weight for neonates, infants and young children, and by body surface area for larger patients, including older children, adolescents, and adults (Table 1).

Table 1: Dosage and Administration

Abbreviations: CPS - carbamyl phosphate synthetase; OTC - ornithine transcarbamylase; ASS - argininosuccinate synthetase; ASL - argininosuccinate lyase

Special populations  

Pediatric Use 

Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% has been used as a treatment for acute hyperammonemia in pediatric patients including patients in the early neonatal period [Posology and method of administration 4.2]. 

Geriatric Use 

Clinical studies of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% 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 Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% 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. 

Gender 

Pharmacokinetic parameters of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% 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. 

Hepatic Insufficiency 

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 Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% to patients with hepatic insufficiency. 

Renal Impairment 

The drug metabolites of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%

(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 Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%.

Method of administration

Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% is a concentrated solution and must be diluted before intravenous administration via a central venous catheter. Administration through a peripheral intravenous catheter may cause burns. Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% may not be administered by any other route. 

Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% should be administered as a loading dose infusion over 90 to 120 minutes, followed by the same dose repeated as a maintenance infusion administered over 24 hours. 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. Maintenance infusions may be continued until elevated plasma ammonia levels have been normalized or the patient can tolerate oral nutrition and medications. An antiemetic may be administered during Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% infusion to aid control of infusion-associated nausea and vomiting. Administration of analogous oral drugs, such as sodium phenylbutyrate, should be terminated prior to Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% infusion. 

Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% infusion should be started as soon as the diagnosis of hyperammonemia is made. Treatment of hyperammonemia also requires caloric supplementation and restriction of dietary protein. Non-protein calories should be supplied principally as glucose (8–10 mg/kg/min) with an intravenous fat emulsion added. Attempts should be made to maintain a caloric intake of greater than 80 kcal/kg/day. During and after infusion of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%, ongoing monitoring of the following clinical laboratory values is crucial: plasma ammonia, glutamine, quantitative plasma amino acids, blood glucose, electrolytes, venous or arterial blood gases, AST and ALT. On-going monitoring of the following clinical responses is also crucial to assess patient response to treatment: neurological status, Glasgow Coma Scale, tachypnea, CT or MRI scan or fundoscopic evidence of cerebral edema, and/or of gray matter and white matter damage. Hemodialysis should be considered in patients with severe hyperammonemia or who are not responsive to Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% administration [see Warnings and Precautions 4.4]. In the non-neonatal study patient population treated with Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%, dialysis was required in 13% of hyperammonemic episodes. Standard hemodialysis was the most frequently used dialysis method. High levels of ammonia can be reduced quickly when Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% is used with hemodialysis, as the ammonia-scavenging of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% suppresses the production of ammonia from catabolism of endogenous protein and hemodialysis eliminates the ammonia and ammonia conjugates. 

Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% solutions are physically and chemically stable for up to 24 hours at room temperature and room lighting conditions. No compatibility information is presently available for Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% infusion solutions except for Arginine HCl Injection, 10%, which may be mixed in the same container as Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%. Other infusion solutions and drug products should not be administered together with Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% infusion solution. Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% solutions may be prepared in glass and PVC containers.

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 highdose 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.

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  

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. 

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 [Posology and method of administration 4.2]. 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. 

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 5.3] 

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 pCO₂ should be performed. 

Effect of Benzoic acid

Sodium Phenylacetate and Sodium Benzoate injection contains Benzoic acid which may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% contains up to 30.504 mg/mL sodium per vial, equivalent to 1.525% of the WHO recommended maximum daily intake for sodium.

Formal drug interaction studies have not been performed with Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%. 

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. 

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. Therefore, administration of valproic acid to patients with urea cycle disorders may exacerbate their condition and antagonize the efficacy of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%. 

Use of corticosteroids may cause a protein catabolic state and, thereby, potentially increase plasma ammonia levels in patients with impaired ability to form urea. 

Pregnancy

Pregnancy Category C

Risk Summary  

Available data with Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%. 

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4%, and 15 to 20%, respectively. 

Breastfeeding Risk Summary 

There are no data on the presence of sodium phenylacetate, sodium benzoate in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% and any potential adverse effects on the breastfed infant from Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% or from the underlying maternal condition.

Fertility

Studies to evaluate the possible impairment of fertility or mutagenic potential of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% have not been performed. Results indicate that sodium benzoate is not mutagenic or carcinogenic, and does not impair fertility. 

No studies on the effects on the ability to drive and use machines have been performed.

a. Summary of the safety profile

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 10% / 10% 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%). 

b. Tabulated summary of adverse reactions

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. 

c. Description of selected adverse reactions

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. 

Table 2: Adverse Reactions Occurring in ≥ 3% of Patients Treated with Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%

d. Pediatric Population

Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% has been used as a treatment for acute hyperammonemia in pediatric patients including patients in the early neonatal period [Posology and method of administration 4.2]. 

e. Other special population(s) Geriatric Use 

Clinical studies of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% 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 Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% 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. 

Gender 

Pharmacokinetic parameters of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% 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. 

Hepatic Insufficiency 

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 Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% to patients with hepatic insufficiency. 

Renal Impairment 

The drug metabolites of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%

(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 Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%.

To report any side effect(s): 

Saudi Arabia

•  The National Pharmacovigilance Centre (NPC)

•  •SFDA Call Center: 19999

•  E-mail: npc.drug@sfda.gov.sa

•  Website: https://ade.sfda.gov.sa/

Other GCC states /other countries

-Please contact the relevant competent authority

Overdosage has been reported during Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% treatment in urea cycle-deficient patients. All patients in the uncontrolled open-label study were to be treated with the same dose of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%. However, some patients received more than the dose level specified in the protocol. In 16 of the 64 deaths, the patient received a known overdose of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%. Causes of death in these patients included cardiorespiratory failure/arrest (6 patients), hyperammonemia (3 patients), increased intracranial pressure (2 patients), pneumonitis with septic shock and coagulopathy (1 patient), error in dialysis procedure (1 patient), respiratory failure (1 patient), intractable hypotension and probable sepsis (1 patient), and unknown (1 patient). Additionally, other signs of intoxication may include obtundation (in the absence of hyperammonemia), hyperventilation, a severe compensated metabolic acidosis, perhaps with a respiratory component, large anion gap, hypernatremia and hyperosmolarity, progressive encephalopathy, cardiovascular collapse, and death.  In case of overdose of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%, discontinue the drug and institute appropriate emergency medical monitoring and procedures. In severe cases, the latter may include hemodialysis (procedure of choice) or peritoneal dialysis (when hemodialysis is unavailable). 

Pharmacotherapeutic group: Various alimentary tract and metabolism products, ATC code: A16AX30

Pharmacodynamics

In patients with hyperammonemia due to deficiencies in enzymes of the urea cycle, Sodium

Phenylacetate and Sodium Benzoate Injection 10% / 10% has been shown to decrease elevated plasma ammonia levels. These effects are considered to be the result of reduction in nitrogen overload through glutamine and glycine scavenging by Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% in combination with appropriate dietary and other supportive measures. 

Mechanism of action

Urea cycle disorders can result from decreased activity of any of the following enzymes: Nacetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), argininosuccinate lyase (ASL), or arginase (ARG). 

Sodium phenylacetate and sodium benzoate are metabolically active compounds that can serve as alternatives to urea for the excretion of waste nitrogen. Figure 1 is a schematic illustrating how the components of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%, phenylacetate and benzoate, provide an alternative pathway for nitrogen disposal in patients without a fully functioning urea cycle. Phenylacetate conjugates with glutamine in the liver and kidneys to form phenylacetylglutamine, via acetylation. Phenylacetylglutamine is excreted by the kidneys via glomerular filtration and tubular secretion. The nitrogen content of phenylacetylglutamine per mole is identical to that of urea (both contain two moles of nitrogen). Two moles of nitrogen are removed per mole of phenylacetate when it is conjugated with glutamine. Similarly, preceded by acylation, benzoate conjugates with glycine to form hippuric acid, which is rapidly excreted by the kidneys by glomerular filtration and tubular secretion. One mole of hippuric acid contains one mole of waste nitrogen. Thus, one mole of nitrogen is removed per mole of benzoate when it is conjugated with glycine.

Figure 1

         CPS            = carbamyl phosphate synthetase; 

         OTC           = ornithine transcarbamylase; 

         ASS            = argininosuccinate synthetase; 

         ASL            = argininosuccinate lyase;

         ARG           = arginase;

         NAGS        = N-acetylglutamate synthetase

The pharmacokinetics of intravenously administered Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% was characterized in healthy adult volunteers. Both benzoate and phenylacetate exhibited nonlinear kinetics. Following 90 minute intravenous infusion mean AUC_last for benzoate was

20.3, 114.9, 564.6, 562.8, and 1599.1 mcg/mL following doses of 1, 2, 3.75, 4, and 5.5 g/m², respectively. The total clearance decreased from 5.19 to 3.62 L/h/m² at the 3.75 and 5.5 g/m² doses, respectively. 

Similarly, phenylacetate exhibited nonlinear kinetics following the priming dose regimens. AUC_last was 175.6, 713.8, 2040.6, 2181.6, and 3829.2 mcgh/mL following doses of 1, 2, 3.75, 4, and 5.5 g/m², respectively. The total clearance decreased from 1.82 to 0.89 mcgh/mL with increasing dose (3.75 and 4 g/m², respectively). 

During the sequence of 90 minute priming infusion followed by a 24-hour maintenance infusion, phenylacetate was detected in the plasma at the end of infusion (T_max of 2 hr at 3.75 g/m²) whereas, benzoate concentrations declined rapidly (T_max of 1.5 hr at 3.75 g/m²) and were undetectable at 14 and 26 hours following the 3.75 and 4 g/m² dose, respectively. 

A difference in the metabolic rates for phenylacetate and benzoate was noted. The formation of hippurate from benzoate occurred more rapidly than that of phenylacetylglutamine from phenylacetate, and the rate of elimination for hippurate appeared to be more rapid than that for phenylacetylglutamine.  Pharmacokinetic observations have also been reported from twelve episodes of hyperammonemic encephalopathy in seven children diagnosed (age 3 to 26 months) with urea cycle disorders who had been administered Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% intravenously. These data showed peak plasma levels of phenylacetate and benzoate at approximately the same times as were observed in healthy adults. As in healthy adults, the plasma levels of phenylacetate were higher than benzoate and were present for a longer time. 

The pharmacokinetics of intravenous phenylacetate have been reported following administration to adult patients with advanced solid tumors. The decline in serum phenylacetate concentrations following a loading infusion of 150 mg/kg was consistent with saturable enzyme kinetics. Ninety-nine percent of administered phenylacetate was excreted as phenylacetylglutamine.

Carcinogenesis, Mutagenesis, Impairment of Fertility  

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10%. Studies to evaluate the possible impairment of fertility or mutagenic potential of Sodium Phenylacetate and Sodium Benzoate Injection 10% / 10% have not been performed. Results indicate that sodium benzoate is not mutagenic or carcinogenic, and does not impair fertility. 

Animal Toxicology and/or Pharmacology  

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. Pregnant rats were given phenylacetate at 3.5 μmol/g/day subcutaneously 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. 

Sodium hydroxide, NF

Hydrochloric acid, NF

Sterile water for injection

Not applicable

Store at 25°C (77°F), excursions permitted to 15° to 30°C (59° to 86°F).  Keep out of reach and sight of children.

Sodium phenylacetate and sodium benzoate Injection, 10% / 10%, is supplied in a sterile, nonpyrogenic, single use Type I glass vials closed with rubber stopper and sealed with white aluminium flip-off seal.

Each single dose vial contains 50 mL sodium Phenylacetate and Sodium Benzoate Injection 10% /10%.

Pack size: one vial in one carton.

No special requirements.