Ammonul

Overdosage has been reported during AMMONUL treatment in urea cycle-deficient patients. All patients in the uncontrolled open-label study were to be treated with the same dose of AMMONUL. 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 AMMONUL. 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 AMMONUL, 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).

In the U.S.

• Ammonul

Available Dosage Forms:

• Solution

Therapeutic Class: Hyperammonemia Agent

Sodium phenylacetate and benzoate injection combination is used to treat hyperammonemia, which is a condition where there is too much ammonia in the blood. Ammonia is formed from the breakdown of protein in the body. If the ammonia cannot be removed by the body, high amounts in the blood may cause serious unwanted effects. This medicine works to reduce the amount of ammonia in the blood.

This medicine is to be given only by or under the direct supervision of a doctor.

A nurse or other trained health professional will give you or your child this medicine in a hospital. This medicine is given through a needle placed in one of your veins.

Your doctor will give you or your child a few doses of this medicine until your condition improves, and then switch you to an oral medicine that works the same way. If you have any concerns about this, talk to your doctor.

It is also important that you follow any special diet instructions from your doctor, such as using a low protein diet. If you have any questions about this, check with your doctor.

Ammonul (sodium phenylacetate and sodium benzoate) Injection 10% per 10% (a nitrogen binding agent), is a sterile, concentrated, aqueous solution of sodium phenylacetate and sodium benzoate. The pH of the solution is between 6 and 8. Sodium phenylacetate is a crystalline, white to off-white powder with a strong, offensive odor. It is soluble in water. Sodium benzoate is a white and odorless, crystalline powder that is readily soluble in water.

Figure 1

Sodium phenylacetate has a molecular weight of 158.13 and the molecular formula C8H7NaO2. Sodium benzoate has a molecular weight of 144.11 and the molecular formula C7H5NaO2.

Each mL of Ammonul contains 100 mg of sodium phenylacetate and 100 mg of sodium benzoate, and Water for Injection. Sodium hydroxide and/or hydrochloric acid may have been used for pH adjustment.

Ammonul injection is a sterile, concentrated solution intended for intravenous administration via a central line only after dilution [see Dosage and Administration (2)].

Mechanism of Action

Urea cycle disorders can result from decreased activity of any of the following enzymes: N-acetylglutamate 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 2 is a schematic illustrating how the components of Ammonul, 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 2

CPS = carbamyl phosphate synthetase;
OTC = ornithine transcarbamylase;
ASS = argininosuccinate synthetase;
ASL = argininosuccinate lyase;
ARG = arginase;
NAGS = N-acetylglutamate synthetase

Pharmacodynamics

In patients with hyperammonemia due to deficiencies in enzymes of the urea cycle, Ammonul 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 Ammonul in combination with appropriate dietary and other supportive measures.

Pharmacokinetics

The pharmacokinetics of intravenously administered Ammonul was characterized in healthy adult volunteers. Both benzoate and phenylacetate exhibited nonlinear kinetics. Following 90 minute intravenous infusion mean AUClast 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. AUClast was 175.6, 713.8, 2040.6, 2181.6, and 3829.2 mcg∙h/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 mcg∙h/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 (Tmax of 2 hr at 3.75 g/m2) whereas, benzoate concentrations declined rapidly (Tmax 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 Ammonul 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 Ammonul. Studies to evaluate the possible impairment of fertility or mutagenic potential of Ammonul 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.

Ammonul (sodium phenylacetate and sodium benzoate) Injection 10% per 10% is supplied in a single use glass vial.

NDC 0187-0010-50 single use vial containing 50 mL of sodium phenylacetate and sodium benzoate injection 10% per 10%.

Storage: Store at 25°C (77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).

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 AMMONUL 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%).

Table 2: Adverse Reactions Occurring in ≥ 3% of Patients Treated with AMMONUL

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 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, pruritis generalized, rash, urticaria

VASCULAR DISORDERS: flushing, hemorrhage, hypertension, phlebothrombosis/thrombosis

Read the entire FDA prescribing information for Ammonul (Sodium Phenylacetate and Sodium Benzoate Injection)

Yourdoctor should check your progress at regular visits to make sure that thismedicine is working properly.

Fixed combination of 2 ammonia detoxicants.1

Contraindications

• Known hypersensitivity to sodium phenylacetate or sodium benzoate or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Risk of rapid brain damage or death if acute symptomatic hyperammonemia is left uncontrolled; treat as a life-threatening emergency.1 7 Prompt use of all therapies to reduce serum ammonia concentrations (e.g., dialysis [preferably hemodialysis]) is essential.1 3 4 6 7 (See Acute Hyperammonemia under Uses.)

Manage hyperammonemia due to inborn errors of metabolism in coordination with medical personnel familiar with such conditions; usually requires health-care facilities able to provide multidisciplinary treatment (e.g., hemodialysis, nutritional management, medical support).1 3

Closely monitor plasma ammonia concentrations, neurologic status, laboratory tests, and clinical response during treatment.1

Monitor serum electrolyte concentrations; maintain within the normal range.1

Urinary loss of potassium is enhanced by excretion of nonabsorbable anions phenylacetylglutamine and hippurate; carefully monitor plasma potassium concentrations and provide replacement therapy, when necessary.1 6

Perform blood chemistry profiles and frequent blood pH and blood gases (e.g., pCO2) evaluations to check for salicylate-like toxicity.1 (See Salicylate-like Toxicity under Cautions.)

The Urea Cycle Disorders Conference Group and some experts recommend monitoring plasma concentrations of ammonia scavenging drugs (e.g., sodium phenylacetate and sodium benzoate) to avoid toxicity.6 Weigh the risk of overdosage against potential benefits of repeating a loading dose in the absence of facilities for drug concentration monitoring.4 (See Repeat Loading Doses under Dosage and Administration and also see Repeat Loading Doses under Cautions.)

Experts recommend double-checking the accuracy of prescription orders to avoid possible overdosage.4

Particulate matter has been detected in sodium phenylacetate and sodium benzoate injections.9 Particulates may notbe readily observed on visual inspection.9 Because these particulates could potentially affect injection safety, always use the Millex Durapore GV 33-mm sterile syringe filter (0.22 µm) provided by the manufacturer when diluting the injection (see Dilution under Dosage and Administration).9 Removal of these particulates by this filter has been confirmed.9

Report any quality problems or suspected adverse effects to the manufacturer (800-900-6389) or the FDA MedWatch program.9

For addditional information, see [Web] or [Web].9

Do not administer injection concentrate undiluted; only administer via a central line.1 Peripheral venous administration may cause burns.1

Extravasation into perivenous tissue may lead to skin necrosis.1 Carefully monitor the infusion site during infusion.1 If extravasation is suspected, discontinue the infusion and resume at a different site, if necessary.1 Treatment for extravasation may include aspiration of residual drug from the catheter, limb elevation, and intermittent cooling with cold packs.1

Each g of sodium phenylacetate provides 6.3 mEq (145 mg) of sodium, and each g of sodium benzoate provides 7 mEq (160 mg) of sodium; each mL of injection concentrate labeled as containing 100 mg each of sodium phenylacetate and sodium benzoate provides 1.33 mEq (30.5 mg) of sodium.1 7

Consider sodium content and use with caution, if at all, in patients with CHF, severe renal impairment, or sodium retention with edema.1 If adverse effects associated with increased sodium concentrations occur, discontinue the drug, promptly evaluate the patient, and take appropriate measures.1

Structurally similar to salicylate; possibility of adverse effects (e.g., hyperventilation, metabolic acidosis) typically associated with acute salicylate toxicity.1 2 (See Laboratory Monitoring under Cautions.)

Major Toxicities

Adverse neurotoxic effects (e.g., somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, exacerbation of existing neuropathy) reported in cancer patients receiving IV phenylacetate.1 Acute onset (mainly mild) occurred upon initiation of therapy; reversible upon discontinuance of the drug.1

General Precautions

The manufacturer states that, because plasma concentrations of phenylacetate are prolonged, do not repeat loading doses.1 However, some experts state that a repeat loading dose within 24 hours should be considered only in neonates with severe disorders and/or those receiving dialysis; space loading doses at least 6 hours apart.3 4 (See Repeat Loading Doses under Dosage and Administration and see Laboratory Monitoring under Cautions.)

Risk of indirect hyperbilirubinemia.7 Use with caution in neonates with hyperbilirubinemia.7 In infants at risk, reduce serum bilirubin concentrations to normal range before initiating therapy with sodium phenylacetate and sodium benzoate.7

Manufacturer states drug is complementary with dialysis (e.g., standard hemodialysis, peritoneal dialysis, arteriovenous hemofiltration).1

Specific Populations

Category C.1

Not known whether sodium phenylacetate or sodium benzoate or their conjugated metabolites are distributed into milk.1 Use with caution in nursing women.1

Efficacy is established for treatment of hyperammonemia in pediatric patients 0–16 years of age, including neonates (0–30 days of age) and infants (31 days–2 years of age).1

Use with caution in neonates with hyperbilirubinemia.7 (See Hyperbilirubinemia under Cautions.)

Use with caution in patients with hepatic impairment.1 (See Metabolism under Pharmacokinetics.)

Use with caution and carefully monitor patients with renal impairment.1 (See Elimination under Pharmacokinetics.)

Common Adverse Effects

Vomiting, hyperglycemia, hypokalemia, seizures, mental impairment.1