Ammonul

Description

AMMONUL (sodium phenylacetate and sodium benzoate) Injection 10% per 10% is a sterile, concentrated, aqueous solution designed for intravenous administration via a central line after dilution. The solution contains 100 mg of sodium phenylacetate and 100 mg of sodium benzoate per mL, along with Water for Injection. The pH of the solution ranges from 6 to 8.

Sodium phenylacetate is a crystalline, white to off-white powder with a strong, offensive odor and a molecular weight of 158.13, represented by the molecular formula C8H7NaO2. Sodium benzoate, in contrast, is a white, odorless crystalline powder that is readily soluble in water, with a molecular weight of 144.11 and the molecular formula C7H5NaO2. Sodium hydroxide and/or hydrochloric acid may have been utilized for pH adjustment.

Uses and Indications

AMMONUL is indicated as adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle.

There are no teratogenic or nonteratogenic effects associated with AMMONUL.

Dosage and Administration

AMMONUL must be diluted with sterile 10% Dextrose Injection (D10W) prior to administration. It is essential that AMMONUL is administered through a central venous catheter, as administration via a peripheral line may result in burns.

The initial loading dose of AMMONUL should be infused intravenously over a period of 90 to 120 minutes. Following the loading dose, an equivalent maintenance dose should be administered as a continuous infusion over a duration of 24 hours.

Contraindications

There are no contraindications associated with the use of this product. It is not classified as a controlled substance, and there are no identified risks of abuse, misuse, or dependence. Therefore, the product can be used without specific restrictions related to contraindications.

Warnings and Precautions

Management of acute hyperammonemia requires vigilant monitoring of plasma ammonia levels throughout treatment. Prolonged exposure to elevated plasma ammonia can lead to severe neurological injury or death. Therefore, it is imperative to initiate all necessary therapies promptly to reduce plasma ammonia levels.

Careful monitoring of plasma potassium levels is essential, and appropriate treatment should be administered as needed to address any deficiencies.

AMMONUL contains 30.5 mg of sodium per mL of undiluted product. Caution is advised when administering AMMONUL to patients with conditions associated with fluid overload, such as congestive heart failure or severe renal insufficiency, as well as in patients with sodium retention and edema.

Extravasation of AMMONUL into perivenous tissues during high flow bolus infusion poses a risk of skin necrosis, particularly in infants. The infusion site must be closely monitored for signs of tissue infiltration during administration.

Due to the potential for neurotoxicity associated with phenylacetate, which can result from prolonged plasma levels, repeat loading doses should be avoided. Additionally, neurotoxicity has been reported in cancer patients receiving phenylacetate. Healthcare professionals should monitor patients for symptoms indicative of acute neurotoxicity.

AMMONUL may induce side effects similar to those observed in salicylate overdose, including hyperventilation and metabolic acidosis. It is crucial to monitor patient blood chemistry profiles and conduct frequent assessments of blood pH and pCO2 levels to ensure patient safety.

Side Effects

Most frequently reported adverse reactions occurring in patients receiving AMMONUL, with an incidence of 6% or greater, include vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment.

Serious adverse reactions associated with the use of AMMONUL include the management of acute hyperammonemia, as prolonged exposure to elevated plasma ammonia levels can lead to rapid brain injury or death. Patients' plasma potassium levels should be carefully monitored, and appropriate treatment should be administered when necessary to address decreased potassium levels.

Caution is advised when administering AMMONUL to patients with congestive heart failure, severe renal insufficiency, or conditions associated with sodium retention and edema, as these may lead to fluid overload. Additionally, extravasation of AMMONUL into perivenous tissues during high flow bolus infusion has been reported to cause skin necrosis, particularly in infants; therefore, the infusion site must be closely monitored for potential tissue infiltration during administration.

Neurotoxicity related to phenylacetate has been observed in cancer patients, necessitating careful monitoring for symptoms of acute neurotoxicity. AMMONUL may also induce side effects typically associated with salicylate overdose, such as hyperventilation and metabolic acidosis; thus, it is important to monitor patients' blood chemistry profiles and perform frequent measurements of blood pH and pCO2.

Overdosage of AMMONUL has been reported in urea cycle-deficient patients, with causes of death including cardiorespiratory failure or arrest (6 patients), hyperammonemia (3 patients), increased intracranial pressure (2 patients), and other serious conditions. Signs of intoxication may manifest as obtundation (in the absence of hyperammonemia), hyperventilation, severe compensated metabolic acidosis, large anion gap, hypernatremia, hyperosmolarity, progressive encephalopathy, cardiovascular collapse, and death.

Drug Interactions

The use of certain antibiotics, particularly penicillin, may influence the overall disposition of the infused drug, potentially altering its therapeutic effectiveness.

Probenecid has been shown to impact the renal excretion of phenylacetylglutamine and hippurate, which may necessitate monitoring of these metabolites in patients receiving both agents.

In patients with urea cycle disorders, the administration of valproic acid may exacerbate their condition. This is due to its potential to antagonize the efficacy of AMMONUL by inhibiting the synthesis of N-acetylglutamate, a critical co-factor for carbamyl phosphate synthetase. Caution is advised when considering valproic acid in this patient population.

Corticosteroids may lead to the breakdown of body protein, which can result in increased plasma ammonia levels, particularly in patients with a compromised ability to form urea. Monitoring of ammonia levels is recommended in these patients to prevent potential complications.

Packaging & NDC

The table below lists all NDC Code configurations of Ammonul (sodium phenylacetate and sodium benzoate), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

AMMONUL has been utilized for the treatment of acute hyperammonemia in pediatric patients, including those in the early neonatal period. Clinical experience supports its use in this population, although specific dosage adjustments may be necessary based on the age and clinical condition of the patient. Healthcare professionals should exercise caution and closely monitor these patients due to the unique pharmacokinetic and pharmacodynamic profiles observed in infants and young children.

Geriatric Use

Clinical studies of AMMONUL did not include any patients aged 65 and over, and therefore, it is not known whether elderly patients respond differently from younger patients. Urea cycle disorders primarily affect pediatric and younger adult populations, and as such, there is a lack of pharmacokinetic studies specifically conducted in geriatric patients.

In general, dose selection for elderly patients should be approached with caution. It is advisable to start at the low end of the dosing range, taking into account the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in this demographic. Careful monitoring is recommended to ensure safety and efficacy in this population.

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with AMMONUL. It is not known whether AMMONUL can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. Therefore, AMMONUL should be administered to pregnant patients only if clearly needed, weighing the potential benefits against the risks.

Lactation

It is not known whether sodium phenylacetate, sodium benzoate, or their conjugation products are excreted in human milk. Due to the potential for many drugs to be excreted in human milk, caution should be exercised when AMMONUL is administered to lactating mothers.

Renal Impairment

Caution should be exercised when administering AMMONUL to patients with severe renal insufficiency or conditions associated with sodium retention and edema. Monitoring of renal function is recommended in these patients to ensure safety and efficacy. Dosing adjustments may be necessary based on the degree of renal impairment.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdosage has been documented in patients undergoing treatment with AMMONUL, particularly among those with urea cycle deficiencies. In an uncontrolled open-label study, all participants were intended to receive a uniform dose of AMMONUL; however, deviations occurred, resulting in some patients receiving doses exceeding the protocol specifications.

Among the reported fatalities, 16 out of 64 deaths were associated with known overdoses of AMMONUL. The causes of death in these cases were varied and included cardiorespiratory failure or arrest (6 patients), hyperammonemia (3 patients), increased intracranial pressure (2 patients), and other complications such as pneumonitis with septic shock and coagulopathy (1 patient), error in dialysis procedure (1 patient), respiratory failure (1 patient), intractable hypotension with probable sepsis (1 patient), and one case with an unknown cause.

Signs of intoxication may manifest as obtundation (notably in the absence of hyperammonemia), hyperventilation, severe compensated metabolic acidosis potentially accompanied by a respiratory component, large anion gap, hypernatremia, hyperosmolarity, progressive encephalopathy, cardiovascular collapse, and ultimately, death.

In the event of an AMMONUL overdose, it is imperative to discontinue the medication immediately and initiate appropriate emergency medical monitoring and interventions. In severe cases, the preferred management strategy is hemodialysis; however, peritoneal dialysis may be considered if hemodialysis is not available.

Nonclinical Toxicology

Animal reproduction studies have not been conducted with AMMONUL, and it is classified as Pregnancy Category C. Therefore, it is not known whether AMMONUL can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. AMMONUL should be administered to pregnant women only if clearly needed.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of AMMONUL. Additionally, studies to assess the possible impairment of fertility or mutagenic potential of AMMONUL have not been conducted.

In animal studies, subcutaneous administration of phenylacetate to rat pups at doses ranging from 190 to 474 mg/kg resulted in decreased proliferation and increased loss of neurons, as well as reduced central nervous system myelin. The maturation of cerebral synapses was retarded, and the number of functioning nerve terminals in the cerebrum was diminished, leading to impaired brain growth. Pregnant rats received phenylacetate at a dose of 3.5 µmol/g/day subcutaneously from gestation day 7 through normal delivery. Prenatal exposure of rat pups to phenylacetate resulted in lesions in layer 5 cortical pyramidal cells, characterized by longer and thinner dendritic spines than normal, along with a reduced number of these spines.

Results indicate that sodium benzoate is not mutagenic or carcinogenic and does not impair fertility.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions reported voluntarily or through surveillance programs. The most frequently observed adverse reactions include vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment. These events have been documented in the context of postmarketing surveillance, contributing to the overall understanding of the product's safety profile.

Patient Counseling

Healthcare providers should advise patients and caregivers regarding the safe use of AMMONUL. It is important to inform them that once plasma ammonia levels have normalized, dietary protein intake can typically be increased, with the ultimate goal of achieving unrestricted protein intake.

Providers should exercise caution when administering AMMONUL to nursing women, ensuring that the potential risks and benefits are thoroughly discussed.

Patients should be made aware of the most common adverse reactions associated with AMMONUL, which include vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment.

Additionally, it is essential to communicate that BUPHENYL is generally discontinued during the period when AMMONUL is being used, and patients should be counseled on the importance of adhering to this recommendation.

Storage and Handling

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

This product should be stored at a temperature of 25°C (77°F), with permissible excursions between 15° to 30°C (59° to 86°F). Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Ongoing monitoring of plasma ammonia levels, neurological status, laboratory tests, and clinical response is essential for patients receiving AMMONUL to evaluate their response to treatment. Administration of AMMONUL must occur through a central line, as peripheral line administration may result in burns. Clinicians should ensure that bolus infusion flow rates are appropriately high, particularly for infants, and the product should never be administered undiluted.

In cases where extravasation is suspected, the infusion should be discontinued, and a different site may be used if necessary. Close monitoring of the infusion site for potential infiltration is recommended during administration. Postmarketing experience has indicated that neurotoxicity can occur in cancer patients receiving intravenous phenylacetate at doses of 250–300 mg/kg/day for 14 days, with symptoms such as somnolence, fatigue, and lightheadedness being most common. Other less frequent symptoms include headaches, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of pre-existing neuropathy. The acute onset of these symptoms upon treatment initiation and their reversibility upon discontinuation of phenylacetate suggest a drug-related effect.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Ammonul as submitted by Ucyclyd Pharma Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)