2.1 Recommended Dosage

PHEBURANE treatment should be supervised by a healthcare provider experienced in the treatment of urea cycle disorders.

The recommended dosage of PHEBURANE (measured as sodium phenylbutyrate) for patients with urea cycle disorders is:

• Patients weighing less than 20kg: 450 – 600 mg/kg/day of sodium phenylbutyrate orally. Divide the calculated total daily dose into three to six doses. Administer as three to six divided doses and take with food.
• Patients weighing greater than or equal to 20 kg: 9.9 – 13 g/m2/day of sodium phenylbutyrate orally. Divide the calculated total daily dose into three to six doses. Administer as three to six divided doses and take with food.

The maximum dosage is 20 grams per day. Combine PHEBURANE with dietary protein restriction and, in some cases, amino acid supplementation (e.g., essential amino acids, arginine, citrulline, and protein-free calorie supplements).

Measure the dose using only the calibrated spoon provided in the packaging. This calibrated dosing spoon directly measures PHEBURANE oral pellets as sodium phenylbutyrate [see Dosage and Administration (2.4)].

If a dose is missed, take the missed dose as soon as possible. There should be at least 3 hours between two doses and doses should not be doubled to make up for the missed dose.

2.2 Dosage Adjustment and Monitoring

Monitor plasma ammonia levels to determine the need for dosage adjustment. Adjust the PHEBURANE dosage to maintain the plasma ammonia level within the normal range for the patient’s age, taking into consideration their clinical condition (e.g., nutritional requirements, protein intake, growth parameters, etc.).

Monitor patients for potential neurotoxicity and obtain measurements of plasma phenylacetate and phenylacetylglutamine levels [see Warnings and Precautions (5.1), Adverse Reactions (6)]. If neurologic symptoms (e.g. vomiting, nausea, headache, somnolence or confusion) are present in the absence of high ammonia levels or other intercurrent illnesses, consider reducing the dose of PHEBURANE.

2.3 Dosage Adjustment in Patients with Hepatic Impairment

For patients with hepatic impairment, start at the lower end of the recommended dosing range and maintain patients on the lowest dose necessary to control plasma ammonia levels [see Use in Specific Populations (8.7)].

2.4 Administration Instructions

For oral administration only. Administration via gastrostomy or nasogastric tubes has not been evaluated.

1. Schedule PHEBURANE dosages at the same time as food consumption (meal or snack).
2. Use the calibrated dosing spoon to measure PHEBURANE oral pellets. The dosing spoon is directly calibrated in grams of sodium phenylbutyrate.
3. Swallow the coated oral pellets with a drink (e.g., water, fruit juices, protein-free infant formulas) or sprinkle onto spoonful of apple sauce or carrot puree. Do not chew PHEBURANE oral pellets directly or mix into liquids.
4. Swallow immediately to minimize dissolution of coating.

Administration of PHEBURANE oral pellets with other foods has not been studied and is not recommended. Additionally, administration with soft food is only recommended in patients old enough to consume soft foods.

5.1 Neurotoxicity of Phenylacetate

Increased exposure to phenylacetate, the major metabolite of PHEBURANE, may be associated with neurotoxicity in patients with UCDs. In a study of adult cancer patients receiving intravenous phenylacetate, 250-300 mg/kg/day for 14 days, repeated at 4-week intervals, signs and symptoms of neurotoxicity, which were reversible upon discontinuation, were seen at plasma concentrations ≥ 3.5 mmol/L, and included somnolence, fatigue, and light headedness [see Adverse Reactions (6)]. PHEBURANE is not approved for intravenous use or for treatment of patients with cancer.

If symptoms of vomiting, nausea, headache, somnolence or confusion are present in the absence of high ammonia levels or other intercurrent illnesses, consider reducing the dose of PHEBURANE [see Dosage and Administration (2.2)].

Phenylacetate caused neurotoxicity when given subcutaneously in rat pups [see Use in Specific Populations (8.4)].

5.2 Hypokalemia

Renal excretion of phenylacetylglutamine may induce urinary loss of potassium. Monitor serum potassium during therapy and initiate appropriate treatment when necessary.

5.3 Conditions Associated with Edema

PHEBURANE contains 124 mg (5.4 mmol) of sodium per gram of sodium phenylbutyrate, corresponding to 2.5 g (108 mmol) of sodium in the maximum daily dose of 20 g of sodium phenylbutyrate. In order to decide if administration of PHEBURANE is appropriate in patients with diseases that involve edema such as heart failure, cirrhosis, or nephrosis, calculate the total amount of sodium patients will be exposed to based on their weight or body surface area (BSA) [see Dosage and Administration (2.1)]. If a patient develops new-onset edema or worsening edema while on treatment, discontinue administration of PHEBURANE and initiate appropriate therapy.

5.4 Diabetes Mellitus, Hereditary Fructose Intolerance, Glucose-Galactose Malabsorption or Sucrase-Isomaltase Insufficiency

PHEBURANE contains 768 mg of sucrose per gram of sodium phenylbutyrate, corresponding to 15.4 g of sucrose in the maximum daily dose of 20 g of sodium phenylbutyrate. This should be considered in patients with diabetes mellitus. Avoid use of PHEBURANE in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

7.1 Potential for Other Drugs to Affect Ammonia

Corticosteroids

Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels.

Valproic Acid and Haloperidol

Hyperammonemia may be induced by haloperidol and by valproic acid.

Monitor plasma ammonia levels closely when corticosteroids, valproic acid, or haloperidol is used concomitantly with PHEBURANE.

7.2 Potential for Other Drugs to Affect PHEBURANE

Probenecid

Probenecid may inhibit renal excretion of the metabolites of PHEBURANE including phenylacetate and phenylacetylglutamine. Monitor patients for potential neurotoxicity and measure plasma phenylacetate and phenylacetylglutamine levels when probenecid is used concomitantly with PHEBURANE [see Dosage and Administration (2.2)].

8.1 Pregnancy

Risk Summary

Available data with sodium phenylbutyrate 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 phenylbutyrate. Based on published animal data, phenylacetate may be neurotoxic to the developing brain (see Data).

There are serious risks to the mother and fetus associated with untreated urea cycle disorders during pregnancy which can result in serious morbidity and mortality to the mother and fetus (see Clinical Considerations).

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.

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnancy is a time of increased metabolic demand which increases the risk for hyperammonemic episodes when metabolic demands are not met. Hyperammonemic episodes in pregnancy are associated with impaired cognition in the mother and an increased risk of maternal and fetal death.

In rats, intrauterine exposure to phenylacetate produced lesions in the neonatal brain in layer 5 of the cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number.

8.2 Lactation

Risk Summary

There are no data on the presence of sodium phenylbutyrate and its metabolite 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 PHEBURANE and any potential adverse effects on the breastfed infant from PHEBURANE or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of PHEBURANE have been established as adjunctive therapy to the standard of care, which includes dietary management, in the chronic management of pediatric patients with urea cycle disorders (UCDs), involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC) or argininosuccinic acid synthetase (AS).

PHEBURANE is not indicated for the treatment of acute hyperammonemia, which can be a life-threatening medical emergency that requires rapid acting interventions to reduce plasma ammonia levels.

The sodium content of PHEBURANE has the potential to cause new-onset edema or worsening edema from salt and water retention, particularly in patients with underlying predisposing conditions [see Warnings and Precautions (5.3)].

Neurotoxicity has been observed in juvenile animals with phenylacetate exposure [see Warnings and Precautions (5.1)].

Juvenile Animal Toxicity Data

When given subcutaneously to rat pups, 190–474 mg/kg phenylacetate caused decreased proliferation and increased loss of neurons, and it reduced 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.

8.5 Geriatric Use

Clinical studies of PHEBURANE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger 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 of concomitant disease or other drug therapy.

8.6 Renal Impairment

No studies with PHEBURANE were conducted in subjects with renal impairment. Monitor plasma ammonia levels when starting patients with impaired renal function on PHEBURANE [see Clinical Pharmacology (12)].

8.7 Hepatic Impairment

No studies with PHEBURANE were conducted in subjects with hepatic impairment. Start at the lower end of the recommended dosing range and maintain patients with hepatic impairment on the lowest dose necessary to control plasma ammonia levels [see Clinical Pharmacology (12.3), Dosage and Administration (2.3)].

12.1 Mechanism of Action

Sodium phenylbutyrate is a pro-drug and is metabolized to phenylacetate. Phenylacetate is a metabolically-active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine. Phenylacetylglutamine is excreted by the kidneys, hence providing an alternate vehicle for waste nitrogen excretion.

12.2 Pharmacodynamics

In patients with urea cycle disorders, sodium phenylbutyrate decreased elevated plasma ammonia and glutamine levels.

12.3 Pharmacokinetics

The pharmacokinetics of phenylbutyrate and its metabolite phenylacetate were characterized in healthy adult subjects following a single oral administration of PHEBURANE (3 g of sodium phenylbutyrate) under fasted and fed conditions.

Absorption

Under fasted condition, the mean (SD) maximum plasma concentration (Cmax) of phenylbutyrate ranged from 146 (30) to 169 (33) μg/mL, which was achieved at approximately 0.6 hour after PHEBURANE administration. The mean (SD) area under the plasma concentration-time curve (AUC) of phenylbutyrate ranged from 272 (78) to 283 (68) h*μg/mL.

Effect of Food

Compared to fasted condition, AUC of phenylbutyrate decreased by 40-45% and Cmax of phenylbutyrate decreased by 55%, when PHEBURANE was administered with a high-fat, high-calorie meal (total 800 to 1000 calories with approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively). When PHEBURANE was administered with a normal-fat, normal-calorie, low-protein meal (total 600 to 700 calories with approximately 60, 200, and 400 calories from protein, fat, and carbohydrate, respectively), AUC of phenylbutyrate decreased by 56-63% and Cmax decreased by 43-45% compared to fasted condition.

Elimination

The mean half-life of phenylbutyrate ranged from 0.5 to 0.8 hour.

Metabolism

Following oral administration, sodium phenylbutyrate is metabolized by β-oxidation into phenylacetate, which is converted to its coenzyme A ester, phenylacetyl-coenzyme A and further conjugated with glutamine to form phenylacetylglutamine. Phenylacetylglutamine is excreted by the kidneys. The major sites for metabolism of sodium phenylbutyrate are the liver and kidneys. Phenylacetate is also hydrolysed by esterases in liver and blood.

Excretion

Approximately 80–100% of sodium phenylbutyrate is excreted by the kidneys within 24 hours as phenylacetylglutamine. For each gram of sodium phenylbutyrate administered, it is estimated that between 0.12–0.15 grams of phenylacetylglutamine nitrogen are produced.

Specific Populations

Patients with Renal Impairment or Hepatic Impairment

PHEBURANE has not been studied in patients with renal impairment or in patients with hepatic impairment.

Drug Interaction Studies

In vitro or clinical studies with PHEBURANE for determination of potential drug-drug interaction have not been conducted.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies of sodium phenylbutyrate have not been conducted.