Sodium Phenylbutyrate

SODIUM PHENYLBUTYRATE- sodium phenylbutyrate tablet
Par Pharmaceutical, Inc.

DESCRIPTION

Sodium Phenylbutyrate Tablets for oral administration contain Sodium phenylbutyrate, USP. Sodium Phenylbutyrate, USP is an off-white crystalline substance which is soluble in water and has a strong salty taste. Sodium Phenylbutyrate, USP also is freely soluble in methanol and practically insoluble in acetone and diethyl ether. It is known chemically as 4-phenylbutyric acid, sodium salt with a molecular weight of 186 and the molecular formula C10 H11 O2 Na.

Chemical Structure:
sodium-phenyl

Each tablet of Sodium Phenylbutyrate Tablets contains 500 mg of Sodium Phenylbutyrate, USP and the inactive ingredients calcium stearate NF, colloidal silicon dioxide NF, magnesium stearate and microcrystalline cellulose.

CLINICAL PHARMACOLOGY

Sodium phenylbutyrate is a pro-drug and is rapidly metabolized to phenylacetate. Phenylacetate is a metabolically-active compound that conjugates with glutamine via acetylation to form phenylacetylglutamine. Phenylacetylglutamine then is excreted by the kidneys. On a molar basis, it is comparable to urea (each containing two moles of nitrogen). Therefore, phenylacetylglutamine provides an alternate vehicle for waste nitrogen excretion.

PHARMACOKINETICS

General:

Pharmacokinetic studies have not been conducted in the primary patient population (neonates, infants, and children), but pharmacokinetic data were obtained from normal adult subjects.

Absorption:

Peak plasma levels of phenylbutyrate occur within 1 hour after a single dose of 5 grams of sodium phenylbutyrate tablet with a Cmax of 218 mcg/mL under fasting conditions. The effect of food on phenylbutyrate’s absorption is unknown.

Disposition:

The overall disposition of sodium phenylbutyrate and its metabolites has not been characterized fully. However, the drug is known to be metabolized to phenylacetate and subsequently to phenylacetylglutamine.

Following oral administration of 5 grams (tablets), measurable plasma levels of phenylbutyrate and phenylacetate were detected 15 and 30 minutes after dosing, respectively, and phenylacetylglutamine was detected shortly thereafter. The pharmacokinetic parameters for phenylbutyrate for Cmax (mcg/mL), Tmax (hours), and elimination half-life (hours) were 218, 1.35, and 0.77, respectively, and for phenylacetate were 48.5, 3.74, and 1.15, respectively.

The major sites for metabolism of sodium phenylbutyrate are the liver and kidney.

Excretion:

A majority of the administered compound (approximately 80 to 100%) was excreted by the kidneys within 24 hours as the conjugation product, phenylacetylglutamine. For each gram of sodium phenylbutyrate administered, it is estimated that between 0.12 to 0.15 grams of phenylacetylglutamine nitrogen are produced.

Pharmacodynamics:

In patients with urea cycle disorders, sodium phenylbutyrate decreases elevated plasma ammonia glutamine levels. It increases waste nitrogen excretion in the form of phenylacetylglutamine.

Special Populations

Gender:

Significant gender differences were found in the pharmacokinetics of phenylbutyrate and phenylacetate, but not for phenylacetylglutamine. The pharmacokinetic parameters (AUC and Cmax ), for both plasma phenylbutyrate and phenylacetate were about 30 to 50 percent greater in females than in males.

Hepatic insufficiency:

In patients who did not have urea cycle disorders but had impaired hepatic function, the metabolism and excretion of sodium phenylbutyrate were not affected. However, this information was obtained from unvalidated, uncontrolled case studies.

INDICATIONS & USAGE

Sodium Phenylbutyrate Tablets is indicated as adjunctive therapy in the chronic management of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). It is indicated in all patients with neonatal-onset deficiency (complete enzymatic deficiency, presenting within the first 28 days of life). It is also indicated in patients with late-onset disease (partial enzymatic deficiency, presenting after the first month of life) who have a history of hyperammonemic encephalopathy. It is important that the diagnosis be made early and treatment initiated immediately to improve survival. Any episode of acute hyperammonemia should be treated as a life-threatening emergency.

Sodium Phenylbutyrate Tablets must be combined with dietary protein restriction and, in some cases, essential amino acid supplementation. (See Nutritional Supplementation subsection of the DOSAGE AND ADMINISTRATION section.)

Previously, neonatal-onset disease was almost universally fatal within the first year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen-free analogs. However, with hemodialysis, use of alternative waste nitrogen excretion pathways (sodium phenylbutyrate, sodium benzoate, and sodium phenylacetate), dietary protein restriction, and, in some cases, essential amino acid supplementation, the survival rate in newborns diagnosed after birth but within the first month of life is almost 80%. Most deaths have occurred during an episode of acute hyperammonemic encephalopathy. Patients with neonatal-onset disease have a high incidence of mental retardation. Those who had IQ tests administered had an incidence of mental retardation as follows: ornithine transcarbamylase deficiency, 100% (14/14 patients tested); argininosuccinic acid synthetase deficiency, 88% (15/17 patients tested); and carbamylphosphate synthetase deficiency, 57% (4/7 patients tested). Retardation was severe in the majority of the retarded patients.

In patients diagnosed during gestation and treated prior to any episode of hyperammonemic encephalopathy, survival is 100%, but even in these patients, most subsequently demonstrate cognitive impairment or other neurologic deficits.

In late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase deficiency, who recover from hyperammonemic encephalopathy and are then treated chronically with Sodium Phenylbutyrate Tablets and dietary protein restriction, the survival rate is 98%. The two deaths in this group of patients occurred during episodes of hyperammonemic encephalopathy. However, compliance with the therapeutic regimen has not been adequately documented to allow evaluation of the potential for Sodium Phenylbutyrate Tablets and dietary protein restriction to prevent mental deterioration and recurrence of hyperammonemic encephalopathy if carefully adhered to. The majority of these patients tested (30/46 or 65%) have IQ’s in the average to low average/borderline mentally retarded range. Reversal of pre-existing neurologic impairment is not likely to occur with treatment and neurologic deterioration may continue in some patients.

Even on therapy, acute hyperammonemic encephalopathy recurred in the majority of patients for whom the drug is indicated.

Sodium Phenylbutyrate Tablets may be required life-long unless orthotopic liver transplantation is elected.

(See CLINICAL PHARMACOLOGY , Pharmacodynamics subsection for the biochemical effects of Sodium Phenylbutyrate Tablets).

CONTRAINDICATIONS

Sodium phenylbutyrate tablets should not be used to manage acute hyperammonemia, which is a medical emergency.

WARNINGS

Each sodium phenylbutyrate tablet contains 62 mg of sodium (9.2 % w/w) (corresponding to 124 mg of sodium per gram of sodium phenylbutyrate [12.4% w/w]). Sodium phenylbutyrate 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.

Because sodium phenylbutyrate is metabolized in the liver and kidney, and phenylacetylglutamine is primarily excreted by the kidney, use caution when administering the drug to patients with hepatic or renal insufficiency or inborn errors of beta oxidation. Probenecid is known to inhibit the renal transport of many organic compounds, including hippuric acid, and may affect renal excretion of the conjugated product of sodium phenylbutyrate as well as its metabolite.

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

PRECAUTIONS

General:

Sodium phenylbutyrate should not be administered to patients with known hypersensitivity to sodium phenylbutyrate or any component of this preparation.

There have been published reports of hyperammonemia being induced by haloperidol and by valproic acid.

Neurotoxicity of phenylacetate in animals:

When given subcutaneously to rat pups, 190 to 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. Prenatal exposure of rat pups to phenylacetate produced lesions in layer 5 of the cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number.

Information for Patients:

The full text of the separate insert of information for patients is reprinted at the end of the labeling.

Laboratory Tests:

Plasma levels of ammonia, arginine, branched-chain amino acids, and serum proteins should be maintained within normal limits, and plasma glutamine should be maintained at levels less than 1,000 ┬Ámol/L. Serum drug levels of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine, should be monitored periodically.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

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

Pregnancy:

Pregnancy Category C. Animal reproduction studies have not been conducted with sodium phenylbutyrate. It is also not known whether sodium phenylbutyrate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Sodium phenylbutyrate should be given to a pregnant woman only if clearly needed.

Nursing Mothers:

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sodium phenylbutyrate is administered to a nursing woman.

Pediatric Use:

The use of tablets for neonates, infants and children to the weight of 20 kg is not recommended. (See DOSAGE AND ADMINISTRATION).

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