Sodium Phenylbutyrate (Monograph)

Drug class: Ammonia Detoxicants
Chemical name: sodium benzenebutanoic acid
Molecular formula: C₁₀H₁₁NaO₂
CAS number: 1716-12-7

Medically reviewed by Drugs.com on Dec 23, 2024. Written by ASHP.

Introduction

Sodium phenylbutyrate is an ammonia detoxicant.

Uses for Sodium Phenylbutyrate

Urea Cycle Disorders

Sodium phenylbutyrate is used as adjunctive therapy for the chronic management of hyperammonemia in patients with urea cycle disorders, including deficiencies in carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (ASS) enzymes. Sodium phenylbutyrate is designated an orphan drug by the US Food and Drug Administration (FDA) for this condition. The drug is used in patients with neonatal-onset deficiency (complete enzymatic deficiency, presenting within the first 28 days of life) and in those 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 diagnosis of the urea cycle disorder be made early and treatment initiated immediately to improve survival. Treatment includes hemodialysis, administration of drugs that provide alternative pathways for elimination of waste nitrogen (e.g., sodium phenylbutyrate, sodium phenylacetate, sodium benzoate), dietary protein restriction, and possibly, essential amino acid supplementation. Survival rate in neonates diagnosed after birth, but within the first month of life, receiving such therapy is about 80%, while survival rate of those diagnosed during gestation and treated prior to development of a hyperammonemic encephalopathic episode is 100%. It should be considered that most patients subsequently will have cognitive impairment or other neurologic deficits.

In late-onset urea cycle disorders including those in females with heterozygous OTC deficiency, the survival rate is higher than 90% following recovery from hyperammonemic encephalopathy and subsequent treatment with sodium phenylbutyrate and dietary protein restriction. Sodium phenylbutyrate does not reverse preexisting neurologic impairment; in addition, neurologic deterioration may continue in some patients.

Many patients continue to have hyperammonemic episodes while receiving sodium phenylbutyrate therapy; however, the drug should not be used to treat acute hyperammonemia. Because uncontrolled hyperammonemia can rapidly result in brain damage or death, any episode of acute symptomatic hyperammonemia should be treated as a life-threatening emergency, and prompt use of all therapies necessary to reduce ammonia concentrations is essential. Hemodialysis is the most rapid and effective method for removing ammonia in patients with acute neonatal hyperammonemic coma, moderate to severe episodes of hyperammonemic encephalopathy, or episodes of hyperammonemia that fail to respond to an initial course of sodium phenylacetate and sodium benzoate therapy. (For further information on the treatment of acute hyperammonemic episodes, see Uses: Acute Hyperammonemia in Sodium Phenylacetate and Sodium Benzoate 40:10.)

For the chronic management of urea cycle disorders, life-long therapy with sodium phenylbutyrate may be required, unless orthotopic liver transplant is performed.

Sodium Phenylbutyrate Dosage and Administration

General

Sodium phenylbutyrate therapy should be combined with dietary protein restriction and, in some patients, with essential amino acid supplementation. For additional information concerning nutritional management of patients receiving the drug, the manufacturer’s labeling or urea cycle disorders website ([Web]) should be consulted.

Administration

Sodium phenylbutyrate is administered orally. Sodium phenylbutyrate powder also may be administered via a gastrostomy or nasogastric tube. Although the effect of food on the drug has not been determined, sodium phenylbutyrate should be administered with meals or feedings. Sodium phenylbutyrate powder should be lightly shaken before use and then mixed with solid or liquid food before administration. Although sodium phenylbutyrate is very soluble in water and will dissolve when the powder is added to a liquid, the excipients in the commercially available formulation will not dissolve.

Dosage

Dosage of sodium phenylbutyrate is expressed in terms of the salt. Dosage of sodium phenylbutyrate is based on body weight in neonates, infants, and children weighing less than 20 kg and on body surface area in pediatric patients weighing at least 20 kg and in adults. Sodium phenylbutyrate tablets are used in pediatric patients weighing more than 20 kg and in adults. When the teaspoon provided by the manufacturer is used to measure sodium phenylbutyrate oral powder, each level teaspoonful of the powder provides 3 g of sodium phenylbutyrate. When the tablespoon provided by the manufacturer is used, each level tablespoonful of the powder provides 8.6 g of sodium phenylbutyrate.

For the chronic management of hyperammonemia in patients with urea cycle disorders, the usual oral dosage of sodium phenylbutyrate powder in neonates, infants and children weighing less than 20 kg is 450–600 mg/kg daily, given in 3–6 equally divided doses. In children weighing 20 kg or more and in adults, the usual oral dosage of sodium phenylbutyrate powder or tablets is 9.9–13 g/m² daily, given in 3–6 equally divided doses. Safety and efficacy of dosages exceeding 20 g daily have not been established.

Special Populations

No special population recommendations at this time.

Cautions for Sodium Phenylbutyrate

Contraindications

Known hypersensitivity to sodium phenylbutyrate or any ingredient in the formulation. Treatment of acute hyperammonemia which is a medical emergency.

Warnings/Precautions

Warnings

Sodium Content

Each g of sodium phenylbutyrate powder or tablets contains about 5.4 mEq (125 or 124 mg, respectively) of sodium. The drug should be used with great caution, if at all, in patients with congestive heart failure (CHF), severe renal impairment, or clinical conditions associated with sodium retention and edema.

General Precautions

Neurotoxicity

Evidence of neurotoxicity (decreased proliferation and loss of neurons, decreased CNS myelin, retarded maturation of cerebral synapses, impaired brain growth resulting from decreased number of functioning cerebral nerve terminals) was reported in rat pups receiving subcutaneous administration of phenylacetate (metabolite of phenylbutyrate). Prenatal exposure of rat pups to phenylacetate resulted in lesions in layer 5 of the cortical pyramidal cell; reduced number and longer and thinner than normal dendritic spines were observed.

Adverse neurotoxic effects (principally somnolence, fatigue, lightheadedness) have been reported in cancer patients receiving IV phenylacetate (metabolite of sodium phenylbutyrate), administered in dosages of 250–300 mg/kg daily for 14 days, repeated at 4–week intervals. Less frequently, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of existing neuropathy were reported. Acute onset of these effects (which were mainly mild) occurred upon initiation of such therapy and were reversible upon discontinuance of the drug.

Monitoring

Serum protein concentrations and plasma concentrations of ammonia, arginine, and branched-chain amino acids should be monitored and maintained within normal limits. Plasma glutamine concentrations should be maintained at less than 1000 µmol/L. Serum phenylbutyrate, phenylacetate, and phenylacetylglutamine concentrations should be monitored periodically. Urinalysis, blood chemistry profiles, and hematologic tests should be monitored routinely.

Specific Populations

Pregnancy

Category C. (See Users Guide)

Lactation

Not known whether sodium phenylbutyrate is distributed into milk. Caution is advised if the drug is administered in nursing women.

Pediatric Use

Use of sodium phenylbutyrate tablets in neonates, infants and children weighing less than 20 kg is not recommended.

Renal Impairment

Sodium phenylbutyrate is metabolized in the kidneys and phenylacetylglutamine is mainly excreted in the kidneys. Use with caution in patients with renal impairment.

Hepatic Impairment

Sodium phenylbutyrate is metabolized in the liver. Use with caution in patients with hepatic impairment or in those with congenital β-oxidation deficiencies. In unvalidated uncontrolled case reports in patients with hepatic impairment but without urea cycle disorder, the metabolism and excretion of sodium phenylbutyrate was unaffected.

Common Adverse Effects

Adverse effects reported in 3% or more of patients receiving sodium phenylbutyrate include amenorrhea or menstrual dysfunction, decreased appetite, body odor, dysgeusia, acidosis, hypoalbuminemia, alkalosis and hyperchloremia, anemia, hypophosphatemia, increased concentrations of alkaline phosphatase and aminotransferase, leukopenia, leukocytosis, and thrombocytopenia.

Drug Interactions

Corticosteroids

Potential pharmacologic interaction (may increase plasma ammonia concentrations by causing protein catabolism). Use with caution in patients with urea cycle disorders.

Haloperidol

Potential pharmacologic interaction (may induce hyperammonemia); use not recommended in patients with urea cycle disorders.

Probenecid

Potential pharmacokinetic interaction (may inhibit renal excretion of sodium phenylbutyrate and phenylacetylglutamine).

Valproic Acid

Potential pharmacologic interaction (may induce hyperammonemia); use not recommended in patients with urea cycle disorders.

Description

Sodium phenylbutyrate is used as adjunctive therapy for the chronic management of hyperammonemia in patients with urea cycle disorders.

Sodium phenylbutyrate is a prodrug that is rapidly metabolized to phenylacetate, an active metabolite. Phenylacetate is conjugated with glutamine in the liver and kidneys to form phenylacetylglutamine, a nitrogen waste product that is excreted by the kidneys and provides an alternative to urea for the excretion of waste nitrogen. The nitrogen content of phenylacetylglutamine is identical to that of urea (i.e., both contain 2 moles of nitrogen). Glutamine used in these reactions is replaced by synthesis, thereby reducing the nitrogen pool and attenuating the risk of ammonia- and glutamine-induced neurotoxicity in patients with deficiencies of urea cycle enzymes. (For further information on the role of ammonia detoxicants in the management of urea cycle disorders, see Description in Sodium Phenylacetate and Sodium Benzoate 40:10.)

Although sodium phenylbutyrate lacks the extremely disagreeable odor of sodium phenylacetate, it has a strong, musty odor, and has a strong unpleasant salty taste.

Advice to Patients

Patients should be advised of the importance of taking the drug exactly as prescribed. Dosage should not be increased or decreased without approval of the clinician.

Importance of immediately notifying a clinician if decreased mental awareness, vomiting, combativeness, slurred speech, unstable gait, or unconsciousness occurs, because these symptoms may indicate recurrence of urea cycle disorder, a medical emergency.

Importance of immediately notifying a clinician if fever develops since it may be a sign of infection that may cause loss of urea cycle disorder control.

Importance of immediately notifying a clinician if sleepiness or lightheadedness occurs in order to determine the cause of symptoms; such symptoms may indicate increased ammonia concentrations associated with recurrence of urea cycle disorder.

Importance of patients wearing a Medic Alert tag stating diagnosis so that hyperammonemic unconsciousness can be treated appropriately.

Importance of taking a missed dose as soon as possible, on the same day.

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

Importance of informing patients of other precautionary information. (See Cautions.)

Additional Information

Overview (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the manufacturer’s labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.