Sodium Phenylbutyrate is used to treat patients with urea cycle disorders along with dietary intervention. Its metabolites provide an alternative pathway for the excretion of nitrogenous wastes from the body.

Sodium phenylbutyrate Uses:

• Urea cycle disorders:

  • Adjunctive therapy in the chronic management of patients with urea cycle disorder involving deficiencies of carbamoylphosphate synthetase, ornithine transcarbamylase, or argininosuccinic acid synthetase;
  • neonatal-onset deficiency (a complete enzymatic deficiency, presenting within the first 28 days of life);
  • late-onset disease (a partial enzymatic deficiency, presenting after the first month of life) who have a history of hyperammonemic encephalopathy.

Sodium Phenylbutyrate dose in Adults

Sodium Phenylbutyrate dose in the treatment of Urea cycle disorders:

• Powder or tablet: Oral:

  • 9.9 to 13 g/m²/day, administered in equally divided doses 3 to 6 times/day;
  • The safety and efficacy of doses at  >20 g/day have not been established.

Sodium Phenylbutyrate dose in Childrens

Sodium Phenylbutyrate dose in the chronic management of Urea Cycle Disorder:

• Note: The use of sodium phenylbutyrate tablets in children weighing ≤20 kg is not recommended.

• Infants and Children <20 kg:

  • Oral: at 450 to 600 mg/kg/day in divided doses with meals/feedings 3 to 6 times daily;
  • maximum daily dose: 20 g/day

• Children ≥20 kg and Adolescents:

  • Oral: at 9.9 to 13 g/m /day in divided doses with meals 3 to 6 times daily;
  • maximum daily dose: 20 g/day

Pregnancy Risk Factor C

• Animal reproduction studies have not been conducted.
• Use during pregnancy is contraindicated in Canadian labeling.

Use during breastfeeding:

• It is not known if the drug is excreted in breast milk.
• The drug manufacturer recommends that caution be exercised when administering sodium phenylbutyrate to nursing women.
• Use during breastfeeding is contraindicated in Canadian labeling.

Sodium Phenylbutyrate Dose in Kidney Disease:

• There are no dosage adjustments provided in the drug manufacturer’s labeling.
• Use with caution.

Sodium Phenylbutyrate Dose in Liver disease:

• There are no dosage adjustments provided in the drug manufacturer’s labeling.
• Use with caution.

Common Side Effects of Sodium phenylbutyrate:

• Endocrine & Metabolic:

  • Amenorrhea
  • Menstrual Disease
  • Acidosis
  • Hypoalbuminemia

Less Common Side Effects of Sodium Phenylbutyrate:

• Cardiovascular:

  • Syncope

• Central Nervous System:

  • Depression
  • Headache

• Dermatologic:

  • Body Odor
  • Skin Rash

• Endocrine & Metabolic:

  • Alkalosis
  • Hyperchloremia
  • Hypophosphatemia
  • Decreased Serum Total Protein
  • Hyperuricemia
  • Hyperphosphatemia
  • Hypernatremia
  • Hypokalemia

• Gastrointestinal:

  • Anorexia
  • Dysgeusia
  • Abdominal Pain
  • Gastritis
  • Nausea
  • Vomiting

• Hematologic & Oncologic:

  • Anemia
  • Leukocytosis
  • Leukopenia
  • Thrombocytopenia
  • Thrombocythemia

• Hepatic:

  • Increased Serum Alkaline Phosphatase
  • Increased Serum Transaminases
  • Hyperbilirubinemia

• Renal:

  • Renal Tubular Acidosis

Contraindications to Sodium phenylbutyrate:

• Hypersensitivity/Allergy to the drug or any component of the formulation;
• management of acute hyperammonemia

Canadian labeling: Additional contraindications (not in US labeling):

• • Pregnancy,
  • breast-feeding

Warnings and Precautions

• Fluid retention:

  • May cause sodium and fluid retention;
  • use with caution, if at all, in patients where fluid accumulation may be poorly tolerated, such as in HF.

• Hyperammonemia:

  • Hyperammonemia and hyperammonemic encephalopathy may still occur while on therapy;
  • manage acute hyperammonemia as a medical emergency.

• Neurotoxicity:

  • Signs and symptoms of neurotoxicity were observed at plasma concentrations ≥3.5 mmol/L, including somnolence, fatigue, lightheadedness, headache, dysgeusia, hyperacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy;
  • signs and symptoms were reversible upon discontinuation.

• Hepatic impairment:

  • Use with caution in patients with hepatic impairment.

• Inborn errors of beta-oxidation:

  • Use with caution in patients with inborn errors of beta-oxidation.

• Renal impairment:

  • Use with caution in patients with renal impairment; especially in severe renal impairment when sodium restriction is required.

Sodium phenylbutyrate: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Blood ammonia,
• serum proteins and plasma amino acid quantitation,
• serum electrolytes,
• CBC with differential,
• hepatic and renal function tests
• urinalysis;
• monitor for physical signs/symptoms of hyperammonemia (eg, lethargy, ataxia, confusion, vomiting, seizures, and memory impairment);
• nutritional parameters (weight, height, head circumference, albumin, prealbumin)

How to administer Sodium phenylbutyrate?

• Administer the total daily dose in equally divided doses with each meal or feeding (ie, 3 to 6 times/day).

• Granules (Pheburane [Canadian product]):

  • Measure dose using the dosing spoon provided which dispenses up to 3 g of sodium phenylbutyrate in graduations of 250 mg.
  • The granules may be swallowed with a drink (eg, water, fruit juices, protein-free infant formulas) or sprinkled on solid food (eg, mashed potatoes or apple sauce).
  • When mixed with food, the mixture should be administered immediately.
  • Do not administer granules by tube; use a 50 mg/mL prepared solution, administer with a syringe directly through the nasogastric or gastrostomy tube and rinse with water to clear tube.

• Powder:

  • May administer via the mouth, gastrostomy tube, or nasogastric tube.
  • Measure the dose using the teaspoon or tablespoon provided;
  • one level teaspoon equals 3 g of sodium phenylbutyrate;
  • 1 level tablespoon equals 8.6 g of sodium phenylbutyrate.
  • The powder may be mixed with solid food, liquid food, or water.
  • When mixed with food, the mixture should be used immediately; if mixed with water, the mixture may be stored at room temperature or refrigerated and must be used within 1 week.
  • When mixing with a liquid, shake lightly prior to use; only sodium phenylbutyrate will dissolve, the excipients will not.

Mechanism of action of Sodium phenylbutyrate:

• Sodium phenylbutyrate is a prodrug that is rapidly converted to phenylacetate, followed by conjugation with glutamine to form phenylacetylglutamine; phenylacetylglutamine serves as a substitute for urea as it clears the nitrogenous waste from the body when excreted in the urine.

Metabolism:

• Hepatic and renal: Phenylbutyrate, a prodrug, is metabolized to phenylacetate followed by conjugation with glutamine to phenylacetylglutamine

Half-life elimination:

• Phenylbutyrate (tablets and powder): 0.76 to 0.77 hours;
• Phenylacetate (tablets and powder): 1.15 to 1.29 hours

Time to peak plasma concentrations:

• Phenylbutyrate (tablets and powder): 1 to 1.35 hours; Phenylacetate (tablets and powder): 3.55 to 3.74 hours

Excretion:

• Urine (80% to 100%, primarily as phenylacetylglutamine)

International Brands of Sodium phenylbutyrate:

• Buphenyl
• Pheburane
• Ammonaps

Sodium phenylbutyrate Brand Names in Pakistan:

No Brands Available in Pakistan.