Sodium phenylbutyrate is a medication used primarily in the treatment of urea cycle disorders (UCD). UCDs are a group of rare genetic disorders that affect the body's ability to remove ammonia from the blood, leading to its accumulation to toxic levels. Sodium phenylbutyrate works by providing an alternative pathway for the excretion of nitrogen in the form of phenylacetylglutamine, which is eliminated through urine.

In addition to its use in UCDs, sodium phenylbutyrate has also been explored for its potential therapeutic effects in various other conditions, including certain types of cancer, neurodegenerative diseases like Huntington's disease and amyotrophic lateral sclerosis (ALS), and sickle cell disease. However, its efficacy in these conditions is still under investigation, and it may be prescribed off-label in some cases.

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:

• For this, it's taken by mouth either as a powder or a tablet.
• The typical dose is between 9.9 to 13 grams per square meter of the person's body surface area per day.
• This amount is split into smaller doses and taken 3 to 6 times throughout the day.
• It's important not to take more than 20 grams per day, as the safety and effectiveness of higher doses haven't been confirmed.

Sodium Phenylbutyrate dose in Childrens

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

Infants and Children weighing less than 20 kg:

• They shouldn't use sodium phenylbutyrate tablets.
• Instead, they can take it orally as a liquid in doses ranging from 450 to 600 milligrams per kilogram of body weight per day.
• This is divided into smaller doses and taken with meals or feedings 3 to 6 times each day.
• The maximum they should take per day is 20 grams.

Children weighing 20 kg or more and Adolescents:

• They can take sodium phenylbutyrate tablets orally.
• The typical dose ranges from 9.9 to 13 grams per square meter of body surface area per day.
• This is divided into smaller doses and taken with meals 3 to 6 times daily.
• Just like for younger children, the maximum they should take per day is 20 grams.

Pregnancy Risk Factor C

• Sodium phenylbutyrate is classified as a Pregnancy Risk Factor C.
• This means that animal reproduction studies haven't been conducted, and its safety during pregnancy hasn't been confirmed.
• In Canada, the labeling advises against using it during pregnancy, which means it's not recommended for pregnant individuals.

Use during breastfeeding:

• Sodium phenylbutyrate's presence in breast milk isn't established.
• The manufacturer advises caution when giving it to nursing women.
• However, in Canada, the labeling advises against using it during breastfeeding.
• This means it's not recommended for breastfeeding individuals.

Sodium Phenylbutyrate Dose in Kidney Disease:

• The manufacturer's labeling does not include specific dosage adjustments for individuals with renal impairment.
• However, it suggests using sodium phenylbutyrate cautiously in such cases.

Sodium Phenylbutyrate Dose in Liver disease:

• The manufacturer's labeling does not specify dosage adjustments for individuals with hepatic impairment.
• However, it advises using sodium phenylbutyrate cautiously in such cases.

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:

• Sodium phenylbutyrate is contraindicated in individuals with hypersensitivity to sodium phenylbutyrate or any component of the formulation.
• Additionally, in the Canadian labeling, it's contraindicated during pregnancy and breastfeeding.
• It's important to note these contraindications, especially for individuals who may be pregnant, breastfeeding, or have known hypersensitivity to the medication or its components.

Warnings and Precautions

Fluid retention:

• Sodium phenylbutyrate can potentially cause retention of sodium and fluid in the body.
• This means it might lead to an accumulation of fluids, especially in patients with conditions like heart failure where fluid buildup is poorly tolerated.
• If someone has heart failure or another condition where fluid retention could be problematic, it's essential to use sodium phenylbutyrate cautiously, if at all.

Hyperammonemia:

• Even when taking sodium phenylbutyrate, there's still a risk of hyperammonemia (high levels of ammonia in the blood) and hyperammonemic encephalopathy (a condition where high ammonia levels affect the brain).
• If someone experiences acute hyperammonemia, it's crucial to treat it as a medical emergency.
• This means seeking immediate medical attention to manage the condition effectively and prevent any potential complications.

Neurotoxicity:

• Neurotoxicity can occur with sodium phenylbutyrate, especially at plasma concentrations equal to or greater than 3.5 mmol/L.
• Signs and symptoms may include somnolence (feeling drowsy), fatigue, lightheadedness, headache, changes in taste (dysgeusia), hearing impairment (hypoacusis), disorientation, memory impairment, and worsening of existing nerve-related conditions (neuropathy).
• However, these symptoms are reversible upon discontinuing the medication.

Hepatic impairment:

• Sodium phenylbutyrate should be used cautiously in patients with hepatic impairment, meaning liver problems.
• This caution is necessary because individuals with liver issues may metabolize the medication differently or be more susceptible to its effects.

Inborn errors of beta-oxidation:

• Sodium phenylbutyrate should be used with caution in patients with inborn errors of beta-oxidation.
• These are genetic disorders that affect the body's ability to break down fatty acids for energy.
• Using sodium phenylbutyrate in such patients requires careful monitoring because it may impact the metabolism of fatty acids, potentially worsening their condition.

Renal impairment:

• Sodium phenylbutyrate should be used cautiously in patients with renal impairment, particularly in cases of severe renal impairment where sodium restriction is necessary.
• In such situations, the presence of sodium in sodium phenylbutyrate may need to be taken into account.

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 Acids: Check these regularly to monitor ammonia levels and protein metabolism.
• Serum Electrolytes: Keep an eye on electrolyte levels in the blood.
• CBC with Differential: Periodically check complete blood count for any abnormalities.
• Hepatic and Renal Function Tests: Monitor liver and kidney function to ensure the medication isn't causing any harm.
• Urinalysis: Regularly analyze urine for any signs of problems.
• Physical Signs/Symptoms of Hyperammonemia: Watch out for lethargy, coordination problems, confusion, vomiting, seizures, and memory issues.
• Nutritional Parameters: Monitor weight, height, head circumference, and levels of albumin and prealbumin to assess nutritional status.

How to administer Sodium phenylbutyrate?

• Total Daily Dose: Split the total daily dose into equal parts and take with each meal or feeding, typically 3 to 6 times a day.
• Granules (Pheburane [Canadian Product]):
  • Use the dosing spoon provided, which dispenses up to 3 g of sodium phenylbutyrate in 250 mg increments.
  • The granules can be swallowed with a drink like water, fruit juices, or protein-free infant formulas, or sprinkled on solid food like mashed potatoes or applesauce.
  • If mixed with food, use immediately. Do not administer granules through a tube. Instead, use a prepared solution (50 mg/mL) and administer through a syringe directly into the nasogastric or gastrostomy tube. Rinse the tube with water afterward.
• Powder:
  • Administer orally, through a gastrostomy tube, or nasogastric tube.
  • Measure the dose using the provided teaspoon or tablespoon. One level teaspoon equals 3 g of sodium phenylbutyrate, and one level tablespoon equals 8.6 g.
  • The powder can be mixed with solid food, liquid food, or water.
  • If mixed with food, use immediately. If mixed with water, the mixture can be stored at room temperature or refrigerated but must be used within 1 week.
  • Shake lightly before use if mixed with liquid. Only sodium phenylbutyrate will dissolve; the excipients will not.

Mechanism of action of Sodium phenylbutyrate:

• Sodium phenylbutyrate is a prodrug, meaning it transforms into another active form in the body.
• It quickly changes into phenylacetate, which then combines with glutamine to create phenylacetylglutamine.
• This compound acts like urea, helping to eliminate nitrogen waste from the body through urine.
• This process helps in managing conditions where the body struggles to remove ammonia and other nitrogen-containing substances effectively.

Distribution:

• Volume of distribution: 0.2 liters per kilogram of body weight.

Metabolism:

• Sodium phenylbutyrate undergoes hepatic and renal metabolism. It is converted to phenylacetate, which then combines with glutamine to form 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:

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

Excretion:

• The medication is primarily excreted in urine, with 80% to 100% eliminated, mainly as phenylacetylglutamine.

International Brands of Sodium phenylbutyrate:

• Buphenyl
• Pheburane
• Ammonaps

Sodium phenylbutyrate Brand Names in Pakistan:

No Brands Available in Pakistan.