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Overview
Sodium phenylbutyrate is a histone deacetylase inhibitor that is FDA approved for the treatment of chronic management of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). Common adverse reactions include acidosis, hypoalbuminemia, anemia, amenorrhea , irregular periods.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
BUPHENYL 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.
BUPHENYL 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 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 BUPHENYL 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.
BUPHENYL may be required life-long unless orthotopic liver transplantation is elected.
For oral use only.
The use of BUPHENYL Tablets is indicated for children weighing more than 20 kg and for adults.
The usual total daily dose of BUPHENYL Tablets and Powder for patients with urea cycle disorders is 450 – 600 mg/kg/day in patients weighing less than 20 kg, or 9.9 – 13.0 g/m2/day in larger patients. The tablets and powder are to be taken in equally divided amounts with each meal or feeding (i.e., three to six times per day).
BUPHENYL Powder is indicated for oral use (via mouth, gastrostomy, or nasogastric tube) only. The powder is to be mixed with food (solid or liquid) for immediate use; however, when dissolved in water, BUPHENYL Powder has been shown to be stable for up to one week at room temperature or refrigerated. Sodium phenylbutyrate is very soluble in water (5 grams per 10 mL). When BUPHENYL Powder is added to a liquid, only sodium phenylbutyrate will dissolve, the excipients will not. The effect of food on sodium phenylbutyrate has not been determined.
Each level teaspoon (enclosed) dispenses 3.2 grams of powder and 3.0 grams of sodium phenylbutyrate. Each level tablespoon (enclosed) dispenses 9.1 grams of powder and 8.6 grams of sodium phenylbutyrate.
Shake lightly before use.
The safety or efficacy of doses in excess of 20 grams (40 tablets) per day has not been established.
NUTRITIONAL MANAGEMENT
To promote growth and development, plasma levels of ammonia, arginine, branched-chain amino acids, and serum protein should be maintained within normal limits while plasma glutamine is maintained at levels less than 1,000 µmol/L. Minimum daily protein intake for a patient of a particular age should be taken from, for example, "Recommended Dietary Allowances", 10th ed., Food and Nutrition Board, National Academy of Sciences, 1989. The allocation of dietary nitrogen into natural protein and essential amino acids is a function of age, residual urea-cycle enzyme activity, and the dose of sodium phenylbutyrate.
At the recommended dose of sodium phenylbutyrate, it is suggested that infants with neonatal-onset CPS and OTC deficiencies initially receive a daily dietary protein intake limited to approximately 1.6 g/kg/day for the first 4 months of life. If tolerated, the daily protein intake may be increased to 1.9 g/kg/day during this period. Protein tolerance will decrease as the growth rate decreases, requiring a reduction in dietary nitrogen intake. From 4 months to 1 year of age, it is recommended that the infant receive at least 1.4 g/kg/day, but 1.7 g/kg/day is advisable. From 1 to 3 years of age, the protein intake should not be less than 1.2 g/kg/day; 1.4 g/kg/day is advisable during this period. For neonatal-onset patients with carbamylphosphate synthetase deficiency or ornithine transcarbamylase deficiency who are at least 6 months of age, it is recommended that the daily protein intake be equally divided between natural protein and supplemental essential amino acids.
Patients with argininosuccinic acid synthetase deficiency and those with late-onset disease (partial deficiencies, including females heterozygous for ornithine transcarbamylase), initially may receive a diet containing the age-determined minimal daily natural protein allowance. The protein intake may be increased as tolerated and determined by plasma glutamine and other amino acid levels. However, many patients with partial deficiencies avoid dietary protein.
Citrulline supplementation is required and recommended for patients diagnosed with neonatal-onset deficiency of carbamylphosphate synthetase or ornithine transcarbamylase; citrulline daily intake is recommended at 0.17 g/kg/day or 3.8 g/m2/day.
The free-base form of arginine may be used instead of citrulline in patients with milder forms of carbamylphosphate synthetase and ornithine transcarbamylase deficiency (daily intake is recommended at 0.17 g/kg/day or 3.8 g/m2/day).
Arginine supplementation is needed for patients diagnosed with deficiency of argininosuccinic acid synthetase; arginine (free base) daily intake is recommended at 0.4 – 0.7 g/kg/day or 8.8 – 15.4 g/m2/day.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sodium phenylbutyrate in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium phenylbutyrate in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Sodium phenylbutyrate in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sodium phenylbutyrate in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium phenylbutyrate in pediatric patients.
Contraindications
BUPHENYL should not be used to manage acute hyperammonemia, which is a medical emergency
Warnings
Each BUPHENYL 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]) and BUPHENYL Powder contains 11.7 grams of sodium per 100 grams of powder, corresponding to 125 mg of sodium per gram of sodium phenylbutyrate (12.4% w/w). BUPHENYL 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 BUPHENYL 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 BUPHENYL as well as its metabolite.
Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels.
Adverse Reactions
Clinical Trials Experience
The assessment of clinical adverse events came from 206 patients treated with sodium phenylbutyrate. Adverse events (both clinical and laboratory) were not collected systematically in these patients, but were obtained from patient-visit reports by the 65 co-investigators. Causality of adverse effects is sometimes difficult to determine in this patient population because they may result from either the underlying disease, the patient's restricted diet, intercurrent illness, or BUPHENYL. Furthermore, the rates may be under-estimated because they were reported primarily by parent or guardian and not the patient.
Clinical Adverse Events
In female patients, the most common clinical adverse event reported was amenorrhea/menstrual dysfunction (irregular menstrual cycles), which occurred in 23% of the menstruating patients.
Decreased appetite occurred in 4% of all patients. Body odor (probably caused by the metabolite, phenylacetate) and bad taste or taste aversion were each reported in 3% of patients.
Other adverse events reported in 2% or fewer patients were:
Gastrointestinal: abdominal pain, gastritis, nausea and vomiting; constipation, rectal bleeding, peptic ulcer disease, and pancreatitis each occurred in one patient.
Hematologic: aplastic anemia and ecchymoses each occurred in one patient.
Cardiovascular: arrhythmia and edema each occurred in one patient.
Renal: renal tubular acidosis
Psychiatric: depression
Skin: rash
Miscellaneous: headache, syncope, and weight gain
Neurotoxicity was reported in cancer patients receiving intravenous phenylacetate, 250–300 mg/kg/day for 14 days, repeated at 4-week intervals. Manifestations were predominately somnolence, fatigue, and lightheadedness; with less frequent headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of a pre-existing neuropathy. These adverse events were mainly mild in severity. The acute onset and reversibility when the phenylacetate infusion was discontinued suggest a drug effect.
Postmarketing Experience
In patients with urea cycle disorders, the frequency of laboratory adverse events by body system were:
Metabolic: acidosis (14%), alkalosis and hyperchloremia (each 7%), hypophosphatemia (6%), hyperuricemia and hyperphosphatemia (each 2%), and hypernatremia and hypokalemia (each 1%).
Nutritional: hypoalbuminemia (11%) and decreased total protein (3%).
Animal reproduction studies have not been conducted with BUPHENYL. It is also not known whether BUPHENYL can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sodium phenylbutyrate in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Sodium phenylbutyrate during labor and delivery.
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 BUPHENYL 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.
Geriatic Use
There is no FDA guidance on the use of Sodium phenylbutyrate with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Sodium phenylbutyrate with respect to specific gender populations.
Race
There is no FDA guidance on the use of Sodium phenylbutyrate with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Sodium phenylbutyrate in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Sodium phenylbutyrate in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sodium phenylbutyrate in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Sodium phenylbutyrate in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Monitoring
There is limited information regarding Monitoring of Sodium phenylbutyrate in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Sodium phenylbutyrate in the drug label.
Overdosage
No adverse experiences have been reported involving overdoses of sodium phenylbutyrate in patients with urea cycle disorders.
In the event of an overdose, discontinue the drug and institute supportive measures.
Hemodialysis or peritoneal dialysis may be beneficial.
Pharmacology
There is limited information regarding Sodium phenylbutyrate Pharmacology in the drug label.
There is limited information regarding Pharmacodynamics of Sodium phenylbutyrate in the drug label.
Pharmacokinetics
odium 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.
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Sodium phenylbutyrate in the drug label.
Clinical Studies
There is limited information regarding Clinical Studies of Sodium phenylbutyrate in the drug label.
How Supplied
BUPHENYL Tablets are available in 250 cc bottles which contain 250 sodium phenylbutyrate tablets (NDC 62592-496-03). The bottles are equipped with child-resistant caps. Each tablet is off-white, oval, and embossed with "UCY 500". Each tablet contains 500 mg of sodium phenylbutyrate. STORE AT ROOM TEMPERATURE 15°C – 30°C (59°F – 86°F). AFTER OPENING, KEEP BOTTLE TIGHTLY CLOSED.
BUPHENYL Powder is available in 500 cc bottles, which hold 266 grams of powder, containing 250 grams of sodium phenylbutyrate (NDC 62592-188-64). The bottles are equipped with child-resistant caps. Measurers are provided. Each level teaspoon (enclosed) dispenses 3.2 grams of powder and 3.0 grams of sodium phenylbutyrate. Each level tablespoon (enclosed) dispenses 9.1 grams of powder and 8.6 grams of sodium phenylbutyrate.
Storage
STORE AT ROOM TEMPERATURE 15°C – 30°C (59°F – 86°F). AFTER OPENING, KEEP BOTTLE TIGHTLY CLOSED.
BUPHENYL is a registered trademark of Ucyclyd Pharma, Inc. All other trademarks are the property of their respective owners.
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