Version May 2024
Urea cycle disorders: Oral: 9.9 to 13 g/m2/day, administered in equally divided doses 3 to 6 times/day; maximum dose: 20 g/day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution.
There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution; start at the lower end of the dosing range.
Neurotoxicity (confusion, headache, nausea, somnolence, or vomiting in the absence of high ammonia levels or other illnesses): Consider dosage reduction.
Refer to adult dosing.
(For additional information see "Sodium phenylbutyrate: Pediatric drug information")
Urea cycle disorder, chronic management:
Infants and Children <20 kg: Oral powder or pellets: Oral: 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: Tablets, oral powder or pellets: Oral: 9.9 to 13 g/m2/day in divided doses with meals 3 to 6 times daily; maximum daily dose: 20 g/day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosage adjustment for toxicity:
Neurotoxicity (confusion, headache, nausea, somnolence, or vomiting in the absence of high ammonia levels or other illnesses): Consider dosage reduction.
There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution.
There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution; start at the lower end of the dosing range and use lowest effective dose for maintenance.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Endocrine & metabolic: Acidosis (14%), amenorrhea (≤23%), hypoalbuminemia (11%), menstrual disease (≤23%; including irregular menses)
1% to 10%:
Cardiovascular: Syncope (≤2%)
Dermatologic: Body odor (3%), skin rash (≤2%)
Endocrine & metabolic: Alkalosis (7%), decreased serum total protein (3%), hyperchloremia (7%), hypernatremia (1%), hyperphosphatemia (2%), hyperuricemia (2%), hypokalemia (1%), hypophosphatemia (6%), weight gain (≤2%)
Gastrointestinal: Abdominal pain (≤2%), decreased appetite (4%), dysgeusia (3%; including taste aversion and unpleasant taste), gastritis (≤2%), nausea (≤2%), vomiting (≤2%)
Hematologic & oncologic: Anemia (9%), leukocytosis (4%), leukopenia (4%), thrombocytopenia (3%), thrombocytosis (1%)
Hepatic: Hyperbilirubinemia (1%), increased serum alkaline phosphatase (6%), increased serum transaminases (4%)
Nervous system: Depression (≤2%), headache (≤2%)
Renal: Renal tubular acidosis (≤2%)
<1%:
Cardiovascular: Cardiac arrhythmia, edema
Dermatologic: Ecchymoses
Gastrointestinal: Constipation, pancreatitis, peptic ulcer, rectal hemorrhage
Hematologic & oncologic: Aplastic anemia
Buphenyl: Hypersensitivity to sodium phenylbutyrate or any component of the formulation; management of acute hyperammonemia.
Olpruva, Pheburane: There are no contraindications listed within the manufacturer’s US labeling.
Canadian labeling: Pregnancy, breastfeeding.
Concerns related to adverse effects:
• 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 metabolite (phenylacetate) plasma concentrations ≥490 mg/L (~3.5 mmol/L), including somnolence, fatigue, and light-headedness; signs and symptoms were reversible upon discontinuation.
Disease-related concerns:
• 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.
Special populations:
• Restricted sodium intake: May contain 125 mg sodium per gram of sodium phenylbutyrate; use with caution, if at all, in patients who must maintain a low sodium intake.
• Sucrose intolerance: Some formulations may contain sucrose; take sucrose content into consideration in patients with diabetes mellitus; avoid use in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.
Dosage form specific issues:
• Tablet formulation: The use of sodium phenylbutyrate tablets in children weighing ≤20 kg is not recommended.
Other warnings/precautions:
• Appropriate use: Use in conjunction with protein restriction diet and in some cases, essential amino acid supplementation.
Powder products: 1 level teaspoon provides 3 g sodium phenylbutyrate, 1 level tablespoon provides 8.6 g sodium phenylbutyrate. Measurers provided with the product.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Packet for Suspension, Oral:
Olpruva: 2 g (2s, 180s), 3 g (2s, 180s), 4 g (two 2 g packets) (3s, 270s), 5 g (one 2 g packet and one 3 g packet) (3s, 270s), 6 g (two 3 g packets) (3s, 270s), 6.67 g (one 3 g packet and one 3.67 g packet) (3s, 270s)
Pellets, Oral:
Pheburane: 483 mg/g (174 g)
Powder, Oral:
Buphenyl: (250 g) [contains sodium 125 mg/g]
Generic: (250 g)
Tablet, Oral:
Buphenyl: 500 mg [contains sodium 62 mg/tablet]
Generic: 500 mg
Yes
Pellet (Pheburane Oral)
483 mg/g (per gram): $30.17
Powder (Buphenyl Oral)
3 g/teaspoon (per gram): $61.48
Powder (Sodium Phenylbutyrate Oral)
3 g/teaspoon (per gram): $21.10
Tablets (Buphenyl Oral)
500 mg (per each): $32.71
Tablets (Sodium Phenylbutyrate Oral)
500 mg (per each): $26.78
Therapy Pack (Olpruva (2 GM Dose) Oral)
2 g (per each): $114.00
Therapy Pack (Olpruva (3 GM Dose) Oral)
3 g (per each): $171.00
Therapy Pack (Olpruva (4 GM Dose) Oral)
2 & 2 g (per each): $152.00
Therapy Pack (Olpruva (5 GM Dose) Oral)
2 & 3 g (per each): $190.00
Therapy Pack (Olpruva (6 GM Dose) Oral)
3 & 3 g (per each): $228.00
Therapy Pack (Olpruva (6.67 GM Dose) Oral)
3 & 3.67 g (per each): $253.46
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Oral: Administer the total daily dose in equally divided doses with each meal or feeding (ie, 3 to 6 times/day).
Granules: Measure dose using the dosing spoon provided which dispenses up to 3 g of sodium phenylbutyrate in graduations of 0.25 grams. The granules may be swallowed with a drink (eg, water, fruit juices, protein-free infant formulas) or sprinkled on a spoonful of soft food (eg, carrot puree, apple sauce); do not chew granules or mix into liquids. When mixed with food, the mixture should be administered immediately. The US labeling does not recommend administering granules via NG or gastrostomy tube; has not been studied. According to the Canadian labeling, do not administer granules by tube; use a 50 mg/mL prepared solution, administer with a syringe directly through the NG or gastrostomy tube and rinse with water to clear tube.
Powder: May administer via mouth, gastrostomy tube, or NG 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.
Suspension: For oral administration only; do not administer via NG or gastrostomy tube. Pour entire Mix-Aid packet into a cup with ~4 ounces of water and stir to form a suspension, then pour the entire contents of the sodium phenylbutyrate packet into the suspension and stir. Administer suspension within 5 minutes of stirring; pour an additional 4 ounces of water into the cup and drink to ensure all medication is consumed. Discard any unused suspension 30 minutes after preparation.
Oral: Administer in equally divided doses with meals or feedings.
Pellets: Measure dose using the dosing spoon provided, which is calibrated in 0.25 g increments. The pellets may be swallowed with a drink (eg, water, fruit juices, protein-free infant formulas) or sprinkled on a spoonful of soft food (eg, applesauce, carrot puree); do not chew pellets or mix into liquids; the mixture should be administered immediately. Discard bulk container 45 days after opening.
NG or gastrostomy tube: US labeling does not recommend administering pellets via NG or gastrostomy tube; has not been studied. According to the Canadian labeling, Pheburane granules may be used to prepare an extemporaneous solution for NG or gastrostomy tube administration; do not administer granules directly by tube. Administer 50 mg/mL extemporaneously prepared solution with a syringe directly through the NG or gastrostomy tube and flush with water to clear tube.
Powder: May administer via mouth, NG tube, or gastrostomy tube. Measure the dose using the provided teaspoon or tablespoon; 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.
Urea cycle disorders:
Buphenyl: 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 (complete enzymatic deficiency, presenting within the first 28 days of life); late-onset disease (partial enzymatic deficiency, presenting after the first month of life) who have a history of hyperammonemic encephalopathy.
Olpruva: Adjunctive therapy to standard care (eg, dietary management) in the chronic management of pediatric patients ≥20 kg or ≥1.2 m2 BSA and adult patients with urea cycle disorder involving deficiencies of carbamoylphosphate synthetase, ornithine transcarbamylase, or argininosuccinic acid synthetase.
Pheburane: Adjunctive therapy to standard care (eg, dietary management) in the chronic management of pediatric and adult patients with urea cycle disorder involving deficiencies of carbamoylphosphate synthetase, ornithine transcarbamylase, or argininosuccinic acid synthetase.
Limitations of use: Not indicated for the treatment of acute hyperammonemia.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Benperidol: May diminish the therapeutic effect of Urea Cycle Disorder Agents. Risk C: Monitor therapy
Corticosteroids (Systemic): May diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Corticosteroids (Systemic) may increase protein catabolism and plasma ammonia concentrations, thereby increasing the doses of Urea Cycle Disorder Agents needed to maintain these concentrations in the target range. Risk C: Monitor therapy
Haloperidol: May diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Haloperidol may increase plasma ammonia concentrations and thereby increase the doses of Urea Cycle Disorder Agents needed to maintain concentrations in the target range. Risk C: Monitor therapy
Probenecid: May increase serum concentrations of the active metabolite(s) of Urea Cycle Disorder Agents. Specifically, concentrations of phenylacetate and phenylacetylglutamine may be increased. Risk C: Monitor therapy
Taurursodiol: Histone Deacetylase Inhibitors may enhance the adverse/toxic effect of Taurursodiol. Risk X: Avoid combination
Valproate Products: May diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Valproate Products may increase plasma ammonia concentrations and thereby increase the doses of Urea Cycle Disorder Agents needed to maintain concentrations in the target range. Risk C: Monitor therapy
Animal reproduction studies have not been conducted.
It is not known if sodium phenylbutyrate is excreted in breast milk. The manufacturer recommends that caution be exercised when administering sodium phenylbutyrate to nursing women. Use during breast-feeding is contraindicated in the Canadian labeling.
A clinician with experience in inborn metabolism errors should manage the nutrition delivery. Medication must be used in conjunction with a protein-restricted diet and, if indicated, essential amino acid supplementation. Patients requiring calorie supplementation should receive protein-free caloric supplements.
Infants with neonatal-onset ornithine transcarbamylase and carbamoylphosphate synthetase deficiency: Initially limit to a protein intake of approximately 1.6 g/kg/day. May increase (after the first 4 months of life) to 1.9 g/kg/day if tolerated. Protein tolerance will decrease with decreasing growth rate. Infants from 4 months to 1 year should receive at least 1.4 g/kg/day protein, although 1.7 g/kg/day is advisable. From 1 to 3 years, protein intake should be at least 1.2 g/kg/day although 1.4 g/kg/day is advisable. Citrulline supplementation is recommended at 0.17 g/kg/day or 3.8 g/m2/day; free-base arginine may be used for mild disease.
Late-onset or infants with neonatal-onset argininosuccinic acid synthetase deficiency: May initially receive age-determined minimal protein allowance; increase as tolerated based on amino acid levels.
Argininosuccinic acid synthetase deficiency: Arginine (free base) supplementation is recommended at 0.4 to 0.7 g/kg/day or 8.8 to 15.4 g/m2/day.
Some products may contain sodium.
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); signs and symptoms of neurotoxicity; obtain plasma phenylacetate and phenylacetylglutamine levels in patients with neurologic symptoms (eg, confusion, headache, nausea, somnolence, vomiting).
Target biochemical markers for control:
Plasma ammonia: <40 micromol/L; Plasma glutamine <1000 micromol/L; normal plasma levels of alanine, glycine, lysine, and arginine (except in arginase deficiency), no subnormal concentrations of essential amino acids (eg, leucine, isoleucine, valine)
Sodium phenylbutyrate is a prodrug which is rapidly converted to phenylacetate, followed by conjugation with glutamine to form phenylacetylglutamine; phenylacetylglutamine serves as a substitute for urea as it is clears nitrogenous waste from the body when excreted in the urine.
Absorption: Suspension: Compared to administration under fasted conditions, phenylbutyrate Cmax decreased by 50% and AUCinf decreased by 39% and phenylacetate Cmax decreased by 50% and AUCinf decreased by 39% when administered with a high-fat meal (980 total calories with 55% fat).
Distribution: Vd: Suspension: 7.2 L.
Metabolism: Hepatic and renal: Phenylbutyrate, a prodrug, is metabolized to phenylacetate followed by conjugation with glutamine to phenylacetylglutamine.
Half-life elimination: Phenylbutyrate: Pellets: 0.5 to 0.8 hours; Suspension: 0.5 hours; Tablets and powder: 0.76 to 0.77 hours; Phenylacetate: Tablets and powder: 1.15 to 1.29 hours; Suspension: 1.2 hours.
Time to peak, plasma: Phenylbutyrate: Pellets: 0.6 hours; 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).
Sex: Plasma concentration were increased for both phenylbutyrate and phenylacetate and were about 30% to 50% greater in females than in males.
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