Buphenyl

Urea Cycle Disorder Agents

Equally divide the total daily dose and administer with each meal or feeding (i.e., 3 to 6 times/day). If a dose is missed, take the missed dose as soon as possible. There should be at least 3 hours between doses; do not administer double or extra doses.

Administer with a meal.

Oral powder
The powder can be administered, after it is prepared, via mouth, gastrostomy tube, or nasogastric tube.
Review the preparation instructions, as the vehicle used for administration (i.e., food vs. water) affects drug stability.
Mixing the powder with food (solid or liquid) requires immediate administration. The effect of food on sodium phenylbutyrate has not been determined. Of note, when Buphenyl Powder is added to a liquid, only sodium phenylbutyrate will dissolve, the excipients will not.
Dissolving the powder in water has been shown to be stable for up to 1 week at room temperature or under refrigeration. Sodium phenylbutyrate is very soluble in water (5 g per 10 mL). When Buphenyl Powder is added to a liquid, only sodium phenylbutyrate will dissolve, the excipients will not.
Shake the powder container lightly before each use. Measure the dose using the teaspoon or tablespoon that is provided. Each level teaspoon dispenses 3.2 g of powder and 3 g of sodium phenylbutyrate. Each level tablespoon dispenses 9.1 g of powder and 8.6 g of sodium phenylbutyrate.
 
Oral granules (Olpruva)
Do not administer via gastrostomy or nasogastric tube.
Pour the entire contents of the Mix-Aid packet into approximately 4 ounces of water in a cup and stir for at least 30 seconds.
Pour the entire contents of the Olpruva packet(s) into the suspension and stir for at least 15 seconds.
Drink the entire suspension within 5 minutes after stirring to minimize dissolution of coating. Pour another 4 ounces of water into the cup and drink to make sure that any Olpruva remaining in the cup is consumed.
Discard any suspension that is not taken right away after 30 minutes.
 
Oral granules (Pheburane)
Administration via gastrostomy or nasogastric tube has not been evaluated.
Measure the dose using the calibrated dosing spoon that is provided with the product. The dosing spoon is calibrated in grams of sodium phenylbutyrate.
Swallow the oral granules with a drink (e.g., water, fruit juices, protein-free infant formulas) or sprinkle onto a spoonful of apple sauce or carrot puree; administration with other food has not been studied and is not recommended. Do NOT chew the oral granules or mix into liquids.
Swallow immediately to minimize dissolution of coating.

pancreatitis / Delayed / 0-1.0
peptic ulcer / Delayed / 0-1.0
GI bleeding / Delayed / 0-1.0
arrhythmia exacerbation / Early / 0-1.0
aplastic anemia / Delayed / 0-1.0
renal tubular acidosis (RTA) / Delayed / 0-1.0

metabolic acidosis / Delayed / 14.0-14.0
hypoalbuminemia / Delayed / 11.0-11.0
anemia / Delayed / 9.0-9.0
metabolic alkalosis / Delayed / 7.0-7.0
hyperchloremia / Delayed / 7.0-7.0
hypophosphatemia / Delayed / 6.0-6.0
elevated hepatic enzymes / Delayed / 4.0-6.0
leukopenia / Delayed / 4.0-4.0
thrombocytopenia / Delayed / 3.0-3.0
gastritis / Delayed / 0-2.0
depression / Delayed / 0-2.0
hyperuricemia / Delayed / 2.0-2.0
hyperphosphatemia / Delayed / 2.0-2.0
constipation / Delayed / 0-1.0
edema / Delayed / 0-1.0
thrombocytosis / Delayed / 1.0-1.0
hyperbilirubinemia / Delayed / 1.0-1.0
hypokalemia / Delayed / 1.0-1.0
hypernatremia / Delayed / 1.0-1.0
neurotoxicity / Early / Incidence not known

menstrual irregularity / Delayed / 23.0-23.0
leukocytosis / Delayed / 4.0-4.0
dysgeusia / Early / 3.0-3.0
amenorrhea / Delayed / 3.0-3.0
drug-induced body odor / Delayed / 3.0-3.0
vomiting / Early / 0-2.0
nausea / Early / 0-2.0
abdominal pain / Early / 0-2.0
weight gain / Delayed / 0-2.0
headache / Early / 0-2.0
rash / Early / 0-2.0
syncope / Early / 0-2.0
ecchymosis / Delayed / 0-1.0

Buphenyl, OLPRUVA, Pheburane

Rx

Adjunctive therapy in chronic management of urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS)
Must be combined with dietary protein restriction and, in some cases, essential amino acid supplementation
Indicated in all patients with neonatal-onset deficiency, as well as in patients with late-onset disease who have a history of hyperammonemic encephalopathy

9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.

9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.

9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.

9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.

450 to 600 mg/kg/day PO, given in equally divided doses with each meal or feeding (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.

450 to 600 mg/kg/day PO, given in equally divided doses with each feeding (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.

9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.

9.9 to 13 g/m2/day (Max: 20 g/day) PO, given in equally divided doses with each meal (i.e., 3 to 6 times/day). Monitor response and modify the dose to maintain plasma concentrations of ammonia, arginine, branched-chain amino acids, and serum proteins within normal limits, and maintain plasma glutamine at concentrations less than 1,000 micromol/L.

For patients with hepatic impairment, initiate therapy with a dosage at the lower end of the recommended dosing range; use the lowest dosage necessary to achieve acceptable ammonia concentrations.

Monitor ammonia levels closely when starting patients with impaired renal function on sodium phenylbutyrate; specific dosage adjustment guidance is not available.

Albuterol; Budesonide: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Azelastine; Fluticasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Beclomethasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Belinostat: (Major) Avoid coadministration of sodium phenylbutyrate and belinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and belinostat are inhibitors of histone deacetylase (HDAC).
Betamethasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Budesonide: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Budesonide; Formoterol: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Ciclesonide: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Corticosteroids: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Cortisone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Deflazacort: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Dexamethasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Fludrocortisone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Flunisolide: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Fluticasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Fluticasone; Salmeterol: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Fluticasone; Vilanterol: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Formoterol; Mometasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Haloperidol: (Moderate) Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with haloperidol. Haloperidol has been reported to increase plasma ammonia levels (hyperammonemia).
Hydrocortisone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Methylprednisolone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Mometasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Olopatadine; Mometasone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Panobinostat: (Major) Avoid coadministration of sodium phenylbutyrate and panobinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and panobinostat are inhibitors of histone deacetylase (HDAC).
Prednisolone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Prednisone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Probenecid: (Major) Avoid coadministration of probenecid and sodium phenylbutyrate. Coadministration may increase the risk for potential for neurotoxicity. Probenecid may inhibit renal excretion of the metabolites of sodium phenylbutyrate, including phenylacetate and phenylacetylglutamine.
Probenecid; Colchicine: (Major) Avoid coadministration of probenecid and sodium phenylbutyrate. Coadministration may increase the risk for potential for neurotoxicity. Probenecid may inhibit renal excretion of the metabolites of sodium phenylbutyrate, including phenylacetate and phenylacetylglutamine.
Romidepsin: (Major) Avoid coadministration of sodium phenylbutyrate and romidepsin. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and romidepsin are inhibitors of histone deacetylase (HDAC).
Triamcinolone: (Moderate) The concurrent use of corticosteroids with sodium phenylbutyrate may increase plasma ammonia levels (hyperammonemia) by causing the breakdown of body protein. Patients with urea cycle disorders being treated with sodium phenylbutyrate usually should not receive regular treatment with corticosteroids.
Trofinetide: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and trofinetide. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and trofinetide is an OATP1B3 inhibitor.
Valproic Acid, Divalproex Sodium: (Contraindicated) Valproic acid and its analogs are contraindicated in patients with urea cycle disorders, including those being treated with sodium phenylbutyrate. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with known or suspected urea cycle disorders. Do not administer valproic acid to a patient who is being treated with sodium phenylbutyrate.
Vorinostat: (Major) Avoid coadministration of sodium phenylbutyrate and vorinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and vorinostat are inhibitors of histone deacetylase (HDAC).

Buphenyl Nasogastric Pwd F/Recon: 1dose, 3g
Buphenyl/Sodium Phenylbutyrate Oral Pwd F/Recon: 1dose, 3g
Buphenyl/Sodium Phenylbutyrate Oral Tab: 500mg
OLPRUVA Oral Susp: 2g, 3g, 2-3g, 3-3.67g
Pheburane Oral Gran: 174g

13 g/m2/day (Max: 20 g/day) PO.

13 g/m2/day (Max: 20 g/day) PO.

13 g/m2/day (Max: 20 g/day) PO.

weight 20 kg or more: 13 g/m2/day (Max: 20 g/day) PO.
weight less than 20 kg: 600 mg/kg/day PO (oral powder or Pheburane granules only); safety and efficacy of other formulations have not been established.

600 mg/kg/day PO (oral powder or Pheburane granules only); safety and efficacy of other formulations have not been established.

600 mg/kg/day PO (oral powder or Pheburane granules only); safety and efficacy of other formulations have not been established.

Sodium 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, which is excreted by the kidneys. On a molar basis, phenylacetylglutamine is comparable to urea (each containing two moles of nitrogen). Renal excretion of the glutamine conjugate is an alternate vehicle for waste nitrogen excretion. In patients with urea cycle disorders, sodium phenylbutyrate decreases elevated plasma ammonia and glutamine levels.

Sodium phenylbutyrate is administered orally. The apparent volume of distribution of phenylbutyrate is 7.2 L under fasted conditions. After oral administration, sodium phenylbutyrate is metabolized by beta-oxidation into phenylacetate, which is converted to its coenzyme A ester, phenylacetyl-coenzyme A and further conjugated with glutamine to form phenylacetylglutamine. Phenylacetylglutamine is excreted by the kidneys. The major sites for metabolism of sodium phenylbutyrate are the liver and kidneys. Phenylacetate is also hydrolyzed by esterases in liver and blood. Approximately 80% to 100% of the administered dose was excreted by the kidneys within 24 hours as the conjugation product. For each gram of sodium phenylbutyrate administered, it is estimated that between 0.12 to 0.15 g of phenylacetylglutamine nitrogen are produced. The mean half-life of sodium phenylbutyrate during studies of the oral granules ranged from 0.5 to 0.8 hour.

Oral tablets and powder
After oral administration of sodium phenylbutyrate 5 g (tablet) under fasting conditions, measurable plasma concentrations of phenylbutyrate and phenylacetate were detected 15 and 30 minutes after dosing, respectively, and phenylacetylglutamine was detected shortly thereafter. Phenylbutyrate Cmax was 195 mcg/mL at 1 hour after administration of the oral powder and 218 mcg/mL at 1.35 hours after administration of the oral tablets. Phenylacetate Cmax was 45.3 mcg/mL at 3.55 hours after administration of the oral powder and 48.5 mcg/mL at 3.74 hours after administration of the oral tablets. The effect of food on absorption is unknown.
 
Oral granules
After oral administration of sodium phenylbutyrate 5 g oral granules (Olpruva) under fasting conditions, the mean phenylbutyrate Cmax and AUC were 229 mcg/mL and 510 hour x mcg/mL, respectively. Compared to fasted conditions, the AUC of phenylbutyrate decreased by 39% and Cmax decreased by 50% when administered with a high-fat meal.
After oral administration of sodium phenylbutyrate 3 g oral granules (Pheburane) under fasting conditions, the mean phenylbutyrate Cmax ranged from 146 to 169 mcg/mL at approximately 0.6 hours after administration. The mean phenylbutyrate AUC ranged from 272 to 283 hour x mcg/mL. Compared to fasted conditions, the AUC of phenylbutyrate decreased by 40% to 45% and Cmax decreased by 55% when administered with a high-fat, high-calorie meal. When administered with a normal-fat, normal-calorie, low-protein meal, the AUC of phenylbutyrate decreased by 56% to 63% and Cmax decreased by 43% to 45% compared to fasted conditions.

Data are insufficient to evaluate for risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes associated with sodium phenylbutyrate use during human pregnancy. Animal studies have not been conducted, however, based on published animal data, phenylacetate may be neurotoxic to the developing brain. Prenatal exposure of rat pups to phenylacetate produced lesions in layer 5 of the cortical pyramidal cells; dendritic spines were longer and thinner than normal and reduced in number.

There are no data on the presence of sodium phenylbutyrate in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.