Glycerol phenylbutyrate is a nitrogen-binding agent that provides an alternative vehicle for waste nitrogen excretion in patients with urea cycle disorders (UCD). In patients with UCD, toxic concentrations of ammonia accumulate due to inherited deficiencies of necessary enzymes or transporters, preventing the synthesis of urea from ammonia. It often results in hyperammonemia and subsequent damage to the central nervous system and can be fatal if left untreated. Glycerol phenylbutyrate is indicated for chronic management of urea cycle disorders that cannot be managed by a protein-restricted diet and amino acid supplements alone; it is not indicated for the treatment of acute hyperammonemia. Increased exposure to phenylacetate (PAA), the major metabolite of glycerol phenylbutyrate, may be associated with neurotoxicity.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Liquid Formulations
-Administer glycerol phenylbutyrate orally to all patients who can swallow, even those with a nasogastric or gastrostomy tube. For patients who cannot swallow, follow recommendations for nasogastric or gastrostomy tube administration.
-Use a new reclosable bottle cap adapter with each new bottle that is opened.
-Measure each dose with a new and dry oral syringe.
-Storage: Discard bottle and any remaining contents 28 days after opening.
-If water or moisture enters the glycerol phenylbutyrate bottle, the contents will become cloudy. If the contents appear cloudy, do not use the glycerol phenylbutyrate; return the bottle to the pharmacy to be discarded.
Oral Administration
-Administer with food or formula directly into the mouth using an oral syringe.
-Administer just prior to breast-feeding in infants who are breast-feeding.
Nasogastric tube or Gastrostomy tube Administration
-Withdraw prescribed dose from the bottle using an oral syringe.
-Place the tip of the syringe into the tip of the gastrostomy/nasogastric tube to administer dose.
-After administration, use a separate syringe to flush once with 10 mL of water or formula and allow the flush to drain. If needed, flush a second time with an additional 10 mL of water or formula to clear the tube.
-For patients who require a volume of less than 1 mL per dose via nasogastric or gastrotomy tube, the delivered dose may be less than expected due to adherence of glycerol phenylbutyrate to the plastic tubing. Therefore, monitor these patients closely using ammonia concentrations after initiation of glycerol phenylbutyrate dosing or dosage adjustments.
The effect of multiple doses of glycerol phenylbutyrate on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin) clinical trial. In this trial, QT prolongation was not found; however, because assay sensitivity was not established, a potential increase in mean QTc interval of 10 ms cannot be ruled out.
In clinical trials, headache occurred in 10% or more of patients treated with glycerol phenylbutyrate. Dizziness occurred in 10% or more of patients in open-label trials, and fatigue occurred in 10% or more of patients in open-label trials and 7% in the double-blind trial. Seizures, tremor, and peripheral neuropathy have also been reported. In clinical trials of pediatric patients younger than 2 months (n = 16), lethargy and irritability/agitation were reported in 10% or more of patients. Phenylacetate (PAA), the major metabolite of glycerol phenylbutyrate, is associated with neurotoxicity. Signs and symptoms of PAA neurotoxicity may include somnolence (drowsiness), fatigue, lightheadedness, headache, altered sense of taste, hypoacusis (hearing loss), confusion, memory impairment, and exacerbation of peripheral neuropathy. These symptoms were observed at plasma PAA concentrations of 500 mcg/mL in a study of cancer patients receiving IV PAA. The adverse events in this study were reversible. In a trial of healthy subjects who received glycerol phenylbutyrate, a dose-dependent increase in nervous system adverse reactions was observed. Plasma PAA concentrations, which were measured on day 3 and not always at the onset of symptoms, ranged from 8 to 56 mcg/mL with a glycerol phenylbutyrate dose of 4 mL PO 3 times daily and 31 to 242 mcg/mL with a glycerol phenylbutyrate dose of 6 mL PO 3 times daily. If symptoms of headache, somnolence, or confusion are present without high ammonia concentrations or other intercurrent illnesses, reduce the glycerol phenylbutyrate dosage.
Gastrointestinal (GI) effects are among the most common adverse reactions to glycerol phenylbutyrate. In a trial comparing glycerol phenylbutyrate (n = 44) to sodium phenylbutyrate (n = 45), diarrhea (16% vs. 7%), flatulence (14% vs. 2%), abdominal pain (7% vs. 4%), anorexia (7% vs. 4%), and vomiting (7% vs. 4%) occurred more frequently in the glycerol phenylbutyrate group. Nausea (2% vs. 7%) and dyspepsia (5% vs. 7%) were reported less frequently in the glycerol phenylbutyrate group. In open-label trials (n = 77; 43 pediatric patients 2 months to 17 years), diarrhea, anorexia, nausea, and vomiting were reported in 10% or more of patients; abdominal pain was reported in 10% or more of pediatric patients. In clinical trials of pediatric patients younger than 2 months (n = 16), GI adverse reactions reported in 10% or more of patients included constipation, diarrhea, feeding disorder (decreased appetite, hypophagia), flatulence, gastroesophageal reflux, and vomiting. Retching/gagging and dysgeusia or burning sensation in the mouth have been reported in postmarketing surveillance. Nausea/vomiting can also be a symptom of phenylacetate (PAA) toxicity. If vomiting or nausea are present without high ammonia concentrations or other intercurrent illnesses, the glycerol phenylbutyrate dosage should be reduced.
Although not reported in adult patients in clinical trials, rash and/or papule was reported in 10% or more of pediatric patients during long-term studies (n = 59) of glycerol phenylbutyrate and should be considered a possible adverse reaction in adults. Fever was also reported in 10% or more of infants and young children (younger than 2 years) receiving glycerol phenylbutyrate in clinical trials (n = 33). Abnormal body odor, including from skin, hair, and urine, has been reported in postmarketing surveillance.
Although not reported in adult patients in clinical trials, cough, nasal congestion, and rhinorrhea were reported in 10% or more of infants and young children (2 months to younger than 2 years) receiving glycerol phenylbutyrate in clinical trials (n = 17). Cough was also commonly reported (10% or more) in infants younger than 2 months in clinical trials (n = 16).
Although not reported in adult patients in clinical trials, neutropenia was reported in 10% or more of infants and young children (younger than 2 years) receiving glycerol phenylbutyrate in clinical trials (n = 33). In clinical trials of infants younger than 2 months (n = 16), anemia, lymphocytosis, thrombocytosis, and thrombocytopenia were also reported in 10% or more of patients.
Although not reported in adult patients in clinical trials of glycerol phenylbutyrate, dehydration, elevated hepatic enzymes, and metabolic acidosis were reported in 10% or more of infants younger than 2 months (n = 16).
Glycerol phenylbutyrate is contraindicated in patients with known phenylbutyrate hypersensitivity.
Use glycerol phenylbutyrate cautiously and monitor ammonia concentrations closely in patients with pancreatic insufficiency or fat malabsorption syndromes. Pancreatic enzymes in the small intestine are responsible for separating phenylbutyrate, the active moiety, from the glycerol backbone. This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal conditions resulting in fat malabsorption may impair or prohibit the digestion of glycerol phenylbutyrate, which may result in reduced phenylbutyrate absorption and ultimately less control of plasma ammonia concentrations.
Use glycerol phenylbutyrate cautiously in patients with hepatic disease and initiate therapy at the low end of the dosage range in patients with moderate to severe hepatic impairment. Phenylacetate (PAA) is the major metabolite of phenylbutyrate and is the active moiety. PAA conjugates with glutamine in the liver and kidneys to form phenylacetylglutamine (PAGN), which is excreted in the urine. Because conversion of PAA to PAGN occurs in the liver, patients with hepatic impairment may have reduced conversion ability, which may result in increased PAA concentrations. PAA has been associated with neurotoxicity. Signs of neurotoxicity may include somnolence, fatigue, lightheadedness, headache, dysgeusia, hearing impairment, disorientation, impaired memory, seizures, and exacerbation of preexisting neuropathy. If neurotoxicity symptoms develop in the absence of high ammonia levels or other intercurrent illnesses, reduce the dosage of glycerol phenylbutyrate.
Safety and efficacy of glycerol phenylbutyrate have not been established in patients with renal impairment. Monitor ammonia concentrations closely in patients with impaired renal function. Phenylacetate (PAA) is the major metabolite of phenylbutyrate and is the active moiety. PAA conjugates with glutamine in the liver and kidneys to form phenylacetylglutamine (PAGN); PAGN is then excreted in the urine. The effects of renal disease on the conversion of PAA to PAGN or the excretion of PAGN have not been defined.
The prescribing of glycerol phenylbutyrate requires an experienced clinician familiar with the management of patients with urea cycle disorders.
The limited data available with use of glycerol phenylbutyrate in human pregnancy are insufficient to determine a drug-associated risk of major birth defects and miscarriage. No effects on embryo-fetal development were observed in rabbits or rats when doses approximately 2 to 3 times an adult dose of 6.87 mL/m2/day were administered during the period of organogenesis; however, maternal toxicity was observed at doses approximately 3 times an adult dose of 6.87 mL/m2/day. Maternal toxicity, reduced fetal weights, and variations in skeletal development were observed when pregnant rats were given doses greater than or equal to 5.7 times a dose of 6.87 mL/m2/day. Report pregnancies to Horizon at 1-866-479-6742.
It is not known whether glycerol phenylbutyrate is excreted in human milk, affects milk production, or has an adverse effect on nursing infants. However, because of the potential for serious adverse effects, including neurotoxicity and tumorigenicity in nursing infants, breast-feeding is not recommended with maternal use of glycerol phenylbutyrate.
-Glycerol phenylbutyrate must be used in combination with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
-Glycerol phenylbutyrate is not indicated for the treatment of acutely elevated ammonia concentrations in patients with urea cycle disorders (UCDs) because rapidly acting interventions are essential to reduce plasma ammonia concentrations.
-The safety and efficacy of glycerol phenylbutyrate for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.
For the chronic management of hyperammonemia in patients with urea cycle disorders:
NOTE: Glycerol phenylbutyrate is designated as an orphan drug for the maintenance treatment of patients with urea cycle enzyme deficiencies.
Oral dosage:
Adults switching from sodium phenylbutyrate: For switching from sodium phenylbutyrate tablets: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86. For switching from sodium phenylbutyrate powder: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.81. Divide the total daily dosage into 3 equal doses and round each dose up to the nearest 0.5 mL. Max daily dose: 17.5 mL (19 g).
Adults who are phenylbutyrate naive: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) PO divided into 3 equal doses, each rounded up to the nearest 0.5 mL. Start with 4.5 mL/m2/day in patients with some residual enzyme activity. When determining a starting dosage, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. In general, an estimated initial glycerol phenylbutyrate dosage per 24-hour period is 0.6 mL per gram of dietary protein ingested per 24 hours (Max: 17.5 mL/day). Adjust dosage as needed based on plasma ammonia, urinary phenylacetylglutamine, and/or plasma phenylacetate concentrations.
Children and Adolescents 2 to 17 years switching from sodium phenylbutyrate: For switching from sodium phenylbutyrate tablets: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86. For switching from sodium phenylbutyrate powder: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.81. Divide the total daily dosage into 3 equal doses and round each dose up to the nearest 0.5 mL. Max daily dose: 17.5 mL (19 g).
Children and Adolescents 2 to 17 years who are phenylbutyrate naive: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) PO divided into 3 equal doses, each rounded up to the nearest 0.5 mL. Start with 4.5 mL/m2/day in patients with some residual enzyme activity. When determining a starting dosage, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. In general, an estimated initial glycerol phenylbutyrate dosage per 24-hour period is 0.6 mL per gram of dietary protein ingested per 24 hours (Max: 17.5 mL/day). Adjust dosage as needed based on plasma ammonia, urinary phenylacetylglutamine, and/or plasma phenylacetate concentrations.
Infants and Children 1 month to 1 year switching from sodium phenylbutyrate: For switching from sodium phenylbutyrate tablets: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86. For switching from sodium phenylbutyrate powder: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.81. Divide the total daily dosage into at least 3 equal doses and round each dose up to the nearest 0.1 mL. Max daily dose: 17.5 mL (19 g).
Infants and Children 1 month to 1 year who are phenylbutyrate-naive: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) PO divided into at least 3 equal doses, each rounded up to the nearest 0.1 mL. Start with 4.5 mL/m2/day in patients with some residual enzyme activity. When determining a starting dosage, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. In general, an estimated initial glycerol phenylbutyrate dosage per 24-hour period is 0.6 mL per gram of dietary protein ingested per 24 hours (Max: 17.5 mL/day). Adjust dosage as needed based on plasma ammonia, urinary phenylacetylglutamine, and/or plasma phenylacetate concentrations.
Neonates switching from sodium phenylbutyrate: For switching from sodium phenylbutyrate tablets: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86. For switching from sodium phenylbutyrate powder: Total daily oral dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.81. Divide the total daily dosage into at least 3 equal doses and round each dose up to the nearest 0.1 mL. Max daily dose: 17.5 mL (19 g).
Neonates who are phenylbutyrate-naive: 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) PO divided into at least 3 equal doses, each rounded up to the nearest 0.1 mL. Start with 4.5 mL/m2/day in patients with some residual enzyme activity. When determining a starting dosage, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. In general, an estimated initial glycerol phenylbutyrate dosage per 24-hour period is 0.6 mL per gram of dietary protein ingested per 24 hours (Max: 17.5 mL/day). Adjust dosage as needed based on plasma ammonia, urinary phenylacetylglutamine, and/or plasma phenylacetate concentrations.
Therapeutic Drug Monitoring:
-The methods used for measuring plasma ammonia concentrations may vary among different laboratories and values obtained by different assay methods may not be interchangeable. Normal and therapeutic target concentrations of ammonia depend upon the assay method used by the individual laboratory. During treatment with glycerol phenylbutyrate, refer to assay-specific normal and therapeutic target ranges for plasma ammonia.
-Dosage adjustment based on plasma ammonia: If patients experience symptoms of vomiting, nausea, headache, somnolence, or confusion in the absence of high ammonia concentrations or other intercurrent illnesses, reduce the glycerol phenylbutyrate dosage and monitor patient clinically. In patients with high ammonia concentrations, increase the glycerol phenylbutyrate dosage to reduce the fasting ammonia concentration to less than half the upper limit of normal (ULN) in patients 6 years and older. For infants and children younger than 6 years, where obtaining a fasting ammonia concentration is problematic due to frequent feedings, adjust the glycerol phenylbutyrate dosage to keep the first ammonia of the morning below the ULN.
-Dosage adjustment based on urinary phenylacetylglutamine (U-PAGN): If available, U-PAGN may be used to help guide dosage adjustments. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the upper limit of normal (ULN), increase the glycerol phenylbutyrate dosage. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. The amount of dose adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-hour U-PAGN concentration and the estimated glycerol phenylbutyrate dose needed per gram of dietary protein ingested. Consider concomitant medications when making a dosage adjustment (e.g., probenecid may reduce the urinary excretion of PAGN).
-Dosage adjustment based on plasma phenylacetate: Plasma phenylacetate (PAA) concentrations may be useful to guide dosing if symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or intercurrent illness. In patients with a high PAA to PAGN ratio, a further increase in glycerol phenylbutyrate dose may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction. The PAA to PAGN ratio has been observed to be generally less than 1 in patients without significant PAA accumulation.
Maximum Dosage Limits:
-Adults
17.5 mL/day (19 g/day) PO.
-Geriatric
17.5 mL/day (19 g/day) PO.
-Adolescents
17.5 mL/day (19 g/day) PO.
-Children
17.5 mL/day (19 g/day) PO.
-Infants
17.5 mL/day (19 g/day) PO.
-Neonates
17.5 mL/day (19 g/day) PO.
Patients with Hepatic Impairment Dosing
For patients with moderate to severe hepatic impairment, initiate therapy with a dosage at the lower end of the recommended dosing range (4.5 mL/m2/day); use the lowest dosage necessary to achieve acceptable ammonia concentrations.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available. Initial dosage adjustments are not required; however, ammonia concentrations should be closely monitored and dosages adjusted accordingly.
*non-FDA-approved indication
Acetaminophen; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If glycerol phenylbutyrate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with glycerol phenylbutyrate can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of hydrocodone as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of oxycodone as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Albuterol; Budesonide: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary. If glycerol phenylbutyrate is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a weak CYP3A inducer like glycerol phenylbutyrate with alfentanil, a CYP3A substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If glycerol phenylbutyrate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with glycerol phenylbutyrate can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of oxycodone as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Atogepant: (Major) Avoid use of atogepant and glycerol phenylbutyrate when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with glycerol phenylbutyrate. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Coadministration with a weak CYP3A inducer resulted in a 25% reduction in atogepant overall exposure and a 24% reduction in atogepant peak concentration.
Avanafil: (Major) Coadministration of avanafil with glycerol phenylbutyrate is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Azelastine; Fluticasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Beclomethasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Benzhydrocodone; Acetaminophen: (Moderate) Monitor for reduced efficacy of benzhydrocodone and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of benzhydrocodone as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of benzhydrocodone and frequently monitor for signs of respiratory depression and sedation. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Betamethasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Budesonide: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Budesonide; Formoterol: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Buprenorphine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If glycerol phenylbutyrate is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer.
Buprenorphine; Naloxone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If glycerol phenylbutyrate is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If glycerol phenylbutyrate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with glycerol phenylbutyrate can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If glycerol phenylbutyrate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with glycerol phenylbutyrate can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Carbamazepine: (Moderate) Monitor carbamazepine concentrations closely during coadministration of glycerol phenylbutyrate; carbamazepine dose adjustments may be needed. Concomitant use may decrease carbamazepine concentrations. Carbamazepine is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer.
Cariprazine: (Major) Coadministration of cariprazine with glycerol phenylbutyrate is not recommended as the net effect of CYP3A induction on cariprazine and its metabolites is unclear. Cariprazine is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Coadministration of cariprazine with CYP3A inducers has not been evaluated.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of tramadol as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Chlorpheniramine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If glycerol phenylbutyrate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with glycerol phenylbutyrate can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of hydrocodone as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ciclesonide: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Clozapine: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with glycerol phenylbutyrate. Consideration should be given to increasing the clozapine dose if necessary. When glycerol phenylbutyrate is discontinued, reduce the clozapine dose based on clinical response. Glycerol phenylbutyrate is a weak inducer of CYP3A, one of the isoenzymes responsible for the metabolism of clozapine.
Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If glycerol phenylbutyrate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with glycerol phenylbutyrate can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If glycerol phenylbutyrate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with glycerol phenylbutyrate can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If glycerol phenylbutyrate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with glycerol phenylbutyrate can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If glycerol phenylbutyrate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with glycerol phenylbutyrate can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If glycerol phenylbutyrate is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with glycerol phenylbutyrate can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Corticosteroids: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Cortisone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with glycerol phenylbutyrate is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A and has a narrow therapeutic index; glycerol phenylbutyrate is a weak CYP3A inducer.
Deflazacort: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Dexamethasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Dextromethorphan; Quinidine: (Moderate) Concomitant use of glycerol phenylbutyrate and quinidine may result in decreased exposure of quinidine. Quinidine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of quinidine during coadministration.
Diazepam: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with glycerol phenylbutyrate is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer.
Doravirine: (Minor) Concurrent administration of doravirine and glycerol phenylbutyrate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; glycerol phenylbutyrate is a weak CYP3A inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Concurrent administration of doravirine and glycerol phenylbutyrate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; glycerol phenylbutyrate is a weak CYP3A inducer.
Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of glycerol phenylbutyrate is necessary. If glycerol phenylbutyrate is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like glycerol phenylbutyrate with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Fludrocortisone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Flunisolide: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Fluticasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Fluticasone; Salmeterol: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Fluticasone; Vilanterol: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Formoterol; Mometasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Haloperidol: (Moderate) Haloperidol may induce elevated blood ammonia concentrations. Use caution and monitor ammonia concentrations closely if co-administration of haloperidol and glycerol phenylbutyrate is necessary.
Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of hydrocodone as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of hydrocodone as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of hydrocodone as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Hydrocortisone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of oxycodone as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Isradipine: (Minor) Monitor for decreased efficacy of isradipine if coadministration with glycerol phenylbutyrate is necessary. Concomitant use may decrease isradipine exposure. Isradipine is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Lopinavir; Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with glycerol phenylbutyrate. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Lumateperone: (Major) Avoid coadministration of lumateperone and glycerol phenylbutyrate as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A substrate; glycerol phenylbutyrate is a weak CYP3A inducer. Although data are unavailable for weak CYP3A inducers, coadministration with a strong CYP3A inducer significantly decreased lumateperone exposure.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with glycerol phenylbutyrate is necessary as concurrent use may decrease mefloquine exposure and efficacy. Mefloquine is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Meperidine: (Moderate) Monitor for reduced efficacy of meperidine and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary. Consider increasing the dose of meperidine as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of meperidine and frequently monitor for signs of respiratory depression and sedation. Meperidine is a substrate of CYP3A; glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use can decrease meperidine exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Methadone: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary. Consider increasing the dose of methadone as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of methadone and frequently monitor for signs of respiratory depression and sedation. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use can decrease methadone exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Methylprednisolone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Midazolam: (Moderate) Concomitant use of glycerol phenylbutyrate and midazolam may result in decreased exposure of midazolam. Monitor for decreased efficacy of midazolam during coadministration. Midazolam is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. In a drug interaction study in healthy subjects, coadministration with glycerol phenylbutyrate reduced the mean Cmax and AUC of midazolam by 25% and 32%, respectively, compared to administration of midazolam alone. Additionally, the mean Cmax and AUC for 1-hydroxy midazolam were 28% and 52% higher, respectively, compared to administration of midazolam alone.
Mometasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with glycerol phenylbutyrate is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for reduced sirolimus efficacy if sirolimus is coadministered with glycerol phenylbutyrate. Concomitant use may decrease sirolimus exposure. Sirolimus is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Nimodipine: (Moderate) Monitor for decreased efficacy of nimodipine if coadministration with glycerol phenylbutyrate is necessary as concomitant use may decrease plasma concentrations of nimodipine. Nimodipine is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of glycerol phenylbutyrate is necessary. Concomitant use of nirmatrelvir and glycerol phenylbutyrate may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with glycerol phenylbutyrate. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with glycerol phenylbutyrate as concurrent use may decrease nisoldipine exposure and efficacy. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer. Coadministration with a strong CYP3A inducer lowered nisoldipine plasma concentrations to undetectable levels.
Olopatadine; Mometasone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of oxycodone as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with glycerol phenylbutyrate is necessary due to the risk of decreased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Prednisolone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Prednisone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Probenecid: (Moderate) Probenecid may inhibit renal excretion of glycerol phenylbutyrate metabolites, including phenylacetate (PAA) and phenylacetylglutamine (PAGN). PAA has been associated with neurotoxicity. If probenecid must be used in combination with glycerol phenylbutyrate, monitor the patient closely for signs and symptoms of neurotoxicity. In addition, because probenecid alters PAGN excretion, use caution when interpreting urinary PAGN concentrations for the purpose of dosage adjustments.
Probenecid; Colchicine: (Moderate) Probenecid may inhibit renal excretion of glycerol phenylbutyrate metabolites, including phenylacetate (PAA) and phenylacetylglutamine (PAGN). PAA has been associated with neurotoxicity. If probenecid must be used in combination with glycerol phenylbutyrate, monitor the patient closely for signs and symptoms of neurotoxicity. In addition, because probenecid alters PAGN excretion, use caution when interpreting urinary PAGN concentrations for the purpose of dosage adjustments.
Quinidine: (Moderate) Concomitant use of glycerol phenylbutyrate and quinidine may result in decreased exposure of quinidine. Quinidine is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of quinidine during coadministration.
Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with glycerol phenylbutyrate. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with glycerol phenylbutyrate is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A inducers.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of glycerol phenylbutyrate. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if glycerol phenylbutyrate must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of sufentanil injection as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs of respiratory depression and sedation. Sufentanil is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with glycerol phenylbutyrate is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; glycerol phenylbutyrate is a weak CYP3A inducer.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of tramadol as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of tramadol as needed. If glycerol phenylbutyrate is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Triamcinolone: (Moderate) Corticosteroids may induce elevated blood ammonia concentrations. Corticosteroids should be used with caution in patients receiving glycerol phenylbutyrate. Monitor ammonia concentrations closely.
Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with glycerol phenylbutyrate as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A substrate; glycerol phenylbutyrate is a weak CYP3A inducer.
Ulipristal: (Major) Avoid coadministration of ulipristal with glycerol phenylbutyrate. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal. Ulipristal is a substrate of CYP3A and glycerol phenylbutyrate is a CYP3A inducer.
Valproic Acid, Divalproex Sodium: (Moderate) Valproic acid may induce elevated blood ammonia concentrations. Use caution and monitor ammonia concentrations closely if co-administration of valproic acid and glycerol phenylbutyrate is necessary.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with glycerol phenylbutyrate is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Glycerol phenylbutyrate is a triglyceride that contains 3 molecules of phenylbutyrate. It serves as an alternative vehicle for waste nitrogen excretion, which helps to reduce blood ammonia and glutamine concentrations in patients with certain urea cycle disorders. Patients with high blood ammonia and glutamine concentrations are at particular risk for encephalopathies and neurotoxicity.
The urea cycle is responsible for maintaining low blood concentrations of ammonia and glutamine produced by protein breakdown. The normal urea cycle requires numerous enzyme-catalyzed steps to convert ammonia into nitrogenous waste (i.e., urea) that can be excreted from the body. Hyperammonemia may occur when there is a deficiency in one or more urea cycle enzymes or transporters. Ammonia in the blood is converted to glutamine. Phenylacetate, the major metabolite of glycerol phenylbutyrate, conjugates with glutamine in the liver and kidneys to form glutamine phenylacetate, which is then acetylated to form phenylacetylglutamine. Phenylacetylglutamine is excreted by the kidneys. Similar to urea, two moles of nitrogen are removed per mole of phenylacetylglutamine.
Glycerol phenylbutyrate is administered orally. Pancreatic lipases hydrolyze glycerol phenylbutyrate and release phenylbutyrate (PBA) from the glycerol backbone. PBA is converted by beta-oxidation to phenylacetate (PAA), which is then conjugated with glutamine in the liver and kidneys to form phenylacetylglutamine (PAGN). In healthy subjects, exposure to PAA, PBA, and PAGN increased in a dose-dependent manner. PAGN is eliminated in the urine. In vitro pharmacokinetic studies found protein binding to be 81% to 98% for PBA (over 1 to 250 mcg/mL); 37% to 66% for PAA (over 5 to 500 mcg/mL); and 7% to 12% for PAGN (no concentration effects noted). During a premarketing pharmacokinetic study, the mean percentage of administered PBA excreted as PAGN was approximately 69% in adult patients with a urea cycle disorder (UCD) and 66% in pediatric UCD patients. PAA and PBA were also detected in the urine and accounted for less than 1% of the administered dose.
Possibly affected cytochrome P450 isoenzymes: CYP2C9, CYP2D6, and CYP3A4/5
During in vitro studies, phenylbutyrate (PBA), at a concentration of 800 mcg/mL, caused more than 60% reversible inhibition of cytochrome P450 isoenzymes CYP2C9, CYP2D6, and CYP3A4/5. In addition, inhibition of CYP1A2, CYP2C8, CYP2C19, and CYP2D6 by phenylacetate (PAA) at a concentration of 2,800 mcg/mL was observed in vitro. However, in healthy subjects who received glycerol phenylbutyrate 6 mL PO 3 times daily for 3 days, the mean PBA and PPA Cmax were 100 mcg/mL and 65 mcg/mL, respectively. The clinical implications of the in vitro data are not known.
-Route-Specific Pharmacokinetics
Oral Route
Glycerol phenylbutyrate is a prodrug. When orally ingested, pancreatic lipases in the gastrointestinal tract release phenylbutyrate (PBA) from the glycerol backbone. In healthy fasting adults who received a single oral dose of glycerol phenylbutyrate 2.9 mL/m2, peak PBA, PAA, and PAGN plasma concentrations occurred at 2 hours, 4 hours, and 4 hours, respectively. In adult UCD patients who received multiple doses, maximum plasma concentrations at steady state of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day. The mean peak PAA concentration was 39 mcg/mL in adults.
-Special Populations
Hepatic Impairment
The disposition of glycerol phenylbutyrate in urea cycle disorder patients with hepatic impairment has not been determined; however, because conversion of PAA to PAGN occurs in the liver, patients with hepatic impairment may have reduced conversion ability, which may result in increased PAA concentrations and a decreased ability to eliminate nitrogen via PAGN. In adult volunteers with hepatic impairment (Child-Pugh A, B, and C), PBA AUC was 42%, 84%, and 50% higher, respectively, than in healthy subjects. PAA AUC was 22%, 53%, and 94% higher than in healthy subjects. In contrast, the PAGN AUC was 42%, 27%, and 22% lower in patients with Child-Pugh A, B, and C hepatic impairment compared to that of healthy volunteers.
Renal Impairment
The disposition of glycerol phenylbutyrate in patients with renal impairment has not been studied.
Pediatrics
In clinical studies in pediatric patients, mean peak PAA concentrations were 257, 142, and 70 mcg/mL for patients younger than 2 months, 2 months to younger than 2 years, and 2 to 17 years, respectively. Population pharmacokinetic modeling and dosing simulations suggest body surface area is the most significant covariate explaining the variability of PAA clearance in children. PAA clearance was 3.8 L/hour, 6.8 L/hour, 10.9 L/hour, 16.4 L/hour, and 24.4 L/hour for UCD patients younger than 2 months, 2 months to younger than 2 years, 3 to 5, 6 to 11, and 12 to 17 years, respectively. The mean peak ratio of PAA to PAGN in UCD patients younger than 2 months was higher (mean: 1.6; range: 0.1 to 7.1) than that of patients 2 months to younger than 2 years (mean: 0.5; range: 0.1 to 1.2).
Gender Differences
In healthy adult volunteers, women generally had higher plasma concentrations of all metabolites than men. In healthy female volunteers, mean Cmax for PAA was 51% and 120% higher than male volunteers after administration of 4 mL and 6 mL 3 times daily for 3 days, respectively. The dose normalized mean AUC0- 23h for PAA was 108% higher in females than males.