RAVICTI

Urea Cycle Disorder Agents

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.[53022]
 
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.[53022]
 
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.[53022]

seizures / Delayed / Incidence not known
hearing loss / Delayed / Incidence not known

constipation / Delayed / 10.0
thrombocytopenia / Delayed / 10.0
neutropenia / Delayed / 10.0
anemia / Delayed / 10.0
thrombocytosis / Delayed / 10.0
lymphocytosis / Delayed / 10.0
dehydration / Delayed / 10.0
metabolic acidosis / Delayed / 10.0
elevated hepatic enzymes / Delayed / 10.0
confusion / Early / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
memory impairment / Delayed / Incidence not known

flatulence / Early / 14.0-14.0
dyspepsia / Early / 5.0-5.0
agitation / Early / 10.0
fatigue / Early / 7.0
irritability / Delayed / 10.0
headache / Early / 10.0
lethargy / Early / 10.0
dizziness / Early / 10.0
vomiting / Early / 7.0
gastroesophageal reflux / Delayed / 10.0
abdominal pain / Early / 7.0
nausea / Early / 2.0
diarrhea / Early / 10.0
anorexia / Delayed / 7.0
rash / Early / 10.0
fever / Early / 10.0
nasal congestion / Early / 10.0
cough / Delayed / 10.0
rhinorrhea / Early / 10.0
drowsiness / Early / Incidence not known
tremor / Early / Incidence not known
dysgeusia / Early / Incidence not known

RAVICTI

Rx

Nitrogen-binding agent
Used for chronic management of urea cycle disorders (UCD)
Increased exposure to phenylacetate (major metabolite) may be associated with neurotoxicity

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).

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.[53022]

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).

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.[53022]

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).

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.[53022]

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).[53022]

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.[53022]

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.

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.

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.
Guaifenesin; 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.
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.
Hydrocodone; Pseudoephedrine: (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.
Praziquantel: (Moderate) Monitor for reduced response to praziquantel if coadministered with glycerol phenylbutyrate. Concomitant use may produce therapeutically ineffective concentrations of praziquantel. In vitro and drug interactions studies suggest that the CYP3A isoenzyme is the major enzyme involved in praziquantel metabolism; 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.

RAVICTI Oral Sol: 1mL, 1.1g

17.5 mL/day (19 g/day) PO.

17.5 mL/day (19 g/day) PO.

17.5 mL/day (19 g/day) PO.

17.5 mL/day (19 g/day) PO.

17.5 mL/day (19 g/day) PO.

17.5 mL/day (19 g/day) PO.

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.[53022]
 
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.[53022]

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.

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.