Glycerol phenylbutyrate
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From MedlinePlus, U.S. National Library of Medicine
Dosing in kidney impairment
Renal Impairment The efficacy and safety of RAVICTI in patients with renal impairment are unknown. Monitor ammonia levels closely when starting patients with impaired renal function on RAVICTI.
Dosing in liver impairment
Dosage Modifications in Patients with Hepatic Impairment For patients with moderate to severe hepatic impairment, the recommended starting dosage is at the lower end of the recommended dosing range (4.5 mL/m 2 /day) and the dosage should be kept at the lowest necessary to control the patient's plasma ammonia [see Use in Specific Populations ] .
Preparation and administration
Important Administration Instructions RAVICTI should be prescribed by a physician experienced in the management of UCDs. Instruct patients to take RAVICTI with food or formula and to administer directly into the mouth via oral syringe. Instruct patients to use the RAVICTI bottle and oral syringe as follows: Use a new reclosable bottle cap adapter with each new bottle that is opened.
Open the RAVICTI bottle and twist on the new reclosable bottle cap adapter. Use a new and dry oral syringe to withdraw each prescribed dose of RAVICTI. Discard the oral syringe after each dose. Tightly close the tethered tab on the reclosable bottle cap adapter after each use. Do not rinse the reclosable bottle cap adapter.
Discard bottle and any remaining contents 28 days after opening. If water or moisture enters the RAVICTI bottle, the contents will become cloudy in appearance. If the contents of the bottle appear cloudy at any time, do not use the remaining RAVICTI in the bottle and return it to the pharmacy to be discarded. Instruct that RAVICTI should be administered just prior to breastfeeding in infants who are breastfeeding.
For patients who cannot swallow, see the instructions on administration of RAVICTI by nasogastric tube or gastrostomy tube [see Dosage and Administration ] . For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dose may be less than anticipated. Closely monitor these patients using ammonia levels [see Dosage and Administration ] .
The recommended dosages for patients switching from sodium phenylbutyrate to RAVICTI and patients naïve to phenylbutyric acid are different [see Dosage and Administration (2.2 , 2.3) ] . For both subpopulations: Patients 2 years of age and older: Give RAVICTI in 3 equally divided dosages, each rounded up to the nearest 0.5 mL Patients less than 2 years: Give RAVICTI in 3 or more equally divided dosages, each rounded up to the nearest 0.1 mL.
The maximum total daily dosage is 17.5 mL (19 g). RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
Preparation for Nasogastric Tube or Gastrostomy Tube Administration It is recommended that all patients who can swallow take RAVICTI orally, even those with nasogastric and/or gastrostomy tubes. For patients who cannot swallow, a nasogastric tube or gastrostomy tube may be used to administer RAVICTI as follows: Utilize a new dry oral syringe to withdraw each prescribed dosage of RAVICTI from the bottle.
Place the tip of the syringe into the nasogastric/gastrostomy tube. Utilizing the plunger of the syringe, administer RAVICTI into the tube. Use a separate syringe to flush the nasogastric/gastrostomy tube. 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 gastrostomy tube, the delivered dosage may be less than anticipated due to adherence of RAVICTI to the plastic tubing. Therefore, these patients should be closely monitored using ammonia levels following initiation of RAVICTI dosing or dosage adjustments.
Drug interactions
Check glycerol phenylbutyrate against a medication listLabel text (4 paragraphs)
Corticosteroids, valproic acid, or haloperidol : May increase plasma ammonia level; monitor ammonia levels closely. ( 7.1 ) Probenecid : May affect renal excretion of metabolites of RAVICTI, including phenylacetylglutamine (PAGN) and PAA. ( 7.2 ) CYP3A4 Substrates with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine) : RAVICTI may decrease exposure; monitor for decreased efficacy of the narrow therapeutic index drug. ( 7.3 ) Midazolam : Decreased exposure; monitor for suboptimal effect of midazolam. ( 7.3 )
7.1 Potential for Other Drugs to Affect Ammonia Corticosteroids Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Monitor ammonia levels closely when corticosteroids and RAVICTI are used concomitantly. Valproic Acid and Haloperidol Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia levels closely when use of valproic acid or haloperidol is necessary in patients with UCDs.
7.2 Potential for Other Drugs to Affect RAVICTI Probenecid Probenecid may inhibit the renal excretion of metabolites of RAVICTI including PAGN and PAA.
7.3 Potential for RAVICTI to Affect Other Drugs Drugs with Narrow Therapeutic Index That are Substrates of CYP3A4 RAVICTI is a weak inducer of CYP3A4 in humans. Concomitant use of RAVICTI may decrease the systemic exposure to drugs that are substrates of CYP3A4. Monitor for decreased efficacy of drugs with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine) [see Clinical Pharmacology (12.3) ] . Midazolam Concomitant use of RAVICTI decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with RAVICTI.
Contraindications
4 CONTRAINDICATIONS RAVICTI is contraindicated in patients with known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Known hypersensitivity to phenylbutyrate. ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
LiverTox has no chapter for glycerol phenylbutyrate. Check the label's hepatic warnings.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Limited available data with RAVICTI use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In an animal reproduction study, administration of oral glycerol phenylbutyrate to pregnant rabbits during organogenesis at doses up to 2.7-times the dose of 6.87 mL/m 2 /day in adult patients resulted in maternal toxicity, but had no effects on embryo-fetal development.
In addition, there were no adverse developmental effects with administration of oral glycerol phenylbutyrate to pregnant rats during organogenesis at 1.9 times the dose of 6.87 mL/m 2 /day in adult patients; however, maternal toxicity, reduced fetal weights, and variations in skeletal development were observed in pregnant rats administered oral glycerol phenylbutyrate during organogenesis at doses greater than or equal to 5.7 times the dose of 6.87 mL/m 2 /day in adult patients [ see Data ] . Report pregnancies to Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Oral administration of glycerol phenylbutyrate during the period of organogenesis up to 350 mg/kg/day in rabbits produced maternal toxicity, but no effects on embryo-fetal development. The dose of 350 mg/kg/day in rabbits is approximately 2.7 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined area under the plasma concentration-time curve [AUCs] for PBA and PAA.
In rats, at an oral dose of 300 mg/kg/day of glycerol phenylbutyrate (1.9 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA) during the period of organogenesis, no effects on embryo-fetal development were observed. Doses of 650 mg/kg/day or greater produced maternal toxicity and adverse effects on embryo-fetal development including reduced fetal weights and cervical ribs at the 7 th cervical vertebra. The dose of 650 mg/kg/day in rats is approximately 5.7 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA.
No developmental abnormalities, effects on growth, or effects on learning and memory were observed through maturation of offspring following oral administration in pregnant rats with up to 900 mg/kg/day of…
Breastfeeding (LactMed)
No information is available on the clinical use of glycerol phenylbutyrate during breastfeeding. Because of the potential for serious adverse reactions in a breastfed infant, breastfeeding is not recommended during treatment with glycerol phenylbutyrate.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
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