Glycerol Phenylbutyrate 1.1 g/mL Liquid
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Various alimentary tract and metabolism products class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Glycerol phenylbutyrate is used to manage urea cycle disorders (UCDs; an inherited condition that affects the ability to metabolize protein). Glycerol phenylbutyrate is in a class of medications called nitrogen binding agents. It works by lowering ammonia levels in the body.
Read the full MedlinePlus article ↗- Glycerol phenylbutyrate — sold as Ravicti or as a generic — is used to manage urea cycle disorders, which are rare inherited conditions where the body can't properly get rid of amm...
- What exactly is this medication for, and why does my child need it?
- Yes — the technique matters. Use the oral syringe that comes with the medication to measure the exact prescribed dose, and give it directly into the mouth. Always take it with food...
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · Q2 2026 | $164.11 | $4,102.63 / 25 ml |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Glycerol phenylbutyrate 1.1 g/mL 00480-3777-58 | Teva | 1 bottle | — | AA | FDA listed | — |
| Glycerol Phenylbutyrate 1.1 g/mL 31722-0605-31 | Camber | 1 bottle | — | AA | FDA listed | — |
| Glycerol Phenylbutyrate 1.1 g/mL 49884-0264-95 | Par | 1 bottle | — | AA | FDA listed | — |
| Glycerol Phenylbutyrate 1.1 g/mL 59651-0988-25 | Aurobindo | 1 bottle | — | AA | FDA listed | — |
| Glycerol Phenylbutyrate 1.1 g/mLthis 70710-2193-05 | Zydus | 1 bottle | — | AA | FDA listed | — |
| glycerol phenylbutyrate 1.1 g/mL 70748-0425-01 | Lupin | 1 bottle | — | AA | FDA listed | — |
| Glycerol phenylbutyrate 1.1 g/mL 72205-0331-57 | Novadoz | 1 bottle | — | AA | FDA listed | — |
| Ravicti 1.1 g/mL 75987-0050-06 | Horizon | 1 bottle | — | AA | FDA listed | — |
| Glycerol Phenylbutyrate 1.1 g/mL 68475-0807-01 | Navinta | 1 bottle | — | AA | FDA listed | — |
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⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
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📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
🔬 Reported adverse events (FAERS)
Top reported reactions
Age at onset
Reporter sex
Serious outcomes
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 70710-2193-05 You're viewing this | 1 BOTTLE in 1 CARTON (70710-2193-5) / 25 mL in 1 BOTTLE | 2026-05-04 | Active |
🧭 About this NDC listing & data coverage
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| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | — Not published for this NDC The labeler did not submit a structured excipient list, or no SPL is available. |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | — Not published for this NDC Most self-administered / retail products have no J-code — that is normal. |
| Medicaid utilization (CMS SDUD) | — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold. |
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📄 Full prescribing information FDA SPL
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Glycerol phenylbutyrate oral liquid is indicated for use as a nitrogen-binding agent for chronic management of patients with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Glycerol phenylbutyrate oral liquid must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements). Limitations of Use: Glycerol phenylbutyrate oral liquid is not indicated for the treatment of acute hyperammonemia in patients with UCDs because more rapidly acting interventions are essential to reduce plasma ammonia levels.
The safety and efficacy of glycerol phenylbutyrate oral liquid for the treatment of N -acetylglutamate synthase (NAGS) deficiency has not been established. Glycerol phenylbutyrate oral liquid is a nitrogen-binding agent indicated for chronic management of patients with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Glycerol phenylbutyrate oral liquid must be used with dietary protein restriction and, in some cases, dietary supplements.
( 1 ) Limitations of Use: Glycerol phenylbutyrate oral liquid is not indicated for treatment of acute hyperammonemia in patients with UCDs. ( 1 ) Safety and efficacy for treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established. ( 1 )
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Glycerol phenylbutyrate oral liquid should be prescribed by a physician experienced in management of UCDs. For administration and preparation, see full prescribing information. ( 2.1 , 2.6 ) Switching From Sodium Phenylbutyrate Tablets or Powder to Glycerol phenylbutyrate oral liquid: Patients should receive the dosage of glycerol phenylbutyrate oral liquid that contains the same amount of phenylbutyric acid, see full prescribing information for conversion.
( 2.2 ) Initial Dosage in Phenylbutyrate-Naïve Patients ( 2.3 ): Recommended dosage range is 4.5 to 11.2 mL/m 2 /day (5 to 12.4 g/m 2 /day). For patients with some residual enzyme activity not adequately controlled with dietary restriction, the recommended starting dose is 4.5 mL/m 2 /day. Take into account patient's estimated urea synthetic capacity, dietary protein intake, and diet adherence.
Dosage Adjustment and Monitoring: Follow plasma ammonia levels to determine the need for dosage titration. ( 2.4 ) Dosage Modifications in Patients with Hepatic Impairment: Start dosage at lower end of range. ( 2.5 , 8.7 )
2.1Important Administration Instructions Glycerol phenylbutyrate oral liquid should be prescribed by a physician experienced in the management of UCDs. Instruct patients to take glycerol phenylbutyrate oral liquid with food or formula and to administer directly into the mouth via oral syringe. Instruct patients to use the glycerol phenylbutyrate oral liquid bottle and oral syringe as follows: Use a new reclosable bottle cap adapter with each new bottle that is opened.
Open the glycerol phenylbutyrate oral liquid bottle and twist on the new reclosable bottle cap adapter. Use a new and dry oral syringe to withdraw each prescribed dose of glycerol phenylbutyrate oral liquid. 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 glycerol phenylbutyrate oral liquid bottle, the contents will become cloudy in appearance. If the contents of the bottle appear cloudy at any time, do not use the remaining glycerol phenylbutyrate oral liquid in the bottle and return it to the pharmacy to be discarded. Instruct that glycerol phenylbutyrate oral liquid should be administered just prior to breastfeeding in infants who are breastfeeding.
For patients who cannot swallow, see the instructions on administration of glycerol phenylbutyrate oral liquid by nasogastric tube or gastrostomy tube [see Dosage and Administration ( 2.6 )] . 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 ( 2.6 )] .
The recommended dosages for patients switching from sodium phenylbutyrate to glycerol phenylbutyrate oral liquid 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 glycerol phenylbutyrate oral liquid in 3 equally divided dosages, each rounded up to the nearest 0.5 mL Patients less than 2 years: Give glycerol phenylbutyrate oral liquid 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). Glycerol phenylbutyrate oral liquid must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
2.2Switching From Sodium Phenylbutyrate to glycerol phenylbutyrate oral liquid Patients switching from sodium phenylbutyrate to glycerol phenylbutyrate oral liquid should receive the dosage of glycerol phenylbutyrate oral liquid that contains the same amount of phenylbutyric acid. The conversion is as fol…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Oral liquid: clear colorless to pale yellow, 1.1 g/mL of glycerol phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate). Oral liquid: 1.1 g/mL. ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Glycerol phenylbutyrate oral liquid 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 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Neurotoxicity : Phenylacetate (PAA), the active moiety of glycerol phenylbutyrate oral liquid, may be toxic; reduce dosage for symptoms of neurotoxicity. ( 5.1 ) Pancreatic Insufficiency or Intestinal Malabsorption : Monitor ammonia levels closely. ( 5.2 )
5.1Neurotoxicity Increased exposure to PAA, the major metabolite of glycerol phenylbutyrate may be associated with neurotoxicity in patients with UCDs. In a study of adult cancer patients, subjects received sodium phenylacetate administered as a 1-hour infusion twice daily at two dose levels of 125 and 150 mg/kg for a 2-week period. Of 18 subjects enrolled, 7 had a history of primary central nervous system tumor.
Signs and symptoms of potential PAA neurotoxicity, which were reversible, were reported at plasma PAA concentrations above 500 micrograms/mL and included somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy. PAA concentrations were not measured when symptoms resolved. In healthy subjects, after administration of 4 mL and 6 mL glycerol phenylbutyrate oral liquid 3 times daily (13.2 g/day and 19.8 g/day, respectively) for 3 days, a dose-dependent increase in non-serious nervous system adverse reactions were observed.
In subjects who had nervous system adverse reactions, plasma PAA concentrations, which were measured on Day 3 per protocol and not always at onset of symptoms, ranged from 8 to 56 micrograms/mL with 4 mL glycerol phenylbutyrate oral liquid 3 times daily and from 31 to 242 micrograms/mL with 6 mL glycerol phenylbutyrate oral liquid 3 times daily. In clinical trials in patients with UCDs who had been on sodium phenylbutyrate prior to administration of glycerol phenylbutyrate oral liquid, adverse reactions of headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor and/or dizziness were reported.
No correlation between plasma PAA concentration and neurologic symptoms was identified but plasma PAA concentrations were generally not consistently measured at the time of neurologic symptom occurrence [see Clinical Pharmacology ( 12.3 )] . If symptoms of vomiting, nausea, headache, somnolence or confusion are present in the absence of high ammonia or other intercurrent illness which explains these symptoms, consider the potential for PAA neurotoxicity which may need reduction in the glycerol phenylbutyrate oral liquid dosage [see Dosage and Administration ( 2.4 )] .
5.2Pancreatic Insufficiency or Intestinal Malabsorption Exocrine pancreatic enzymes hydrolyze glycerol phenylbutyrate oral liquid in the small intestine, separating the active moiety, phenylbutyrate, from glycerol. This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion of glycerol phenylbutyrate oral liquid and/or absorption of phenylbutyrate and reduced control of plasma ammonia.
Monitor ammonia levels closely in patients with pancreatic insufficiency or intestinal malabsorption.
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Neurotoxicity [see Warnings and Precautions ( 5.1 )] • Pancreatic insufficiency or Intestinal Malabsorption [see Warnings and Precautions ( 5.2 )] Most common adverse reactions (≥10%) in adults are: diarrhea, flatulence, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Assessment of adverse reactions was based on exposure of 45 adult patients (31 female and 14 male) with UCD subtype deficiencies of ornithine transcarbamylase (OTC, n=40), carbamoyl phosphate synthetase (CPS, n=2), and argininosuccinate synthetase (ASS, n=1) in a randomized, double-blind, active-controlled (glycerol phenylbutyrate vs sodium phenylbutyrate), crossover, 4-week study (Study 1) that enrolled patients 18 years of age and older [see Clinical Studies ( 14.1 )] .
One of the 45 patients received only sodium phenylbutyrate prior to withdrawing on day 1 of the study due to an adverse reaction. The most common adverse reactions (occurring in at least 10% of patients) reported during short-term treatment with glycerol phenylbutyrate oral liquid were diarrhea, flatulence, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with glycerol phenylbutyrate oral liquid or sodium phenylbutyrate (incidence of at least 4% in either treatment arm).
Table 1: Adverse Reactions Reported in 2 or More Adult Patients with UCDs (at least 4% in Either Treatment Arm) in Study 1 Number (%) of Patients in Study 1 Sodium Phenylbutyrate (N = 45) Glycerol phenylbutyrate oral liquid (N = 44) Diarrhea 3 (7) 7 (16) Headache 4 (9) 6 (14) Flatulence 1 (2) 6 (14) Abdominal pain 2 (4) 3 (7) Vomiting 2 (4) 3 (7) Decreased appetite 2 (4) 3 (7) Fatigue 1 (2) 3 (7) Dyspepsia 3 (7) 2 (5) Nausea 3 (7) 1 (2) Dizziness 4 (9) 0 Abdominal discomfort 3 (7) 0 Other Adverse Reactions Glycerol phenylbutyrate oral liquid has been evaluated in 77 patients with UCDs (51 adult and 26 pediatric patients ages 2 years to 17 years) in 2 open-label long-term studies, in which 69 patients completed 12 months of treatment with glycerol phenylbutyrate oral liquid (median exposure = 51 weeks).
During these studies there were no deaths. Adverse reactions reported in at least 10% of adult patients were nausea, vomiting, diarrhea, decreased appetite, dizziness, headache, and fatigue. Adverse reactions reported in at least 10% of pediatric patients ages 2 years to 17 years were upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache.
Glycerol phenylbutyrate oral liquid has been evaluated in 17 patients with UCDs ages 2 months to less than 2 years in 3 open-label studies. The median exposure was 6 months (range 0.2 to 20 months). Adverse reactions reported in at least 10% of pediatric patients aged 2 months to less than 2 years were neutropenia, vomiting, constipation, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash, and papule.
Glycerol phenylbutyrate oral liquid has been evaluated in 16 patients with UCDs less than 2 months of age (age range 0.1 to 2 months, median age 0.5 months) in a single, open-label study. The median exposure was 10 months (range 2 to 20 months). Adverse reactions reported in at least 10% of pediatric patients aged less than 2 months were vomiting, rash, gastroesophageal reflux, increased hepatic enzymes, feeding disorder (decreased appetite, hypophagia), anemia, cough, dehydration, metabolic acidosis, thrombocytosis, thrombocytopenia, neutropenia, lymphocytosis, diarrh…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Corticosteroids, valproic acid, or haloperidol : May increase plasma ammonia level; monitor ammonia levels closely. ( 7.1 ) Probenecid : May affect renal excretion of metabolites of glycerol phenylbutyrate oral liquid, including phenylacetylglutamine (PAGN) and PAA. ( 7.2 ) CYP3A4 Substrates with narrow therapeutic index (e.g., alfentanil, quinidine, cyclosporine) : glycerol phenylbutyrate oral liquid 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 )
7.1Potential 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 glycerol phenylbutyrate oral liquid 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.
7.2Potential for Other Drugs to Affect glycerol phenylbutyrate oral liquid Probenecid Probenecid may inhibit the renal excretion of metabolites of glycerol phenylbutyrate oral liquid including PAGN and PAA.
7.3Potential for glycerol phenylbutyrate to Affect Other Drugs Drugs with narrow therapeutic index that are substrates of CYP3A4 Glycerol phenylbutyrate oral liquid is a weak inducer of CYP3A4 in humans. Concomitant use of glycerol phenylbutyrate oral liquid 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 glycerol phenylbutyrate oral liquid decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with glycerol phenylbutyrate oral liquid.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended. ( 8.2 )
8.1Pregnancy Risk Summary Limited available data with glycerol phenylbutyrate oral liquid 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] .
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 7th 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 glycerol phenylbutyrate (8.5 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA) during organogenesis and lactation.
8.2Lactation Risk Summary There are no data on the presence of glycerol phenylbutyrate in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including neurotoxicity and tumorigenicity in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with glycerol phenylbutyrate oral liquid.
8.4Pediatric Use Patients 2 Years to 17 Years of Age The safety and effectiveness of glycerol phenylbutyrate oral liquid in patients 2 years to less than 18 years of age have been established in 3 clinical studies: 2 open-label, fixed-sequence, switchover clinical studies from sodium phenylbutyrate to glycerol phenylbutyrate oral liquid, and 1 long-term, open label safety study [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.2 )] . Patients Less Than 2 Years of Age The safety and effectiveness of glycerol phenylbutyrate oral liquid in patients with UCDs less than 2 years of age have been established in 3 open-label studies.
Pharmacokinetics and pharmacodynamics (plasma ammonia), and safety were studied in 17 patients aged 2 months to less than 2 years of age and in 16 patients…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Limited available data with glycerol phenylbutyrate oral liquid 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] .
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 7th 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 glycerol phenylbutyrate (8.5 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA) during organogenesis and lactation.
🧒 Pediatric Use ▾
8.4Pediatric Use Patients 2 Years to 17 Years of Age The safety and effectiveness of glycerol phenylbutyrate oral liquid in patients 2 years to less than 18 years of age have been established in 3 clinical studies: 2 open-label, fixed-sequence, switchover clinical studies from sodium phenylbutyrate to glycerol phenylbutyrate oral liquid, and 1 long-term, open label safety study [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.2 )] . Patients Less Than 2 Years of Age The safety and effectiveness of glycerol phenylbutyrate oral liquid in patients with UCDs less than 2 years of age have been established in 3 open-label studies.
Pharmacokinetics and pharmacodynamics (plasma ammonia), and safety were studied in 17 patients aged 2 months to less than 2 years of age and in 16 patients less than 2 months of age [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.3 )]. Juvenile Animal Toxicity Data In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating and pregnancy after maturation, terminal body weight was dose-dependently reduced by up to 16% in males and 12% in females at 900 mg/kg/day or higher (3 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA).
Learning, memory, and motor activity endpoints were not affected. However, fertility (number of pregnant rats) was decreased by up to 25% at 650 mg/kg/day or higher (2.6 times the dose of 6.87 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA).
🧓 Geriatric Use ▾
8.5Geriatric Use Clinical studies of glycerol phenylbutyrate oral liquid did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
🆘 Overdosage ▾
10 OVERDOSAGE While there is no experience with overdosage in human clinical trials, PAA, a toxic metabolite of glycerol phenylbutyrate oral liquid, can accumulate in patients who receive an overdose [see Warnings and Precautions ( 5.1 )] . If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia (NH 3 , NH 4 + ). Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Glycerol phenylbutyrate is a triglyceride containing 3 molecules of PBA.
PAA, the major metabolite of PBA, is the active moiety of glycerol phenylbutyrate. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys (Figure 1). On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.
Figure 1: Glycerol phenylbutyrate Mechanism of Action
12.2Pharmacodynamics Pharmacological Effects In clinical studies, total 24-hour area under the plasma concentration-time curve (AUC) of ammonia levels was comparable at steady state during the switchover period between glycerol phenylbutyrate oral liquid and sodium phenylbutyrate [see Clinical Studies ( 14 )] . Cardiac Electrophysiology The effect of multiple doses of glycerol phenylbutyrate 13.2 g/day and 19.8 g/day (approximately 69% and 104% of the maximum recommended daily dosage) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg), four-treatment-arm, crossover study in 57 healthy subjects.
The upper bound of the one-sided 95% CI for the largest placebo-adjusted, baseline-corrected QTc, based on individual correction method (QTcI) for glycerol phenylbutyrate, was below 10 ms.
12.3Pharmacokinetics Absorption Glycerol phenylbutyrate is a pro-drug of PBA. Upon oral ingestion, PBA is released from the glycerol backbone in the gastrointestinal tract by lipases. PBA derived from glycerol phenylbutyrate is further converted by β-oxidation to PAA.
In healthy, fasting adult subjects receiving a single oral dose of 2.9 mL/m 2 of glycerol phenylbutyrate, peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively. Upon single-dose administration of glycerol phenylbutyrate oral liquid, plasma concentrations of PBA were quantifiable in 15 of 22 participants at the first sample time postdose (0.25 hours). Mean maximum concentration (C max ) for PBA, PAA, and PAGN was 37.0 micrograms/mL, 14.9 micrograms/mL, and 30.2 micrograms/mL, respectively.
In healthy subjects, intact glycerol phenylbutyrate was detected in plasma. While the study was inconclusive, the incomplete hydrolysis of glycerol phenylbutyrate cannot be ruled out. In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose- dependent manner.
Following 4 mL of glycerol phenylbutyrate oral liquid 3 times a day for 3 days, the mean C max and AUC were 66 micrograms/mL and 930 micrograms•h/mL for PBA and 28 micrograms/mL and 942 micrograms•h/mL for PAA, respectively. In the same study, following 6 mL of glycerol phenylbutyrate oral liquid three times a day for 3 days, mean C max and AUC were 100 micrograms/mL and 1400 micrograms•h/mL for PBA and 65 µg/mL and 2064 micrograms•h/mL for PAA, respectively. In adult patients with UCDs receiving multiple doses of glycerol phenylbutyrate oral liquid, maximum plasma concentrations at steady state (C max,ss ) of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day.
Intact glycerol phenylbutyrate was not detectable in plasma in patients with UCDs. In clinical studies of glycerol phenylbutyrate oral liquid in patients with UCDs, the peak observed PAA concentrations by age group are shown in Table 2. Table 2: Peak PAA Concentrations in Patients with UCDs Treated with glycerol phenylbutyrate oral liquid in Clinical Trials Age Range Glycerol phenylbutyrate oral liquid Dose Mean Peak PAA Concentration* (SD) Median Peak PAA Concentration * (Range) Less than 2 months (n=16…
🧬 Mechanism of Action ▾
12.1Mechanism of Action UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia (NH 3 , NH 4 + ). Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Glycerol phenylbutyrate is a triglyceride containing 3 molecules of PBA.
PAA, the major metabolite of PBA, is the active moiety of glycerol phenylbutyrate. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys (Figure 1). On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.
Figure 1: Glycerol phenylbutyrate Mechanism of Action
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Glycerol phenylbutyrate oral liquid 1.1 g/mL is supplied in multi-use, 25-mL glass bottles. The bottles are supplied in the following configuration: • NDC 70710-2193-5 : Single 25-mL bottle per carton Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Discard bottle 28 days after opening.
📋 Description ▾
11 DESCRIPTION Glycerol phenylbutyrate is a clear, colorless to pale yellow oral liquid. It is insoluble in water and most organic solvents, and it is soluble in dimethylsulfoxide (DMSO) and greater than 65% acetonitrile. Glycerol phenylbutyrate is a nitrogen-binding agent.
It is a triglyceride containing 3 molecules of PBA linked to a glycerol backbone, the chemical name of which is benzenebutanoic acid, 1', 1' ' –(1,2,3-propanetriyl) ester with a molecular weight of 530.67. It has a molecular formula of C 33 H 38 O 6 . The structural formula is structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Neurotoxicity [see Warnings and Precautions ( 5.1 )]. Inform patients/caregivers that adverse reactions of glycerol phenylbutyrate oral liquid are sometimes the same as symptoms of high blood ammonia.
Neurological adverse reactions may also be associated with the major metabolite of glycerol phenylbutyrate, PAA, and may be reversible. Blood tests for PAA may be done to measure the amount of PAA in the blood. Instruct the patient/caregiver to contact the healthcare provider immediately if the patient experiences: nausea, vomiting, headache, fatigue, somnolence, lightheadedness, confusion, exacerbation of preexisting neuropathy, disorientation, impaired memory, dysgeusia, or hypoacusis.
Lactation Advise patients that breastfeeding is not recommended during treatment with glycerol phenylbutyrate oral liquid [see Use in Specific Populations ( 8.2 )] . Administration Instruct patients to take glycerol phenylbutyrate oral liquid with food or formula and to administer directly into the mouth via oral syringe. Instruct patients to use the glycerol phenylbutyrate oral liquid bottle and oral syringe as follows: Use a new reclosable bottle cap adapter with each new bottle that is opened.
Open the glycerol phenylbutyrate oral liquid bottle and twist on the new reclosable bottle cap adapter. Use a new and dry oral syringe to withdraw each prescribed dose of glycerol phenylbutyrate oral liquid. 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 glycerol phenylbutyrate oral liquid bottle, the contents will become cloudy in appearance. If the contents of the bottle appear cloudy at any time, do not use the remaining glycerol phenylbutyrate oral liquid in the bottle and return it to the pharmacy to be discarded. Instruct that glycerol phenylbutyrate oral liquid should be administered just prior to breastfeeding in infants who are breastfeeding.
Instruct patients to take glycerol phenylbutyrate orally, even if they have a nasogastric and/or gastrostomy tube. For patients who cannot swallow and who have a nasogastric tube or gastrostomy tube in place, instruct patients/caregivers to administer glycerol phenylbutyrate oral liquid as follows: Utilize a new dry oral syringe to withdraw the prescribed dosage of glycerol phenylbutyrate oral liquid from the bottle. Place the tip of the syringe into the gastrostomy/nasogastric tube.
Utilizing the plunger of the syringe, administer glycerol phenylbutyrate oral liquid 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. Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington NJ 08534 Made in India 31750326 R0 MEDICATION GUIDE Glycerol phenylbutyrate (glis-er-ol fen-il-bue-ti-rate) oral liquid What is the most important information I should know about glycerol phenylbutyrate oral liquid?
Glycerol phenylbutyrate oral liquid may cause serious side effects, including: Nervous system problems (Neurotoxicity). Phenylacetate (PAA), a breakdown product of glycerol phenylbutyrate, may cause nervous system side effects. Call your doctor or get medical help right away if you get any of these symptoms while taking glycerol phenylbutyrate oral liquid: • sleepiness • worsening of numbness, tingling, or burning in your hands or feet • lightheadedness • headache • change in taste • feeling very tired (fatigue) • problems with hearing • nausea • confusion • vomiting • problems with memory Your doctor may do blood tests to measure the amount of PAA in your blood during your treatment with glycerol…