Glycerol phenylbutyrate: Difference between revisions

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{{DrugProjectFormSinglePage
{{DrugProjectFormSinglePage
|authorTag={{KS}}
|aOrAn=a
|aOrAn=a
|indicationType=treatment
|indicationType=treatment
|hasBlackBoxWarning=Yes
|indication=patients with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone.
|adverseReactions=<!--Black Box Warning-->
|adverseReactions=[[diarrhea]], [[flatulence]] and [[headache]]
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span>
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span>
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i>
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i>
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<!--FDA-Labeled Indications and Dosage (Adult)-->
<!--FDA-Labeled Indications and Dosage (Adult)-->
|fdaLIADAdult======Condition1=====
|fdaLIADAdult===Indications==


* Dosing Information
* RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years of age with [[urea cycle disorders]] (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. 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).


:* Dosage
==Limitations of Use:==


=====Condition2=====
* RAVICTI 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.


* Dosing Information
* The safety and efficacy of RAVICTI for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.


:* Dosage
* The use of RAVICTI in patients <2 months of age is contraindicated.


=====Condition3=====
==DOSAGE==


* Dosing Information
'''Important Instructions'''


:* Dosage
* The recommended dosages for patients switching from sodium phenylbutyrate to RAVICTI and patients naïve to phenylbutyric acid are different . For both subpopulations:


=====Condition4=====
:*Give RAVICTI in 3 equally divided dosages, each rounded up to the nearest 0.5 mL.
The maximum total daily dosage is 17.5 mL (19 g).


* Dosing Information
:*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).


:* Dosage
'''Switching From Sodium Phenylbutyrate to RAVICTI'''


<!--Off-Label Use and Dosage (Adult)-->
* Patients switching from sodium phenylbutyrate to RAVICTI should receive the dosage of RAVICTI that contains the same amount of phenylbutyric acid. The conversion is as follows:


<!--Guideline-Supported Use (Adult)-->
:*Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86
|offLabelAdultGuideSupport======Condition1=====


* Developed by:
'''Initial Dosage in Phenylbutyrate-Naïve Patients'''


* Class of Recommendation:
* The recommended dosage range, based upon body surface area, in patients naïve to phenylbutyrate (PBA) is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day). For patients with some residual enzyme activity who are not adequately controlled with protein restriction, the recommended starting dosage is 4.5 mL/m2/day.


* Strength of Evidence:
* In determining the starting dosage of RAVICTI in treatment-naïve patients, consider the patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated RAVICTI dose for a 24-hour period is 0.6 mL RAVICTI per gram of dietary protein ingested per 24 hour period. The total daily dosage should not exceed 17.5 mL.


* Dosing Information
==Dosage Adjustment and Monitoring==


:* Dosage
'''Adjustment based on Plasma Ammonia''': Adjust the RAVICTI dosage to produce a fasting plasma ammonia level that is less than half the upper limit of normal (ULN) according to age.


=====Condition2=====
'''Adjustment Based on Urinary Phenylacetylglutamine''': If available, U-PAGN measurements may be used to help guide RAVICTI dose adjustment. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the ULN, the RAVICTI dose should be adjusted upward. The amount of dose adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-h U-PAGN level and the estimated RAVICTI dose needed per gram of dietary protein ingested and the maximum total daily dosage i.e., 17.5 mL.


There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
Consider a patient’s use of concomitant medications, such as probenecid, when making dosage adjustment decisions based on U-PAGN. Probenecid may result in a decrease of the urinary excretion of PAGN.


<!--Non–Guideline-Supported Use (Adult)-->
Adjustment Based on Plasma Phenylacetate: If available, measurements of the plasma PAA levels may be useful to guide dosing if symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or intercurrent illness. Ammonia levels must be monitored closely when changing the dose of RAVICTI. The ratio of PAA to PAGN in plasma may provide additional information to assist in dose adjustment decisions. In patients with a high PAA to PAGN ratio, a further increase in RAVICTI dose may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction. The PAA to PAGN ratio has been observed to be generally less than 1 in patients without significant PAA accumulation.
|offLabelAdultNoGuideSupport======Condition1=====


* Dosing Information
'''Dosage Modifications in Patients with Hepatic Impairment'''


:* Dosage
* For patients with moderate to severe hepatic impairment, the recommended starting dosage is at the lower end of the range


=====Condition2=====
==DOSAGE FORMS AND STRENGTHS==


There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
* Oral liquid: colorless to pale yellow, 1.1 g/mL of glycerol phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate).
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.


<!--Pediatric Indications and Dosage-->


<!--FDA-Labeled Indications and Dosage (Pediatric)-->
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
|fdaLIADPed======Condition1=====


* Dosing Information


:* Dosage


=====Condition2=====
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
|fdaLIADPed=There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.


There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.


<!--Off-Label Use and Dosage (Pediatric)-->


<!--Guideline-Supported Use (Pediatric)-->
<!--Guideline-Supported Use (Pediatric)-->
|offLabelPedGuideSupport======Condition1=====
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
* Developed by:
 
* Class of Recommendation:
 
* Strength of Evidence:
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Non–Guideline-Supported Use (Pediatric)-->
|offLabelPedNoGuideSupport======Condition1=====
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Contraindications-->
|contraindications=* Condition1
 
<!--Warnings-->
|warnings=* Description
 
====Precautions====
 
* Description
 
<!--Adverse Reactions-->
 
<!--Clinical Trials Experience-->
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
 
=====Body as a Whole=====
 
 
 
 
=====Cardiovascular=====
 
 
 
 
=====Digestive=====
 
 
 
 
=====Endocrine=====
 
 
 
 
=====Hematologic and Lymphatic=====
 
 
 
 
=====Metabolic and Nutritional=====
 
 
 
 
=====Musculoskeletal=====
 
 
 
 
=====Neurologic=====




|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.




=====Respiratory=====
|contraindications='''RAVICTI is contraindicated in patients'''


* Less than 2 months of age. Children <2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of RAVICTI, leading to impaired absorption of phenylbutyrate and hyperammonemia.


* With known hypersensitivity to phenylbutyrate. Signs of [[hypersensitivity]] include [[wheezing]], [[dyspnea]], coughing, [[hypotension]], [[flushing]], [[nausea]], and [[rash]].
|warnings='''Neurotoxicity'''


* The major metabolite of RAVICTI, PAA, is associated with neurotoxicity. Signs and symptoms of PAA neurotoxicity, including [[somnolence]], [[fatigue]], [[lightheadedness]], [[headache]], [[dysgeusia]], hypoacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy, were observed at plasma PAA concentrations ≥500 µg/mL in a study of cancer patients who were administered IV PAA. In this study, adverse events were reversible.


=====Skin and Hypersensitivy Reactions=====
* In healthy subjects, after administration of 4 mL and 6 mL RAVICTI 3 times daily for 3 days, a dose-dependent increase in all-grade nervous system adverse reactions was observed, even at exposure levels of PAA <100 µg/mL.


* In clinical trials in UCD patients who had been on sodium phenylbutyrate prior to administration of RAVICTI, peak PAA concentrations after dosing with RAVICTI ranged from 1.6 to 178 µg/mL (mean: 39 µg/mL) in adult patients and from 7 to 480 µg/mL (mean: 90 µg/mL) in pediatric patients. Some UCD patients experienced [[headache]], [[fatigue]], symptoms of [[peripheral neuropathy]], [[seizures]], [[tremor]] and/or [[dizziness]]. No correlation between PAA levels and neurotoxicity symptoms was identified but PAA levels were generally not measured at the time of neurotoxicity symptoms.


* If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or other intercurrent illnesses, reduce the RAVICTI dosage.


'''Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption'''


=====Special Senses=====
* Exocrine pancreatic enzymes hydrolyze RAVICTI 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 RAVICTI and/or absorption of phenylbutyrate and reduced control of plasma ammonia. Monitor ammonia levels closely in patients with pancreatic insufficiency or intestinal malabsorption.
|clinicalTrials=* 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), carbamyl phosphate synthetase (CPS, n=2), and argininosuccinate synthetase (ASS, n=1) in a randomized, double-blind, active-controlled (RAVICTI vs sodium phenylbutyrate), crossover, 4-week study (Study 1) that enrolled patients ≥18 years of age [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.


* Table 1 summarizes adverse reactions occurring in ≥2 patients treated with RAVICTI or sodium phenylbutyrate. The most common adverse reactions (occurring in ≥10% of patients) reported during short-term treatment with RAVICTI were [[diarrhea]], [[flatulence, and headache]].


[[File:Raviciti table1.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]


=====Urogenital=====
''Other Adverse Reactions''


* RAVICTI has been evaluated in 77 UCD patients (51 adult and 26 pediatric) in 2 open-label long-term studies, in which 69 patients completed 12 months of treatment with RAVICTI (median exposure = 51 weeks). During these studies there were no deaths.


* Adverse reactions occurring in ≥10% of adult patients were [[nausea]], [[vomiting]], [[diarrhea]], decreased appetite, [[hyperammonemia]], [[dizziness]], [[headache]], and [[fatigue]].


* Adverse reactions occurring in ≥10% of pediatric patients were upper [[abdominal pain]], [[rash]], [[nausea]], [[vomiting]], [[diarrhea]], decreased appetite, [[hyperammonemia]], and [[headache]].


=====Miscellaneous=====






<!--Postmarketing Experience-->
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.


=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
=====Endocrine=====
=====Hematologic and Lymphatic=====
=====Metabolic and Nutritional=====
=====Musculoskeletal=====
=====Neurologic=====
=====Respiratory=====
=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====


|drugInteractions='''Potential for Other Drugs to Affect Ammonia'''


''Corticosteroids''


=====Urogenital=====
* 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 UCD patients.


=====Miscellaneous=====
'''Potential for Other Drugs to Affect RAVICTI'''


''Probenecid''


 
* Probenecid may inhibit the renal excretion of metabolites of RAVICTI including PAGN and PAA.
<!--Drug Interactions-->
|drugInteractions=* Drug
:* Description
 
<!--Use in Specific Populations-->
|useInPregnancyFDA=* '''Pregnancy Category'''
|useInPregnancyFDA=* '''Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
Line 263: Line 154:
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.


<!--Administration and Monitoring-->
 
|administration=* Oral
|administration=* Oral


* Intravenous
* RAVICTI should be prescribed by a physician experienced in the management of UCDs. Instruct patients to take RAVICTI with food and to administer directly into the mouth via oral syringe or dosing cup. See the instructions on the use of RAVICTI by nasogastric tube or g-tube .
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
 
'''Preparation for Nasogastric Tube or Gastrostomy Tube Administration'''
 
* For patients who have a nasogastric tube or gastrostomy tube in place, administer RAVICTI as follows:


* Description
:*Utilize an oral syringe to withdraw the prescribed dosage of RAVICTI from the bottle.


<!--IV Compatibility-->
:*Place the tip of the syringe into to the tip of the gastrostomy/nasogastric tube.
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.


<!--Overdosage-->
:*Utilizing the plunger of the syringe, administer RAVICTI into the tube.
|overdose====Acute Overdose===


====Signs and Symptoms====
:*Flush once with 30 mL of water and allow the flush to drain.


* Description
:*Flush a second time with an additional 30 mL of water to clear the tube.


====Management====


* Description
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.


===Chronic Overdose===


There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.


<!--Pharmacology-->
<!--IV Compatibility-->
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.


<!--Drug box 2-->
<!--Overdosage-->
|overdose=* While there is no experience with overdosage in human clinical trials, PAA, a toxic metabolite of RAVICTI, can accumulate in patients who receive an overdose. In case of overdosage, discontinue the drug and contact poison control.
|drugBox=<!--Mechanism of Action-->
|drugBox=<!--Mechanism of Action-->
|mechAction=*  
|mechAction=*  

Revision as of 14:04, 28 April 2015

Glycerol phenylbutyrate
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Overview

Glycerol phenylbutyrate is a {{{drugClass}}} that is FDA approved for the treatment of patients with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone.. Common adverse reactions include diarrhea, flatulence and headache.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

  • RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. 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).

Limitations of Use:

  • RAVICTI 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 RAVICTI for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.
  • The use of RAVICTI in patients <2 months of age is contraindicated.

DOSAGE

Important Instructions

  • The recommended dosages for patients switching from sodium phenylbutyrate to RAVICTI and patients naïve to phenylbutyric acid are different . For both subpopulations:
  • Give RAVICTI in 3 equally divided dosages, each rounded up to the nearest 0.5 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).

Switching From Sodium Phenylbutyrate to RAVICTI

  • Patients switching from sodium phenylbutyrate to RAVICTI should receive the dosage of RAVICTI that contains the same amount of phenylbutyric acid. The conversion is as follows:
  • Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86

Initial Dosage in Phenylbutyrate-Naïve Patients

  • The recommended dosage range, based upon body surface area, in patients naïve to phenylbutyrate (PBA) is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day). For patients with some residual enzyme activity who are not adequately controlled with protein restriction, the recommended starting dosage is 4.5 mL/m2/day.
  • In determining the starting dosage of RAVICTI in treatment-naïve patients, consider the patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated RAVICTI dose for a 24-hour period is 0.6 mL RAVICTI per gram of dietary protein ingested per 24 hour period. The total daily dosage should not exceed 17.5 mL.

Dosage Adjustment and Monitoring

Adjustment based on Plasma Ammonia: Adjust the RAVICTI dosage to produce a fasting plasma ammonia level that is less than half the upper limit of normal (ULN) according to age.

Adjustment Based on Urinary Phenylacetylglutamine: If available, U-PAGN measurements may be used to help guide RAVICTI dose adjustment. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the ULN, the RAVICTI dose should be adjusted upward. The amount of dose adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-h U-PAGN level and the estimated RAVICTI dose needed per gram of dietary protein ingested and the maximum total daily dosage i.e., 17.5 mL.

Consider a patient’s use of concomitant medications, such as probenecid, when making dosage adjustment decisions based on U-PAGN. Probenecid may result in a decrease of the urinary excretion of PAGN.

Adjustment Based on Plasma Phenylacetate: If available, measurements of the plasma PAA levels may be useful to guide dosing if symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or intercurrent illness. Ammonia levels must be monitored closely when changing the dose of RAVICTI. The ratio of PAA to PAGN in plasma may provide additional information to assist in dose adjustment decisions. In patients with a high PAA to PAGN ratio, a further increase in RAVICTI dose may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction. The PAA to PAGN ratio has been observed to be generally less than 1 in patients without significant PAA accumulation.

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 range

DOSAGE FORMS AND STRENGTHS

  • Oral liquid: colorless to pale yellow, 1.1 g/mL of glycerol phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate).

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Glycerol phenylbutyrate in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Glycerol phenylbutyrate in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Glycerol phenylbutyrate in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Glycerol phenylbutyrate in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Glycerol phenylbutyrate in pediatric patients.

Contraindications

RAVICTI is contraindicated in patients

  • Less than 2 months of age. Children <2 months of age may have immature pancreatic exocrine function, which could impair hydrolysis of RAVICTI, leading to impaired absorption of phenylbutyrate and hyperammonemia.

Warnings

Neurotoxicity

  • The major metabolite of RAVICTI, PAA, is associated with neurotoxicity. Signs and symptoms of PAA neurotoxicity, including somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy, were observed at plasma PAA concentrations ≥500 µg/mL in a study of cancer patients who were administered IV PAA. In this study, adverse events were reversible.
  • In healthy subjects, after administration of 4 mL and 6 mL RAVICTI 3 times daily for 3 days, a dose-dependent increase in all-grade nervous system adverse reactions was observed, even at exposure levels of PAA <100 µg/mL.
  • In clinical trials in UCD patients who had been on sodium phenylbutyrate prior to administration of RAVICTI, peak PAA concentrations after dosing with RAVICTI ranged from 1.6 to 178 µg/mL (mean: 39 µg/mL) in adult patients and from 7 to 480 µg/mL (mean: 90 µg/mL) in pediatric patients. Some UCD patients experienced headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor and/or dizziness. No correlation between PAA levels and neurotoxicity symptoms was identified but PAA levels were generally not measured at the time of neurotoxicity symptoms.
  • If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or other intercurrent illnesses, reduce the RAVICTI dosage.

Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption

  • Exocrine pancreatic enzymes hydrolyze RAVICTI 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 RAVICTI 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

Clinical 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), carbamyl phosphate synthetase (CPS, n=2), and argininosuccinate synthetase (ASS, n=1) in a randomized, double-blind, active-controlled (RAVICTI vs sodium phenylbutyrate), crossover, 4-week study (Study 1) that enrolled patients ≥18 years of age [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.
  • Table 1 summarizes adverse reactions occurring in ≥2 patients treated with RAVICTI or sodium phenylbutyrate. The most common adverse reactions (occurring in ≥10% of patients) reported during short-term treatment with RAVICTI were diarrhea, flatulence, and headache.
This image is provided by the National Library of Medicine.

Other Adverse Reactions

  • RAVICTI has been evaluated in 77 UCD patients (51 adult and 26 pediatric) in 2 open-label long-term studies, in which 69 patients completed 12 months of treatment with RAVICTI (median exposure = 51 weeks). During these studies there were no deaths.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Glycerol phenylbutyrate in the drug label.

Drug Interactions

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 UCD patients.

Potential for Other Drugs to Affect RAVICTI

Probenecid

  • Probenecid may inhibit the renal excretion of metabolites of RAVICTI including PAGN and PAA.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glycerol phenylbutyrate in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Glycerol phenylbutyrate during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Glycerol phenylbutyrate with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Glycerol phenylbutyrate with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Glycerol phenylbutyrate with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Glycerol phenylbutyrate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Glycerol phenylbutyrate with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Glycerol phenylbutyrate in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Glycerol phenylbutyrate in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Glycerol phenylbutyrate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Glycerol phenylbutyrate in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral
  • RAVICTI should be prescribed by a physician experienced in the management of UCDs. Instruct patients to take RAVICTI with food and to administer directly into the mouth via oral syringe or dosing cup. See the instructions on the use of RAVICTI by nasogastric tube or g-tube .

Preparation for Nasogastric Tube or Gastrostomy Tube Administration

  • For patients who have a nasogastric tube or gastrostomy tube in place, administer RAVICTI as follows:
  • Utilize an oral syringe to withdraw the prescribed dosage of RAVICTI from the bottle.
  • Place the tip of the syringe into to the tip of the gastrostomy/nasogastric tube.
  • Utilizing the plunger of the syringe, administer RAVICTI into the tube.
  • Flush once with 30 mL of water and allow the flush to drain.
  • Flush a second time with an additional 30 mL of water to clear the tube.

Monitoring

There is limited information regarding Monitoring of Glycerol phenylbutyrate in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Glycerol phenylbutyrate in the drug label.

Overdosage

  • While there is no experience with overdosage in human clinical trials, PAA, a toxic metabolite of RAVICTI, can accumulate in patients who receive an overdose. In case of overdosage, discontinue the drug and contact poison control.

Pharmacology

There is limited information regarding Glycerol phenylbutyrate Pharmacology in the drug label.

Mechanism of Action

Structure

File:Glycerol phenylbutyrate01.png
This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Glycerol phenylbutyrate in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Glycerol phenylbutyrate in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Glycerol phenylbutyrate in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Glycerol phenylbutyrate in the drug label.

How Supplied

Storage

There is limited information regarding Glycerol phenylbutyrate Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Glycerol phenylbutyrate in the drug label.

Precautions with Alcohol

  • Alcohol-Glycerol phenylbutyrate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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