`
`
` These highlights do not include all the information needed to use
`
`
` RAVICTI safely and effectively. See full prescribing information for
`
`
` RAVICTI.
`
`
`RAVICTI® (glycerol phenylbutyrate) oral liquid
`
`
`
`Initial U.S. Approval: 1996
`
`
` _________________
` _________________
`RECENT MAJOR CHANGES
`
`
`Indications and Usage (1)
`12/2018
`
`
`
`12/2018
`Dosage and Administration (2.4)
`
`
`
`Contraindications (removed) (4)
`12/2018
`
`
`
`
`12/2018
`Warnings and Precautions (5.1)
`
`
`
`
`__________________INDICATIONS AND USAGE _________________
`
`
`
`
`RAVICTI 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. RAVICTI must
`
`
`
`
`be used with dietary protein restriction and, in some cases, dietary
`
`
`supplements. (1)
`
`Limitations of Use:
`• RAVICTI 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 ______________
`
`
`
`
`• RAVICTI 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 RAVICTI:
`
`
`
`
`
`• Patients should receive the dosage of RAVICTI 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/m2/day (5 to 12.4 g/m2/day).
`
`
`
` • For patients with some residual enzyme activity not adequately controlled
`
`
`
` with dietary restriction, the recommended starting dose is 4.5 mL/m2/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)
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`Important Administration Instructions
`2.1
`
`
`
`
`Switching From Sodium Phenylbutyrate to RAVICTI
`2.2
`
`
`
`2.3
`Initial Dosage in Phenylbutyrate-Naïve Patients
`
`
`2.4 Dosage Adjustment and Monitoring
`
`
`
`2.5 Dosage Modifications in Patients with Hepatic Impairment
`
`
`2.6
`Preparation for Nasogastric Tube or Gastrostomy Tube
`
`
`Administration
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Neurotoxicity
`
`
`Pancreatic Insufficiency or Intestinal Malabsorption
`5.2
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`6.2
`Postmarketing Experience
`
`
`
`
`DRUG INTERACTIONS
`
`
`Potential for Other Drugs to Affect Ammonia
`7.1
`
`Potential for Other Drugs to Affect RAVICTI
`7.2
`
`7.3
`Potential for RAVICTI to Affect Other Drugs
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`
`
`
`
`
`
`
`
`
`
`
`
`6
`
`
`7
`
`
`8
`
`
`Reference ID: 4501848
`
`Dosage Modifications in Patients with Hepatic Impairment:
`
`
`
`• Start dosage at lower end of range. (2.5, 8.7)
`
`
`
`
`DOSAGE FORMS AND STRENGTHS______________
`
` _____________
`
`
`Oral liquid: 1.1 g/mL. (3)
`
`___________________ CONTRAINDICATIONS ___________________
`
`
`
`
`Known hypersensitivity to phenylbutyrate. (4)
`
`
`_______________WARNINGS AND PRECAUTIONS _______________
`
`
`
`
`• Neurotoxicity: Phenylacetate (PAA), the active moiety of RAVICTI, may
`
`be toxic; reduce dosage for symptoms of neurotoxicity. (5.1)
`
`• Pancreatic Insufficiency or Intestinal Malabsorption: Monitor ammonia
`
`
`
`levels closely. (5.2)
`
`___________________ ADVERSE REACTIONS ___________________
`
`
`
`
`Most common adverse reactions (≥10%) in adults are: diarrhea, flatulence,
`
`
`
`
`
`and headache. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Horizon
`
`
`Therapeutics at 1-855-823-7878 or FDA at 1-800-FDA-1088 or
`
`
`
`
`www.fda.gov/medwatch.
`___________________ 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 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)
`
` ______________
` _______________
`USE IN SPECIFIC POPULATIONS
`Lactation: Breastfeeding is not recommended. (8.2)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide.
`
`
`Revised: 10/2019
`
`
`
`
`
`8.2 Lactation
`
`
`8.4
`Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Renal Impairment
`
`
`
`8.7 Hepatic Impairment
`
`
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
` 12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Clinical Studies in Adult Patients with UCDs
`
`
`
`14.2 Clinical Studies in Pediatric Patients 2 Years to 17 Years of Age
`
`
`
`
`
`
`with UCDs
`
`
`14.3 Clinical Studies in Pediatric Patients Less Than 2 Years of Age
`
`
`
`
`
`
`with UCDs
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
` 1
`
`
`
`
`
` 2
`
` INDICATIONS AND USAGE
`
` RAVICTI 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. 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.
`
`
`
`•
`
`
`
`
`
` DOSAGE AND ADMINISTRATION
`
` 2.1
`
`
`
` 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 or dosing cup.
`
` 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 (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
`
`
` RAVICTI and patients naïve to phenylbutyric acid are different [see Dosage and
`
`
` Administration (2.2, 2.3)]. For both subpopulations:
` o Patients 2 years of age and older: Give RAVICTI in 3 equally divided dosages,
`
`
`
` each rounded up to the nearest 0.5 mL
` o Patients less than 2 years: Give RAVICTI in 3 or more equally divided dosages,
`
`
`
`
`
` each rounded up to the nearest 0.1 mL.
` o The maximum total daily dosage is 17.5 mL (19 g).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4501848
`
`
`
`
`
`
`
`
`
` o 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).
`
` 2.2 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 tablets (g) x 0.86
` Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81
`
`
`
`
`
` 2.3
` 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.
`
`
`
` 2.4 Dosage Adjustment and Monitoring
` During treatment with RAVICTI, patients should be followed clinically and with plasma
`
`
`
` ammonia levels to determine the need for dosage titration. Closely monitor plasma ammonia
` levels during treatment with RAVICTI and when changing the dosage of RAVICTI.
`
`
`
`
`
`
`The methods used for measuring plasma ammonia levels vary among individual laboratories and
`
`
`values obtained using different assay methods may not be interchangeable. Normal ranges and
`
`therapeutic target levels for plasma ammonia depend upon the assay method used by the
`
`individual laboratory. During treatment with RAVICTI, refer to the assay-specific normal
`
`
`
`
`ranges and to the therapeutic target ranges for plasma ammonia.
`
`Normal Plasma Ammonia
`
`
`
`
`
`
`In patients treated with RAVICTI who experience neurologic symptoms (e.g. nausea,
`
`
`
`vomiting, headache, somnolence or confusion) in the absence of high plasma ammonia or
`
`
`
`other intercurrent illness to explain these symptoms, consider reducing the RAVICTI dosage
`
`and clinically monitor patients for potential neurotoxicity from high phenylacetate (PAA)
` concentrations. If available, obtain measurements of plasma PAA concentrations and plasma
`
`
` phenylacetylglutamine (PAGN) to calculate the ratio of plasma PAA to PAGN which may
`
`
`
`
`
`
`help to guide RAVICTI dosing. The PAA to PAGN ratio has generally been less than 1 in
` patients with UCDs who did not have significant plasma PAA accumulation. In general, a
`
`
`
`
`
`
`
`
`high PAA to PAGN ratio may indicate a slower or less efficient conjugation reaction to form
`
`
`
`
`
`Reference ID: 4501848
`
`
`
`
`
`
`
` PAGN, which may lead to increases in PAA without further conversion to PAGN [see
`
`Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].
`
`
`Elevated Plasma Ammonia
`
`
`In patients 6 years and older, when plasma ammonia is elevated, increase the RAVICTI
`
`
`
`
`dosage to maintain fasting plasma ammonia to less than half the upper limit of normal
`
`
`
`
`(ULN). In infants and pediatric patients below 6 years of age, if obtaining fasting ammonia is
`
`
`
`
`problematic due to frequent feedings, adjust the RAVICTI dosage to keep the first ammonia
`
`
`
`
`
`of the morning below the ULN for age. If available, the ratio of PAA to PAGN in the same
`
`plasma sample may provide additional information to assist in dosage adjustment decisions
`
`
`[see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
`
`
`
`Dietary Protein Intake
`
`
`If available, urinary phenylacetylglutamine (U-PAGN) measurements may be used to help
`
`
`
`
`guide RAVICTI dosage 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 dosage should be increased. The amount of dosage adjustment
`
`
`
`
`
`should factor in the amount of dietary protein that has not been covered, as indicated by the
`
`
`
`24-hour U-PAGN output, 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 [see Drug Interactions (7.2)].
`
`
`
`
`
`
` 2.5 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/m2/day) and the dosage should be
`
`
` kept at the lowest necessary to control the patient’s plasma ammonia [see Use in Specific
`
`
`
`
`
`
` Populations (8.7)].
`
` 2.6 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. However, for patients who cannot swallow, a
`
` nasogastric tube or gastrostomy tube may be used to 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 the nasogastric/gastrostomy tube.
`
`
`
`
`
` • Utilizing the plunger of the syringe, administer RAVICTI into the tube.
`
`
` • Flush once with 10 mL of water or formula and allow the flush to drain.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4501848
`
`
`
`
`
`
`
`
`•
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3
`
`
`
` 4
`
`
`
` 5
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
` Oral liquid: colorless to pale yellow, 1.1 g/mL of glycerol phenylbutyrate (delivers 1.02
`
` g/mL of phenylbutyrate).
`
`
` CONTRAINDICATIONS
`
`
` RAVICTI is contraindicated in patients with known hypersensitivity to phenylbutyrate. Signs
`of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and
`
`rash.
`
`
`
`
`
`
` WARNINGS AND PRECAUTIONS
`
` 5.1 Neurotoxicity
`
` Increased exposure to PAA, the major metabolite of RAVICTI, 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 RAVICTI 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
`
`
`
`
`RAVICTI 3 times daily and from 31 to 242 micrograms/mL with 6 mL RAVICTI 3 times
`
`daily.
`
`
`
`In clinical trials in patients with UCDs who had been on sodium phenylbutyrate prior to
`
`
`administration of RAVICTI, 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)].
`
`
`
`Reference ID: 4501848
`
`
`
`
`
` 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 RAVICTI
`
`
`dosage [see Dosage and Administration (2.4)].
`
`
`
`
`
` 5.2
` 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.
`
`
` 6
`
` ADVERSE REACTIONS
`
`
` Clinical Trials Experience
`
` 6.1
` 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 (RAVICTI 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 RAVICTI were diarrhea, flatulence, and headache. Table 1
`
`summarizes adverse reactions occurring in 2 or more patients treated with RAVICTI or
`
`
`
`sodium phenylbutyrate (incidence of at least 4% in either treatment arm).
`
`
`
`
`
`
`Adverse Reactions Reported in 2 or More Adult Patients with UCDs (at least
`Table 1:
`
`
`4% in Either Treatment Arm) in Study 1
` Number (%) of Patients in Study 1
`
`
`
` Sodium Phenylbutyrate
`RAVICTI
`
` (N = 45)
`
` (N = 44)
`
` 3 (7)
`
` 7 (16)
`
` 4 (9)
`
` 6 (14)
`
` 1 (2)
`
` 6 (14)
`
` 2 (4)
` 3 (7)
`
`
` 2 (4)
`
` 3 (7)
`
` 2 (4)
`
` 3 (7)
`
` 1 (2)
`3 (7)
`
`
` 3 (7)
`2 (5)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Diarrhea
`
`
` Headache
`
` Flatulence
` Abdominal pain
`
` Vomiting
` Decreased appetite
`
` Fatigue
` Dyspepsia
`
`
`
`
`
`
`Reference ID: 4501848
`
`
`
` Number (%) of Patients in Study 1
`
`
`
` Sodium Phenylbutyrate
`RAVICTI
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` (N = 45)
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` (N = 44)
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` 3 (7)
`1 (2)
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` 4 (9)
`0
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` 3 (7)
`0
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` Nausea
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` Dizziness
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` Abdominal discomfort
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` Other Adverse Reactions
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` RAVICTI has been evaluated in 77 patients with UCDs (51 adult and 26 pediatric patients
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` ages 2 years to 17 years) 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
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` there were no deaths.
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` Adverse reactions reported in at least 10% of adult patients were nausea, vomiting, diarrhea,
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`decreased appetite, dizziness, headache, and fatigue.
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` Adverse reactions reported in at least 10% of pediatric patients ages 2 years to 17 years were
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` upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache.
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` RAVICTI has been evaluated in 17 patients with UCDs ages 2 months to less than 2 years in
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` 3 open-label studies. The median exposure was 6 months (range 0.2 to 20 months).
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` Adverse reactions reported in at least 10% of pediatric patients aged 2 months to less than 2
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` years were neutropenia, vomiting, constipation, diarrhea, pyrexia, hypophagia, cough, nasal
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` congestion, rhinorrhea, rash, and papule.
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` RAVICTI 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
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` was 10 months (range 2 to 20 months). Adverse reactions reported in at least 10% of
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` pediatric patients aged less than 2 months were vomiting, rash, gastroesophageal reflux,
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` increased hepatic enzymes, feeding disorder (decreased appetite, hypophagia), anemia,
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` cough, dehydration, metabolic acidosis, thrombocytosis, thrombocytopenia, neutropenia,
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` lymphocytosis, diarrhea, flatulence, constipation, pyrexia, lethargy, and irritability/agitation.
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` 6.2 Postmarketing Experience
` The following adverse reactions have been identified during post-approval use of RAVICTI.
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` Because these reactions are reported voluntarily from a population of uncertain size, it is not
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` always possible to reliably estimate their frequency or establish a causal relationship to drug
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` exposure:
` • Abnormal body odor, including from skin, hair and urine
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` • Retching and gagging
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` • Dysgeusia or burning sensation in mouth
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`Reference ID: 4501848
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` 7
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` DRUG INTERACTIONS
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` 7.1 Potential for Other Drugs to Affect Ammonia
` Corticosteroids
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`Use of corticosteroids may cause the breakdown of body protein and increase plasma
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`ammonia levels. Monitor ammonia levels closely when corticosteroids and RAVICTI are
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`used concomitantly.
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`Valproic Acid and Haloperidol
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`Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia
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`levels closely when use of valproic acid or haloperidol is necessary in patients with UCDs.
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` 7.2 Potential for Other Drugs to Affect RAVICTI
` Probenecid
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` Probenecid may inhibit the renal excretion of metabolites of RAVICTI including PAGN and
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` PAA.
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` 7.3 Potential for RAVICTI to Affect Other Drugs
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`Drugs with narrow therapeutic index that are substrates of CYP3A4
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`RAVICTI is a weak inducer of CYP3A4 in humans. Concomitant use of RAVICTI may
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`decrease the systemic exposure to drugs that are substrates of CYP3A4. Monitor for
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`decreased efficacy of drugs with narrow therapeutic index (e.g., alfentanil, quinidine,
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`cyclosporine) [see Clinical Pharmacology (12.3)].
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`Midazolam
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`Concomitant use of RAVICTI decreased the systemic exposure of midazolam. Monitor for
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`suboptimal effect of midazolam in patients who are being treated with RAVICTI.
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` USE IN SPECIFIC POPULATIONS
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` 8.1 Pregnancy
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` Pregnancy Exposure Registry
` There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed
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` to RAVICTI during pregnancy. Healthcare providers are encouraged to report any prenatal
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` exposure to RAVICTI by calling the Pregnancy Registry at 1-855-823-2595 or visiting
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`www.ucdregistry.com.
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`Risk Summary
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`Limited available data with RAVICTI use in pregnant women are insufficient to inform a
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`drug-associated risk of major birth defects and miscarriage. In an animal reproduction study,
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`administration of oral glycerol phenylbutyrate to pregnant rabbits during organogenesis at
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` doses up to 2.7–times the dose of 6.87 mL/m2/day in adult patients resulted in maternal
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`Reference ID: 4501848
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` 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
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`during organogenesis at 1.9 times the dose of 6.87 mL/m2/day in adult patients; however,
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`maternal toxicity, reduced fetal weights, and variations in skeletal development were
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` 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/m2/day in adult patients [see
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`Data].
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`The estimated background risk of major birth defects and miscarriage for the indicated
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`population is unknown. All pregnancies have a background risk of birth defect, loss or other
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`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%,
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` respectively.
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` Data
`Animal Data
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`Oral administration of glycerol phenylbutyrate during the period of organogenesis up to 350
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`mg/kg/day in rabbits produced maternal toxicity, but no effects on embryo-fetal
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`development. The dose of 350 mg/kg/day in rabbits is approximately 2.7 times the dose of
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`6.87 mL/m2/day in adult patients, based on combined area under the plasma concentration-
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`time curve [AUCs] for PBA and PAA. In rats, at an oral dose of 300 mg/kg/day of glycerol
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`phenylbutyrate (1.9 times the dose of 6.87 mL/m2/day in adult patients, based on combined
`AUCs for PBA and PAA) during the period of organogenesis, no effects on embryo-fetal
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`development were observed. Doses of 650 mg/kg/day or greater produced maternal toxicity
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`and adverse effects on embryo-fetal development including reduced fetal weights and
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`cervical ribs at the 7th cervical vertebra. The dose of 650 mg/kg/day in rats is approximately
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`5.7 times the dose of 6.87 mL/m2/day in adult patients, based on combined AUCs for PBA
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`and PAA. No developmental abnormalities, effects on growth, or effects on learning and
`memory were observed through maturation of offspring following oral administration in
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`pregnant rats with up to 900 mg/kg/day of glycerol phenylbutyrate (8.5 times the dose of
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`6.87 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA) during
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`organogenesis and lactation.
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` 8.2 Lactation
` Risk Summary
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`There are no data on the presence of RAVICTI in human milk, the effects on the breastfed
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`infant, or the effects on milk production. Because of the potential for serious adverse
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`reactions, including neurotoxicity and tumorigenicity in a breastfed infant, advise patients
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`that breastfeeding is not recommended during treatment with RAVICTI.
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` 8.4 Pediatric Use
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` Patients 2 Years to 17 Years of Age
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` The safety and effectiveness of RAVICTI in patients 2 years to less than 18 years of age have
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` been established in 3 clinical studies: 2 open-label, fixed-sequence, switchover clinical
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`Reference ID: 4501848
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` studies from sodium phenylbutyrate to RAVICTI, and 1 long-term, open label safety study
` [see Adverse Reactions (6.1), Clinical Studies (14.2)].
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` Patients Less Than 2 Years of Age
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`The safety and effectiveness of RAVICTI in patients with UCDs less than 2 years of age
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`have been established in 3 open-label studies. Pharmacokinetics and pharmacodynamics
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`(plasma ammonia), and safety were studied in 17 patients aged 2 months to less than 2 years
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`of age and in 16 patients less than 2 months of age [see Adverse Reactions (6.1), Clinical
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`Studies (14.3)].
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`Juvenile Animal Toxicity Data
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`In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating
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`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
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` mL/m2/day in adult patients, based on combined AUCs for PBA and PAA). Learning,
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` 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
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` 6.87 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA).
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` 8.5 Geriatric Use
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` Clinical studies of RAVICTI did not include sufficient numbers of subjects 65 years of age
` and older to determine whether they respond differently than younger subjects. Other
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` reported clinical experience has not identified differences in responses between the elderly
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`and younger patients. In general, dose selection for an elderly patient should be cautious,
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`usually starting at the low end of the dosing range, reflecting the greater frequency of
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`decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug
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`therapy.
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` 8.6 Renal Impairment
` The efficacy and safety of RAVICTI in patients with renal impairment are unknown. Monitor
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` ammonia levels closely when starting patients with impaired renal function on RAVICTI.
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` 8.7 Hepatic Impairment
` No studies were conducted in patients with UCDs and hepatic impairment. Because
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` conversion of PAA to PAGN occurs in the liver, patients with hepatic impairment may have
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` reduced conversion capability and higher plasma PAA and PAA to PAGN ratio [see Clinical
`Pharmacology (12.3)]. Therefore, dosage for patients with moderate to severe hepatic
`impairment should be started at the lower end of the recommended dosing range and should
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`be kept on the lowest dose necessary to control their ammonia levels [see Dosage and
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`Administration (2.5)].
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`Reference ID: 4501848
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` 10
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` 11
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` OVERDOSAGE
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` While there is no experience with overdosage in human clinical trials, PAA, a toxic
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` metabolite of RAVICTI, can accumulate in patients who receive an overdose [see Warnings
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` and Precautions (5.1)].
` If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current
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` information on the management of poisoning or overdosage.
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` DESCRIPTION
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` RAVICTI (glycerol phenylbutyrate) is a clear, colorless to pale yellow oral liquid. It is
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` insoluble in water and most organic solvents, and it is soluble in dimethylsulfoxide (DMSO)
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` and greater than 65% acetonitrile.
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` 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
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` benzenebutanoic acid, 1', 1' ' –(1,2,3-propanetriyl) ester with a molecular weight of 530.67. It
` has a molecular formula of C33H38O6. The structural formula is:
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` 12
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` CLINICAL PHARMACOLOGY
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` 12.1 Mechanism of Action
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` UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of
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` +). Absence of these enzymes or transporters results in the
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` urea from ammonia (NH3, NH4
` accumulation of toxic levels of ammonia in the blood and brain of affected patients.
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` RAVICTI is a triglyceride containing 3 molecules of PBA. PAA, the major metabolite of
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` PBA, is the active moiety of RAVICTI. PAA conjugates with glutamine (which contains 2
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` molecules of nitrogen) via acetylation in the liver and kidneys to form PAGN, which is
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` excreted by the kidneys (Figure 1). On a molar basis, PAG