`
`
`
`
`
`
`
`
`Take into account patient's estimated urea synthetic capacity,
`dietary protein intake, and diet adherence. (2.3)
`
`Dosage Modifications in Patients With Hepatic Impairment:
`
`
`
` Start dosage at lower end of range. (2.5, 8.6)
`
`
`______________
`______________
`DOSAGE FORMS AND STRENGTHS
`
`Oral liquid: 1.1 g/mL of glycerol phenylbutyrate. (3)
`
`___________________ CONTRAINDICATIONS____________________
`
`
`
`Patients <2 months of age. (4)
`
`
`
`
`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)
`Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or
`Intestinal Malabsorption: Monitor ammonia levels closely. (5.2)
`
`____________________ADVERSE REACTIONS____________________
`
`Most common adverse reactions in ≥10% of patients are diarrhea, flatulence,
`and headache. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Hyperion
`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 PAGN and PAA. (7.2)
`
`_______________
`USE IN SPECIFIC POPULATIONS _______________
`
`
`
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
`
`Nursing Mothers: Discontinue nursing or discontinue the drug.
`
`(8.3)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`Revised: January 2013
`
`
` 
`14
`
` 
` 
`13.1 Carcinogenesis, mutagenesis, impairment of fertility
` 
`CLINICAL STUDIES
` 
` 
` Clinical Studies in Adult Patients with UCDs
`14.1
` 
` 
`14.2 Clinical Studies in Pediatric Patients With UCDs
` 
` 
`REFERENCES
`15
` 
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
` 
` 
`16.1 How Supplied
` 
` 
`16.2 Storage
` 
`PATIENT COUNSELING INFORMATION
`
` 
`17
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`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
`
`
`_________________
`__________________ INDICATIONS AND USAGE
`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) that 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 (eg, essential
`amino acids, arginine, citrulline, protein-free calorie 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)
`The use of RAVICTI in patients <2 months of age is
`contraindicated (4)
`
`
`
`
`
`
`
`
`______________
`_______________
`
`DOSAGE AND ADMINISTRATION
`
`RAVICTI should be prescribed by a physician experienced in management of
`UCDs. (2.1)
`
`Instruct patients to take with food and to administer directly into
`
`
`
`mouth via oral syringe or dosing cup. (2.1)
`Total daily dosage is given in 3 equally divided dosages, rounded
`
`
`up to nearest 0.5 mL. (2.1)
`
`
`
` Maximum daily dosage is 17.5 mL (19 g). (2.1)
`
`
`
` Must be used with dietary protein restriction. (2.1)
`
`Switching From Sodium Phenylbutyrate to RAVICTI:
`
`
`
`Daily dosage of RAVICTI (mL) = daily dosage of sodium
`
`
`
`phenylbutyrate (g) x 0.86. (2.2)
`Initial Dosage in Phenylbutyrate-Naïve Patients:
`Recommended dosage range is 4.5 to 11.2 mL/m2/day (5 to 12.4
`
`
`g/m2/day). (2.3)
`For patients with some residual enzyme activity who are not
`adequately controlled with dietary restriction, recommended
`starting dose is 4.5 mL/m2/day. (2.3)
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
` 
`1
` 
`2
`
` 
`INDICATIONS AND USAGE
` 
`DOSAGE AND ADMINISTRATION
` 
` 
`2.1
`Important Instructions
` 
` 
`2.2
`Switching From Sodium Phenylbutyrate to RAVICTI
` 
` 
`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
` 
`5.2 Reduced Phenylbuterate Absorption in Pancreatic Insufficiency
`
` 
`or Intestinal Malabsorption
` 
`ADVERSE REACTIONS
` 
`DRUG INTERACTIONS
` 
` 
`Potential for Other Drugs to Affect Ammonia
`7.1
` 
` 
`7.2
`Potential for Other Drugs to Affect RAVICTI
` 
`USE IN SPECIFIC POPULATIONS
` 
` 
`8.1
`Pregnancy
` 
` 
`8.3 Nursing mothers
` 
` 
`8.4
`Pediatric use
` 
` 
`8.5 Geriatric use
` 
` 
`8.6 Hepatic Impairment
` 
` 
`8.7 Renal Impairment
` 
` 
`10 OVERDOSAGE
` 
` 
`11
`DESCRIPTION
` 
` 
`12
`CLINICAL PHARMACOLOGY
` 
` 
`12.1 Mechanism of action
` 
` 
`12.2 Pharmacodynamics
` 
` 
`12.3 Pharmacokinetics
` 
`NONCLINICAL TOXICOLOGY
`
` 
`6
` 
`7
`
` 
`8
`
` 
`13
`
`Reference ID: 3254236
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`1
`
`2
`
`INDICATIONS AND USAGE
`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 (eg,
`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 [see Contraindications
`(4)].
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`Important Instructions
`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 [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:
`
` 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).
`
` 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 (g) x 0.8
`
`Reference ID: 3254236
`
`

`

`Initial Dosage in Phenylbutyrate-Naïve Patients
`2.3
`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
`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 [see Drug Interactions (7.2)].
`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. [see Warnings and Precautions (5.1)].
`
`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 range [see Warnings and Precautions (5.1) and Hepatic Impairment
`(8.6)].
`
`Reference ID: 3254236
`
`

`

`2.6 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.
`
`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
`
` 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. [see Pediatric Use (8.4)]
`
` With known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include
`wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.
`
`3
`
`4
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1 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,
`
`Reference ID: 3254236
`
`

`

`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.
`
`5.2
`
`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.
`
`6
`
`ADVERSE REACTIONS
`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.
`Table 1:
`Adverse Reactions Reported in ≥2 Adult UCD Patients in Study 1
`Number (%) of Patients in Study 1
`Sodium Phenylbutyrate
`RAVICTI
`(N = 45)
`(N = 44)
`
`
`3 (7)
`0
`2 (4)
`3 (7)
`3 (7)
`7 (16)
`3 (7)
`2 (5)
`1 (2)
`6 (14)
`3 (7)
`1 (2)
`
`3 (7)
`2 (4)
`
`
`
`
`
`
`
`
`Gastrointestinal disorders
`
`Abdominal discomfort
`
`
` Abdominal pain
`Diarrhea
` Dyspepsia
`
`Flatulence
`Nausea
`
`Vomiting
`
`General disorders and administration site conditions
`
`Reference ID: 3254236
`
`

`

`
`
`Number (%) of Patients in Study 1
`Sodium Phenylbutyrate
`RAVICTI
`(N = 45)
`(N = 44)
`1 (2)
`3 (7)
`
`
`
`1 (2)
`2 (5)
`
`
`
`2 (4)
`3 (7)
`
`
`
`4 (9)
`0
`
`6 (14)
`4 (9)
`
`
`Fatigue
`Investigations
`Ammonia increased
`
` Metabolism and nutrition disorders
`
`Decreased appetite
`
`Nervous system disorders
`
`Dizziness
`
`Headache
` 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.
`
`7
`
`DRUG INTERACTIONS
`
`7.1 Potential for Other Drugs to Affect Ammonia
`Corticosteroids
`
`Use of corticosteroids may cause the breakdown of body protein and increase plasma
`ammonia levels. Monitor ammonia levels closely when corticosteroids and RAVICTI are
`used concomitantly.
`Valproic Acid and Haloperidol
`Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia
`levels closely when use of valproic acid or haloperidol is necessary in UCD patients.
`
`7.2 Potential for Other Drugs to Affect RAVICTI
`Probenecid
`
`Probenecid may inhibit the renal excretion of metabolites of RAVICTI including PAGN and
`PAA.
`
`Reference ID: 3254236
`
`

`

`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`A voluntary patient registry will include evaluation of pregnancy outcomes in patients with
`UCDs. For more information regarding the registry program, visit www.ucdregistry.com or
`call 1-855-823-2595.
`Pregnancy Category C
`
` Risk Summary
`There are no adequate and well-controlled studies in pregnant women. In rabbits given
`glycerol phenylbutyrate at doses up to 2.7 times the dose of 6.87 mL/m2/day in adult patients
`(based on combined area under the curve [AUCs] for PBA and PAA) during the period of
`organogenesis, maternal toxicity, but no effects on embryo-fetal development, was observed.
`In rats given glycerol phenylbutyrate at 1.9 times the dose of 6.87 mL/m2/day in adult
`patients (based on combined AUCs for PBA and PAA), no adverse embryo-fetal effects were
`observed. Maternal toxicity, reduced fetal weights, and variations in skeletal development
`were observed in rats at doses greater than or equal to 5.7 times the dose of 6.87 mL/m2/day
`in adult patients (based on combined AUCs for PBA and PAA). RAVICTI should be used
`during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`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/m2/day in adult patients, based on combined 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/m2/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 ≥650
`mg/kg/day 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/m2/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 in rats through day 92 postpartum
`
`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/m2/day in adult patients, based on combined
`AUCs for PBA and PAA) during organogenesis and lactation.
`
`
`8.3 Nursing mothers
`It is not known whether RAVICTI or its metabolites are excreted in human milk. Because
`many drugs are excreted in human milk and because of the potential for adverse reactions
`from RAVICTI in nursing infants, a decision should be made whether to discontinue nursing
`or to discontinue the drug, taking into consideration the importance of the drug to the health
`of the mother.
`
`Reference ID: 3254236
`
`

`

`8.4 Pediatric use
`Patients Between 2 and <18 Years of Age
`The safety and efficacy of RAVICTI in patients 2 to <18 years of age were established in 2
`open-label, sodium phenylbutyrate to RAVICTI, fixed-sequence, switchover clinical trials
`[see Adverse Reactions (6) and Clinical Studies ( 14.2)].
`Patients ≥2 Months and <2 Years of Age
`The safety and efficacy of RAVICTI in patients 2 months to <2 years of age has not been
`established. PK and ammonia control were studied in only 4 patients between 2 months and
`<2 years of age, providing insufficient data to establish a safe and effective dose in this age
`range.
`Patients <2 Months of Age
` RAVICTI is contraindicated in patients <2 months of age [see Contraindications (4)].
`
`Children <2 months of age may have immature pancreatic exocrine function, which could
`impair hydrolysis of RAVICTI. Pancreatic lipases may be necessary for intestinal hydrolysis
`of RAVICTI, allowing release of phenylbutyrate and subsequent formation of PAA, the
`active moiety. It is not known whether pancreatic and extrapancreatic lipases are sufficient
`for hydrolysis of RAVICTI. If there is inadequate intestinal hydrolysis of RAVICTI,
`impaired absorption of phenylbutyrate and hyperammonemia could occur.
`Juvenile Animal Study
`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. 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 (2.6 times the dose of 6.87 mL/m2/day in adult patients, based on combined
`AUCs for PBA and PAA). Embryo toxicity (increased resorptions) occurred at 650
`mg/kg/day (2.6 times the dose of 6.87 mL/m2/day in adult patients, based on combined
`AUCs for PBA and PAA) and litter size was reduced at 900 mg/kg/day (3 times the dose of
`6.87 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA).
`
`8.5 Geriatric use
`Clinical studies of RAVICTI did not include sufficient numbers of subjects ≥65 years of age
`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.
`
`8.6 Hepatic Impairment
`No studies were conducted in UCD patients with hepatic impairment. Because conversion of
`PAA to PAGN occurs in the liver, patients with hepatic impairment may have reduced
`conversion capability and higher plasma PAA and PAA to PAGN ratio. Therefore, dosage
`
`Reference ID: 3254236
`
`

`

`for patients with moderate to severe hepatic impairment should be started at the lower end of
`the recommended dosing range and should be kept on the lowest dose necessary to control
`their ammonia levels [see Clinical Pharmacology (12.3)].
`
`8.7 Renal Impairment
`The efficacy and safety of RAVICTI in patients with renal impairment are unknown. Monitor
`ammonia levels closely when starting patients with impaired renal function on RAVICTI.
`
`10
`
`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 [see Warnings and Precautions
`(5.1)].
`
`11
`
`DESCRIPTION
`RAVICTI (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 >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 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
`UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of
`+). Absence of these enzymes or transporters results in the
`urea from ammonia (NH3, NH4
`accumulation of toxic levels of ammonia in the blood and brain of affected patients.
`RAVICTI is a triglyceride containing 3 molecules of phenylbutyrate (PBA). PAA, the major
`metabolite of PBA, is the active moiety of RAVICTI. PAA conjugates with glutamine
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`(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:
`RAVICTI Mechanism of Action
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`12.2 Pharmacodynamics
`Pharmacological Effects
`In clinical studies, total 24-hour AUC of ammonia concentration was comparable at steady
`state during the switchover period between RAVICTI and sodium phenylbutyrate [see
`Clinical Studies (14)].
`Cardiac Electrophysiology
`The effect of multiple doses of RAVICTI 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 RAVICTI, was below 10 ms. However, assay sensitivity was not established in
`this study because the moxifloxacin time-profile was not consistent with expectation.
`Therefore, an increase in mean QTc interval of 10 ms cannot be ruled out.
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`12.3 Pharmacokinetics
`Absorption
`RAVICTI 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 RAVICTI is further
`converted by β-oxidation to PAA.
`In healthy, fasting adult subjects receiving a single oral dose of 2.9 ml/m2 of RAVICTI, peak
`plasma levels of PBA, PAA, and PAGN occurred at 2 h, 4 h, and 4 h, respectively. Upon
`single-dose administration of RAVICTI, plasma concentrations of PBA were quantifiable in
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`15 of 22 participants at the first sample time postdose (0.25 h). Mean maximum
`concentration (Cmax) for PBA, PAA, and PAGN was 37.0 µg/mL, 14.9 µg/mL, and 30.2
`µg/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 RAVICTI for 3 days (3 times a day [TID]), mean
`Cmax and AUC were 66 µg/mL and 930 µg•h/mL for PBA and 28 µg/mL and 942 µg•h/mL
`for PAA, respectively. In the same study, following 6 mL of RAVICTI for 3 days (TID),
`mean Cmax and AUC were 100µg/mL and 1400 µg•h/mL for PBA and 65 µg/mL and 2064
`µg•h/mL for PAA, respectively.
` In adult UCD patients receiving multiple doses of RAVICTI, maximum plasma
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`concentrations at steady state (Cmaxss) of PBA, PAA, and PAGN occurred at 8 h, 12 h, and 10
`h, respectively, after the first dose in the day. Intact glycerol phenylbutyrate was not
`detectable in plasma in UCD patients.
`Distribution
`In vitro, the extent of plasma protein binding for 14C-labeled metabolites was 80.6% to
`98.0% for PBA (over 1-250 μg/mL), and 37.1% to 65.6% for PAA (over 5-500 μg/mL). The
`protein binding for PAGN was 7% to 12% and no concentration effects were noted.
`Metabolism
`Upon oral administration, pancreatic lipases hydrolyze RAVICTI (i.e., glycerol
`phenylbutyrate), and release PBA. PBA undergoes β-oxidation to PAA, which is conjugated
`with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: L­
`glutamine-N-acetyltransferase to form PAGN. PAGN is subsequently eliminated in the urine.
`Saturation of conjugation of PAA and glutamine to form PAGN was suggested by increases
`in the ratio of plasma PAA to PAGN with increasing dose and with increasing severity of
`hepatic impairment.
`In healthy subjects, after administration of 4 mL, 6 mL, and 9 mL 3 times daily for 3 days,
`the ratio of mean AUC0-23h of PAA to PAGN was 1, 1.25, and 1.6, respectively. In a separate
`study, in patients with hepatic impairment (Child-Pugh B and C), the ratios of mean Cmax
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`values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were 3
`and 3.7.
`In in vitro studies, the specific activity of lipases for glycerol phenylbutyrate was in the
`following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and
`pancreatic lipase–related protein 2. Further, glycerol phenylbutyrate was hydrolyzed in vitro
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`by esterases in human plasma. In these in vitro studies, a complete disappearance of glycerol
`phenylbutyrate did not produce molar equivalent PBA, suggesting the formation of mono- or
`bis-ester metabolites. However, the formation of mono- or bis-esters was not studied in
`humans.
`Excretion
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`The mean (SD) percentage of administered PBA excreted as PAGN was approximately
`68.9% (17.2) in adults and 66.4% (23.9) in pediatric UCD patients at steady state. PAA and
`PBA represented minor urinary metabolites, each accounting for <1% of the administered
`dose of PBA.
`Specific Population
`Gender
`In healthy adult volunteers, a gender effect was found for all metabolites, with women
`generally having higher plasma concentrations of all metabolites than men at a given dose
`level. In healthy female volunteers, mean Cmax for PAA was 51 and 120% higher than in
`male volunteers after administration of 4 mL and 6 mL 3 times daily for 3 days, respectively.
`The dose normalized mean AUC0-23h for PAA was 108% higher in females than in males.
`Pediatrics
`Population pharmacokinetic modeling and dosing simulations suggest body surface area to
`be the most significant covariate explaining the variability of PAA clearance. PAA clearance
`was 10.9 L/h, 16.4 L/h, and 24.4 L/h, respectively, for UCD patients ages 3 to 5, 6 to 11, and
`12 to 17 years.
`Hepatic Impairment
`The effects of hepatic impairment on the pharmacokinetics of RAVICTI were studied in
`patients with hepatic impairment of Child-Pugh A, B, and C receiving 100 mg/kg of
`RAVICTI twice daily for 7 days.
`Plasma glycerol phenylbutyrate was not measured in patients with hepatic impairment.
`After multiple doses of RAVICTI in patients with hepatic impairment of Child-Pugh A, B,
`and C, geometric mean AUCt of PBA was 42%, 84%, and 50% higher, respectively, while
`geometric mean AUCt of PAA was 22%, 53%, and 94% higher, respectively, than in healthy
`subjects.
`In patients with hepatic impairment of Child-Pugh A, B, and C, geometric mean AUCt of
`PAGN was 42%, 27%, and 22% lower, respectively, than that in healthy subjects.
`The proportion of PBA excreted as PAGN in the urine in Child-Pugh A, B, and C was 80%,
`58%, and 85%, respectively, and, in healthy volunteers, was 67%.
`In another study in patients with hepatic impairment (Child-Pugh B and C), mean Cmax of
`PAA was 144 μg/mL (range: 14-358 μg/mL) after daily dosing of 6 mL of RAVICTI twice
`daily, while mean Cmax of PAA was 292 μg/mL (range: 57-655 μg/mL) after daily dosing of
`9 mL of RAVICTI twice daily. The ratio of mean Cmax values for PAA to PAGN among all
`patients dosed with 6 mL and 9 mL twice daily were 3 and 3.7, respectively.
` After multiple doses, a PAA concentration >200 μg/L was associated with a ratio of plasma
`PAA to PAGN concentrations higher than 2.5.
`Renal Impairment
`The pharmacokinetics of RAVICTI in patients with impaired renal function, including those
`with end-stage renal disease (ESRD) or those on hemodialysis, have not been studied.