`•
`
`
`•
`
`
`•
`
`
`
`
`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.
`
`
`
`
`
`
`
`
` 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) 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). (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
`INDICATIONS AND USAGE
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`2.1
`Important Instructions
`
`
`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
`
`5.2 Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency
`
`
`
`or Intestinal Malabsorption
`
`
`ADVERSE REACTIONS
`
`DRUG INTERACTIONS
`
`
`Potential for Other Drugs to Affect Ammonia
`7.1
`
`
`Potential for Other Drugs to Affect RAVICTI
`7.2
`
`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
`
`
`6
`
`7
`
`
`
`8
`
`
`
`
`
`
`
`
`Reference ID: 3530007
`
`Revised: June 2014
`
`
`
`
`
`
`
`
`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 With UCDs
`
`
`
`
`15 REFERENCES
`
`
`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.
`
`
`

`

`
`
` 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 (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 [see Contraindications
`
`
`
`(4)].
`
`
`
`
` DOSAGE AND ADMINISTRATION
` Important Instructions
`
` 2.1
`
`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 0.86
`
`
`
`Reference ID: 3530007
`
`

`

` 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 Use in Specific
`
` Populations (8.6)].
`
`
`
`Reference ID: 3530007
`
`

`

`
`
`
`
` 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 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.
`
`
`
`
`
`
`
`
`
` 3
`
`
`
` 4
`
` 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 Use in Specific Populations
`
`
`(8.4)].
`
`• With known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include
`
`
`wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.
`
`
`
`
`
`
` 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:
`
`
`
`Reference ID: 3530007
`
`

`

`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.
`
`
`
`
`
` 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.
`
`
`
`
` 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.
`
`
`
`Adverse Reactions Reported in ≥2 Adult UCD Patients in Study 1
`Table 1:
`
` Number (%) of Patients in Study 1
`
`RAVICTI
`
` Sodium Phenylbutyrate
`
`
` (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)
`
`
` 2 (4)
`3 (7)
`
`
` Gastrointestinal disorders
`
`
` Abdominal discomfort
`
`
`
` Abdominal pain
`
`
` Diarrhea
`
`
` Dyspepsia
`
` Flatulence
`
` Nausea
` Vomiting
`
`
`
`
`
`
`
`
` 6
`
`
`
`
`
`
`Reference ID: 3530007
`
`

`

`
`
` 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
`
`
` 4 (9)
`6 (14)
`
`
`
`
`
`
`
`
` General disorders and administration site conditions
`
`
` 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: 3530007
`
`

`

`
`
` 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
`
`
`
`
` Breastfeeding is not recommended with maternal use of RAVICTI. It is not known whether
`
` RAVICTI or its metabolites are present in breast milk. Because many drugs are present in
`
`
`
`
` breast milk and because of the potential for tumorigencity of glycerol phenylbutyrate
`
`
`
`
`
` identified in animal studies, as well as the potential for serious adverse reactions in nursing
`
`
` infants from RAVICTI, a decision should be made whether to discontinue nursing or to
`
`
`
`
`
`
`Reference ID: 3530007
`
`

`

` discontinue the drug, taking into consideration the importance of the drug to the health of the
`
`
` mother [see Use in Specific Populations (8.4) and Nonclinical Toxicology (13.1)].
`
`
`
`
`
`
` 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.
`
`
`
`
`
`Reference ID: 3530007
`
`

`

`
`
` 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
`
`
`
`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:
`
`
`
`
`
`
`
`Reference ID: 3530007
`
`

`

`
`
` 12
`
`
`
` CLINICAL PHARMACOLOGY
`
` 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
`
`
`
`
` (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.
`
`
` RAVICTI Mechanism of Action
`
`
`
` Figure 1:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`Reference ID: 3530007
`
`

`

`
`
`
` 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 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
`
`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
`
`
` values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were 3
`
`
` and 3.7.
`
`
`
`
`
`Reference ID: 3530007
`
`

`

`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
`
`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
`
`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/