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: 12/2018
`
`
`
`
`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.
`
`
`
`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
` _________________
` _________________
`
`RECENT MAJOR CHANGES
`Indications and Usage (1) 12/2018
`Dosage and Administration (2.4)
`
`12/2018
`Contraindications (removed) (4)
`
`12/2018
`Warnings and Precautions (5.1)
`
`12/2018
` __________________
` _________________
`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
`2.1
`Important Administration 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 Pancreatic Insufficiency or Intestinal Malabsorption
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`DRUG INTERACTIONS
`7.1 Potential for Other Drugs to Affect Ammonia
`7.2 Potential for Other Drugs to Affect RAVICTI
`7.3
`Potential for RAVICTI to Affect Other Drugs
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`
`
`
`
`
`
`
`
`
`6
`
`7
`
`8
`
`
`Reference ID: 4367866
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`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.
`
` 1
`
`
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`
`
`Important Administration Instructions
`2.1
`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).
`
`
`
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`

`
`
`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
`
`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
`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
`
`
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`Reference ID: 4367866
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`

`

`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.
`
`
`
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`

`
`
`3
`
`4
`
`
`
`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.
`
`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.
`
`5
`
`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: 4367866
`
`

`

`
`
`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)].
`
`Pancreatic Insufficiency or Intestinal Malabsorption
`5.2
`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).
`
`Table 1:
`
`Adverse Reactions Reported in 2 or More Adult Patients with UCDs (at least
`4% in Either Treatment Arm) in Study 1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Diarrhea
`Headache
`Flatulence
`Abdominal pain
`Vomiting
`Decreased appetite
`Fatigue
`Dyspepsia
`
`Reference ID: 4367866
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`Number (%) of Patients in Study 1
`
`Sodium Phenylbutyrate
`(N = 45)
`3 (7)
`4 (9)
`1 (2)
`2 (4)
`2 (4)
`2 (4)
`1 (2)
`3 (7)
`
`RAVICTI
`(N = 44)
`7 (16)
`6 (14)
`6 (14)
`3 (7)
`3 (7)
`3 (7)
`3 (7)
`2 (5)
`
`

`

`Number (%) of Patients in Study 1
`
`RAVICTI
`(N = 44)
`1 (2)
`0
`0
`
`Sodium Phenylbutyrate
`(N = 45)
`3 (7)
`4 (9)
`3 (7)
`
`Nausea
`Dizziness
`Abdominal discomfort
`Other Adverse Reactions
`RAVICTI has been evaluated in 77 patients with UCDs (51 adult and 26 pediatric patients
`ages 2 years to 17 years) in 2 open-label long-term studies, in which 69 patients completed
`12 months of treatment with RAVICTI (median exposure = 51 weeks). During these studies
`there were no deaths.
`Adverse reactions reported in at least 10% of adult patients were nausea, vomiting, diarrhea,
`decreased appetite, dizziness, headache, and fatigue.
`Adverse reactions reported in at least 10% of pediatric patients ages 2 years to 17 years were
`upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache.
`RAVICTI has been evaluated in 17 patients with UCDs ages 2 months to less than 2 years in
`3 open-label studies. The median exposure was 6 months (range 0.2 to 18 months).
`Adverse reactions reported in at least 10% of pediatric patients aged 2 months to less than 2
`years were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion,
`rhinorrhea, rash, and papule.
`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
`was 10 months (range 2 to 20 months). Adverse reactions reported in at least 10% of
`pediatric patients aged less than 2 months were vomiting, rash, gastroesophageal reflux,
`increased hepatic enzymes, feeding disorder (decreased appetite, hypophagia), anemia,
`cough, dehydration, metabolic acidosis, thrombocytosis, thrombocytopenia, neutropenia,
`lymphocytosis, diarrhea, flatulence, constipation, pyrexia, lethargy, and irritability/agitation.
`
`6.2 Postmarketing Experience
`The following adverse reactions have been identified during post-approval use of RAVICTI.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure:
` Abnormal body odor, including from skin, hair and urine
` Retching and gagging
` Dysgeusia or burning sensation in mouth
`
`
`
`
`
`
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`
`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 patients with UCDs.
`
`7.2 Potential for Other Drugs to Affect RAVICTI
`Probenecid
`Probenecid may inhibit the renal excretion of metabolites of RAVICTI including PAGN and
`PAA.
`
`7.3 Potential for RAVICTI to Affect Other Drugs
`Drugs with narrow therapeutic index that are substrates of CYP3A4
` RAVICTI is a weak inducer of CYP3A4 in humans. Concomitant use of RAVICTI may
`decrease the systemic exposure to drugs that are substrates of CYP3A4. Monitor for
`decreased efficacy of drugs with narrow therapeutic index (e.g., alfentanil, quinidine,
`cyclosporine) [see Clinical Pharmacology (12.3)].
`Midazolam
`Concomitant use of RAVICTI decreased the systemic exposure of midazolam. Monitor for
`suboptimal effect of midazolam in patients who are being treated with RAVICTI.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Pregnancy Exposure Registry
`There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed
`to RAVICTI during pregnancy. Healthcare providers are encouraged to report any prenatal
`exposure to RAVICTI by calling the Pregnancy Registry at 1-855-823-2595 or visiting
`www.ucdregistry.com.
`
`Risk Summary
`Limited available data with RAVICTI use in pregnant women are insufficient to inform a
`drug-associated risk of major birth defects and miscarriage. In an animal reproduction study,
`administration of oral glycerol phenylbutyrate to pregnant rabbits during organogenesis at
`doses up to 2.7–times the dose of 6.87 mL/m2/day in adult patients resulted in maternal
`
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`Reference ID: 4367866
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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
`during organogenesis at 1.9 times the dose of 6.87 mL/m2/day in adult patients; however,
`maternal toxicity, reduced fetal weights, and variations in skeletal development were
`observed in pregnant rats administered oral glycerol phenylbutyrate during organogenesis at
`doses greater than or equal to 5.7 times the dose of 6.87 mL/m2/day in adult patients [see
`Data].
`The estimated background risk of major birth defects and miscarriage for the indicated
`population is unknown. All pregnancies have a background risk of birth defect, loss or other
`adverse outcomes. In the U.S. general population, the estimated background risk of major
`birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%,
`respectively.
`Data
`
`Animal Data
`Oral administration of glycerol phenylbutyrate during the period of organogenesis up to 350
`mg/kg/day in rabbits produced maternal toxicity, but no effects on embryo-fetal
`development. The dose of 350 mg/kg/day in rabbits is approximately 2.7 times the dose of
`6.87 mL/m2/day in adult patients, based on combined area under the plasma concentration-
`time curve [AUCs] for PBA and PAA. In rats, at an oral dose of 300 mg/kg/day of glycerol
`phenylbutyrate (1.9 times the dose of 6.87 mL/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 of 650 mg/kg/day or greater produced maternal toxicity
`and adverse effects on embryo-fetal development including reduced fetal weights and
`cervical ribs at the 7th cervical vertebra. The dose of 650 mg/kg/day in rats is approximately
`5.7 times the dose of 6.87 mL/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 through maturation of offspring following oral administration in
`pregnant rats with up to 900 mg/kg/day of glycerol phenylbutyrate (8.5 times the dose of
`6.87 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA) during
`organogenesis and lactation.
`
`8.2 Lactation
` Risk Summary
`There are no data on the presence of RAVICTI in human milk, the effects on the breastfed
`infant, or the effects on milk production. Because of the potential for serious adverse
`reactions, including neurotoxicity and tumorigenicity in a breastfed infant, advise patients
`that breastfeeding is not recommended during treatment with RAVICTI.
`
`8.4 Pediatric Use
`Patients 2 Years to 17 Years of Age
`The safety and effectiveness of RAVICTI in patients 2 years to less than 18 years of age have
`been established in 3 clinical studies: 2 open-label, fixed-sequence, switchover clinical
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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)].
`Patients Less Than 2 Years of Age
`The safety and effectiveness of RAVICTI in patients with UCDs less than 2 years of age
`have been established in 3 open-label studies. Pharmacokinetics and pharmacodynamics
`(plasma ammonia), and safety were studied in 17 patients aged 2 months to less than 2 years
`of age and in 16 patients less than 2 months of age [see Adverse Reactions (6.1), Clinical
`Studies (14.3)].
`Juvenile Animal Toxicity Data
`In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating
`and pregnancy after maturation, terminal body weight was dose-dependently reduced by up
`to 16% in males and 12% in females at 900 mg/kg/day or higher (3 times the dose of 6.87
`mL/m2/day in adult patients, based on combined AUCs for PBA and PAA). Learning,
`memory, and motor activity endpoints were not affected. However, fertility (number of
`pregnant rats) was decreased by up to 25% at 650 mg/kg/day or higher (2.6 times the dose of
`6.87 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA).
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`8.5 Geriatric Use
`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
`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.
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`8.6 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.
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`8.7 Hepatic Impairment
`No studies were conducted in patients with UCDs and 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 [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
`be kept on the lowest dose necessary to control their ammonia levels [see Dosage and
`Administration (2.5)].
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`11
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`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 [see Warnings
`and Precautions (5.1)].
`If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current
`information on the management of poisoning or overdosage.
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`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 greater than 65% acetonitrile.
`Glycerol phenylbutyrate is a nitrogen-binding agent. It is a triglyceride containing 3
`molecules of PBA linked to a glycerol backbone, the chemical name of which is
`benzenebutanoic acid, 1', 1' ' –(1,2,3-propanetriyl) ester with a molecular weight of 530.67. It
`has a molecular formula of 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 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.
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`Figure 1:
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`RAVICTI Mechanism of Action
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`12.2 Pharmacodynamics
`Pharmacological Effects
`In clinical studies, total 24-hour area under the plasma concentration-time curve (AUC) of
`ammonia levels was comparable at steady state during the switchover period between
`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 hours, 4 hours, and 4 hours,
`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 hours).
`Mean maximum concentration (Cmax) for PBA, PAA, and PAGN was 37.0 micrograms/mL,
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`14.9 micrograms/mL, and 30.2 micrograms/mL, respectively. In healthy subjects, intact
`glycerol phenylbutyrate was detected in plasma. While the study was inconclusive, the
`incomplete hydrolysis of glycerol phenylbutyrate cannot be ruled out.
`In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose-
`dependent manner. Following 4 mL