`
`
`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 at 1­
`
`
`
`866-479-6742 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: 9/2021
`
`
`
`13
`
`14
`
`
`
`
`10 OVERDOSAGE
`
`
`11
`DESCRIPTION
`
`
`12
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`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 _________________
`
`
`
`
`9/2021
`Dosage and Administration (2.1, 2.6)
`
`
`
`
`
`__________________ INDICATIONS AND USAGE
` _________________
`
`RAVICTI is a nitrogen-binding agent indicated for chronic management of
`
`
`
`
`patients with urea cycle disorders (UCDs) who cannot be managed by dietary
`
`
`
`
`protein restriction and/or amino acid supplementation alone. RAVICTI must
`
`
`
`be used with dietary protein restriction and, in some cases, dietary
`
`supplements. (1)
`
`
`Limitations of Use:
`
`
`
`• RAVICTI is not indicated for treatment of acute hyperammonemia in
`
`patients with UCDs. (1)
`
`
`
`
`• Safety and efficacy for treatment of N-acetylglutamate synthase (NAGS)
`
`deficiency has not been established. (1)
` ______________
`
`
`_______________ DOSAGE AND ADMINISTRATION
`
`
`• RAVICTI should be prescribed by a physician experienced in management
`
`
`
`of UCDs. For administration and preparation, see full prescribing
`
`
`information. (2.1, 2.6)
`
`
`
`Switching From Sodium Phenylbutyrate Tablets or Powder to RAVICTI:
`
`
`
`• Patients should receive the dosage of RAVICTI that contains the same
`
`amount of phenylbutyric acid, see full prescribing information for
`
`
`conversion. (2.2)
`
`
`Initial Dosage in Phenylbutyrate-Naïve Patients (2.3):
` • Recommended dosage range is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day).
`
` • For patients with some residual enzyme activity not adequately controlled
`
`
` with dietary restriction, the recommended starting dose is 4.5 mL/m2/day.
`
`
`
`• Take into account patient's estimated urea synthetic capacity, dietary
`
`
`
`protein intake, and diet adherence.
`
`Dosage Adjustment and Monitoring:
`
`
`
`• Follow plasma ammonia levels to determine the need for dosage titration.
`
`(2.4)
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`
`Important Administration Instructions
`2.1
`
`
`
`
`Switching From Sodium Phenylbutyrate to RAVICTI
`2.2
`
`
`2.3
`Initial Dosage in Phenylbutyrate-Naïve Patients
`
`
`2.4 Dosage Adjustment and Monitoring
`
`
`2.5 Dosage Modifications in Patients with Hepatic Impairment
`
`
`2.6
`Preparation for Nasogastric Tube or Gastrostomy Tube
`
`
`Administration
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Neurotoxicity
`
`
`Pancreatic Insufficiency or Intestinal Malabsorption
`5.2
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`6.2
`Postmarketing Experience
`
`
`
`DRUG INTERACTIONS
`
`
`Potential for Other Drugs to Affect Ammonia
`7.1
`
`Potential for Other Drugs to Affect RAVICTI
`7.2
`
`7.3
`Potential for RAVICTI to Affect Other Drugs
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`
`8.2 Lactation
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`
`6
`
`
`7
`
`
`8
`
`
`Reference ID: 4852147
`
`

`

` 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.
`
`
`
`
`
`
`
`
`
` 2
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
` 1
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
` DOSAGE AND ADMINISTRATION
`
` 2.1
`
`
` Important Administration Instructions
` RAVICTI should be prescribed by a physician experienced in the management of UCDs.
`
`
`
`
`
`
`
` Instruct patients to take RAVICTI with food or formula and to administer directly
`•
` into the mouth via oral syringe.
`
`
`
`
`
` Instruct patients to use the RAVICTI bottle and oral syringe as follows:
` o Use a new reclosable bottle cap adapter with each new bottle that is opened.
`
`
`
`
`
`
`
` o Open the RAVICTI bottle and twist on the new reclosable bottle cap adapter.
`
`
` o Use a new and dry oral syringe to withdraw each prescribed dose of RAVICTI.
`
`
`
`
`
`
`
` o Discard the oral syringe after each dose.
`
`
`
` o Tightly close the tethered tab on the reclosable bottle cap adapter after each use.
`
`
` o Do not rinse the reclosable bottle cap adapter.
`
`
`
`
`
`
`
`
` o Discard bottle and any remaining contents 28 days after opening.
`
`
` o If water or moisture enters the RAVICTI bottle, the contents will become cloudy
`
`
`
`
`
`
` in appearance. If the contents of the bottle appear cloudy at any time, do not use
`
`
`
`
`
`
`
` the remaining RAVICTI in the bottle and return it to the pharmacy to be
`
`
`
`
`
`
`
`
` discarded.
`
` 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)].
`
`
`•
`
`
`
`
`
`
`
`
`
`Reference ID: 4852147
`
`

`

`
`
`
`
`
`
`
`
`
`
`• 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).
`
`
`o RAVICTI must be used with dietary protein restriction and, in some cases, dietary
`supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie
`
`supplements).
` 2.2 Switching From Sodium Phenylbutyrate to RAVICTI
`
`
`
`
` Patients switching from sodium phenylbutyrate to RAVICTI should receive the dosage of
` RAVICTI that contains the same amount of phenylbutyric acid. The conversion is as follows:
`
`
`
`
`
`
` Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate tablets (g) x 0.86
` Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81
`
`
`
` 2.3
` Initial Dosage in Phenylbutyrate-Naïve Patients
`The recommended dosage range, based upon body surface area, in patients naïve to
` phenylbutyrate (PBA) is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day). For patients with some
`
`
`
` residual enzyme activity who are not adequately controlled with protein restriction, the
` recommended starting dosage is 4.5 mL/m2/day.
`
`In determining the starting dosage of RAVICTI in treatment-naïve patients, consider the
`
`patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence.
`
`
`
`
`Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of
`
`
`
`dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose
`
`
`
`will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated
`
`RAVICTI dose for a 24-hour period is 0.6 mL RAVICTI per gram of dietary protein ingested
`
`per 24-hour period. The total daily dosage should not exceed 17.5 mL.
`
`
`
`
`
` 2.4 Dosage Adjustment and Monitoring
` During treatment with RAVICTI, patients should be followed clinically and with plasma
`
`
`
`
`
` ammonia levels to determine the need for dosage titration. Closely monitor plasma ammonia
` levels during treatment with RAVICTI and when changing the dosage of RAVICTI.
`
`
`
` The methods used for measuring plasma ammonia levels vary among individual laboratories
` and values obtained using different assay methods may not be interchangeable. Normal
`
`
`
`
` ranges and therapeutic target levels for plasma ammonia depend upon the assay method used
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4852147
`
`

`

`
`
`
`
` 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
`
`
`
` 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)].
`
`
`
`
`
`Reference ID: 4852147
`
`

`

`
`
`
`
`
`
`
`
`
`
` 3
`
`
`
` 4
`
`
`
` 5
`
`
`
` 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. For patients who cannot swallow, a nasogastric tube or
` gastrostomy tube may be used to administer RAVICTI as follows:
`
`
`
`
`
`
`
` • Utilize a new dry oral syringe to withdraw each 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.
`
`
` • Use a separate syringe to flush the nasogastric/gastrostomy tube. Flush once with
`
`
`
`
` 10 mL of water or formula and allow the flush to drain.
`
`
` 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.
`
`
`
`
`
` 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,
`
`Reference ID: 4852147
`
`

`

`
`
` 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)].
`
` 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
` The following clinically significant adverse reactions are described elsewhere in the labeling:
`
`
`
` • Neurotoxicity [see Warnings and Precautions (5.1)]
` • Pancreatic insufficiency or Intestinal Malabsorption [see Warnings and Precautions (5.2)]
`
`
`
`
`
`
`
`
`
`
` 6.1
` Clinical Trials Experience
`
`
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
` observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
`
`
`
` trials of another drug and may not reflect the rates observed in clinical practice.
`
` Assessment of adverse reactions was based on exposure of 45 adult patients (31 female and
`
` 14 male) with UCD subtype deficiencies of ornithine transcarbamylase (OTC, n=40),
`
` carbamoyl phosphate synthetase (CPS, n=2), and argininosuccinate synthetase (ASS, n=1) in
`
`
`
`
`
`
`Reference ID: 4852147
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a randomized, double-blind, active-controlled (RAVICTI vs sodium phenylbutyrate),
`
`
`
`
`
` crossover, 4-week study (Study 1) that enrolled patients 18 years of age and older [see
` Clinical Studies (14.1)]. One of the 45 patients received only sodium phenylbutyrate prior to
`
`
`
`
` withdrawing on day 1 of the study due to an adverse reaction.
` The most common adverse reactions (occurring in at least 10% of patients) reported during
`
`
` short-term treatment with RAVICTI were diarrhea, flatulence, and headache. Table 1
` summarizes adverse reactions occurring in 2 or more patients treated with RAVICTI or
`
`
`
`
`
`
`
`
` sodium phenylbutyrate (incidence of at least 4% in either treatment arm).
` Adverse Reactions Reported in 2 or More Adult Patients with UCDs (at least
`
`
`
`
`
` Table 1:
` 4% in Either Treatment Arm) in Study 1
`
` Number (%) of Patients in Study 1
`
`
` Sodium Phenylbutyrate
`RAVICTI
`
` (N = 45)
`
` (N = 44)
`
`
` 3 (7)
`
` 7 (16)
`
` 4 (9)
`
`
` 6 (14)
`
` 1 (2)
`
`
` 6 (14)
`
` 2 (4)
`
`
`
` 3 (7)
`
` 2 (4)
`
`
` 3 (7)
`
`
` 2 (4)
`
`
` 3 (7)
`
`
` 1 (2)
`
`
` 3 (7)
`
`
` 3 (7)
`
`
` 2 (5)
`
`
` 3 (7)
`
`
` 1 (2)
`
`
` 4 (9)
`
`0
`
`
` 3 (7)
`
`0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Diarrhea
`
`
` Headache
`
` Flatulence
` Abdominal pain
`
`
` Vomiting
` Decreased appetite
`
`
` Fatigue
` Dyspepsia
`
` 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 20 months).
`
`
`
`
`Adverse reactions reported in at least 10% of pediatric patients aged 2 months to less than 2
`
`
`years were neutropenia, vomiting, constipation, 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,
`
`
`
`Reference ID: 4852147
`
`

`

`
`
`
`
`
`
` 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
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
` 7
`
`
`
`
`
`Reference ID: 4852147
`
`

`

`
`
`
`
` 8
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` USE IN SPECIFIC POPULATIONS
`
` 8.1 Pregnancy
`
` 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
`
`
` 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]. Report pregnancies to Horizon at 1‐866‐479‐6742.
`
`
`
`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
`
`
`
`Reference ID: 4852147
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` 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
` 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).
`
`
`
` 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.
`
`
`
` 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.
`
`
` 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
`
`
`
`
`
`
`
`
`
`Reference ID: 4852147
`
`

`

`
`
`
`
` 10
`
`
`
` 11
`
`
`
`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)].
`
`
` 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.
`
`
`
`
`
`
`
` 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 mo