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)
`04/2017
`Dosage and Administration (2.1)
`04/2017
`Dosage and Administration (2.2)
`04/2017
`__________________ INDICATIONS AND USAGE
` _________________
`RAVICTI is a nitrogen-binding agent indicated for chronic management of
`patients 2 months of age and older 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)
`
`______________
`
`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. (3)
` ___________________ CONTRAINDICATIONS____________________
` Patients less than 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 (≥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: 04/2017
`
`14
`
`13
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
` Clinical Studies in Adult Patients with UCDs
`14.1
`14.2 Clinical Studies in Pediatric Patients Ages 2 to 17 Years with
`UCDs
`14.3 Clinical Studies in Pediatric Patients Ages 2 Months to Less
`Than 2 Years with UCDs
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`Important Administration Instructions
`2.1
`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
`Preparation for Nasogastric Tube or Gastrostomy Tube
`2.6
`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
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`DRUG INTERACTIONS
`Potential for Other Drugs to Affect Ammonia
`7.1
`7.2
`Potential for Other Drugs to Affect RAVICTI
`7.3
`Potential for RAVICTI to Affect Other Drugs
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`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
`
`6
`
`7
`
`8
`
`Reference ID: 4091177
`
`Par Pharmaceutical, Inc. Ex. 1013
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 1 of 26
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`1
`
`INDICATIONS AND USAGE
`RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of
`patients 2 months of age and older 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
`
`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.
` 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 2 months of age to 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).
`
`Reference ID: 4091177
`
`Par Pharmaceutical, Inc. Ex. 1013
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 2 of 26
`
`

`

`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 ammonia levels
`after changing the dosage of RAVICTI.
`Normal Ammonia Levels
`If patients experience symptoms of vomiting, nausea, headache, somnolence or confusion in
`the absence of high ammonia levels or other intercurrent illnesses, reduce the RAVICTI
`dosage and monitor patients clinically. If available, obtain measurements of plasma
`phenylacetate (PAA) concentrations and the ratio of plasma PAA to PAGN to guide dosing.
`A high PAA to PAGN ratio may indicate the saturation of the conjugation reaction to form
`PAGN. The PAA to PAGN ratio has been observed to be generally less than 1 in patients
`with UCDs without significant PAA accumulation [see Warnings and Precautions (5.1),
`Clinical Pharmacology (12.3)].
`Elevated Ammonia Levels
`When plasma ammonia is elevated, increase the RAVICTI dosage to reduce the fasting
`ammonia level to less than half the upper limit of normal (ULN) in patients 6 years and older.
`In infants and pediatric patients (generally below 6 years of age), where obtaining fasting
`ammonia is problematic due to frequent feedings, adjust the dosage to keep the first ammonia
`of the morning below the ULN.
`Urinary Phenylacetylglutamine: If available, 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
`
`Reference ID: 4091177
`
`Par Pharmaceutical, Inc. Ex. 1013
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 3 of 26
`
`

`

`insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half
`the ULN, the RAVICTI dosage should be adjusted upward. 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 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)].
`Plasma Phenylacetate and Phenylacetylglutamine: If available, the ratio of PAA to PAGN in
`plasma may provide additional information to assist in dosage adjustment decisions. In
`patients with a high PAA to PAGN ratio, a further increase in RAVICTI dosage may not
`increase PAGN formation, even if plasma PAA concentrations are increased, due to
`saturation of the conjugation reaction [see Use in Specific Populations (8.7), Clinical
`Pharmacology (12.3)].
`
`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 kept at the lowest
`dose necessary to control the patient’s ammonia levels [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.
`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.
`
`Reference ID: 4091177
`
`Par Pharmaceutical, Inc. Ex. 1013
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 4 of 26
`
`

`

`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. Pediatric patients less than 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 of 500 micrograms/mL in a study
`of adult cancer patients who were administered PAA intravenously. In this study, adverse
`reactions 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 less than 100 micrograms/mL.
`In clinical trials in patients with UCDs who had been on sodium phenylbutyrate prior to
`administration of RAVICTI, peak PAA concentrations after dosing with RAVICTI ranged
`from 1.6 to 178 micrograms/mL (mean: 39 micrograms/mL) in adult patients, from 1 to 410
`micrograms/mL (mean: 70 micrograms/mL; median: 50 micrograms/mL) in pediatric
`patients ages 2 years and older, and from 1 to 1215 micrograms/mL (mean: 142
`micrograms/mL; median: 35 micrograms/mL) in pediatric patients ages 2 months to less than
`2 years. Some patients with UCDs 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 or confusion, are present in the
`absence of high ammonia or other intercurrent illnesses, reduce the RAVICTI dosage [see
`Dosage and Administration (2.4)].
`
`Reference ID: 4091177
`
`Par Pharmaceutical, Inc. Ex. 1013
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 5 of 26
`
`

`

`5.2
`
`Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or
`Intestinal Malabsorption
`Exocrine pancreatic enzymes hydrolyze RAVICTI in the small intestine, separating the
`active moiety, phenylbutyrate, from glycerol. This process allows phenylbutyrate to be
`absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease
`resulting in fat malabsorption may result in reduced or absent digestion of RAVICTI and/or
`absorption of phenylbutyrate and reduced control of plasma ammonia. Monitor ammonia
`levels closely in patients with pancreatic insufficiency or intestinal malabsorption.
`
`6
`
`ADVERSE REACTIONS
`
`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),
`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 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
`
`
`
`Reference ID: 4091177
`
`Par Pharmaceutical, Inc. Ex. 1013
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 6 of 26
`
`

`

`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 occurring in at least 10% of adult patients were nausea, vomiting, diarrhea,
`decreased appetite, dizziness, headache, and fatigue.
`Adverse reactions occurring 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 also 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 occurring 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.
`
`6.2 Postmarketing Experience
`The following adverse reactions have been identified during postapproval 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
`
`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
`
`Reference ID: 4091177
`
`Par Pharmaceutical, Inc. Ex. 1013
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 7 of 26
`
`

`

`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
`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
`
`Reference ID: 4091177
`
`Par Pharmaceutical, Inc. Ex. 1013
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 8 of 26
`
`

`

`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
`Safety and efficacy of RAVICTI have been established in pediatric patients 2 months of age
`and older with UCDs.
`RAVICTI is contraindicated in pediatric patients less than 2 months of age [see
`Contraindications (4)].
`Patients 2 Years to Less Than 18 Years of Age
`The safety and efficacy of RAVICTI in patients 2 years to less than 18 years of age were
`established in 2 open-label, sodium phenylbutyrate to RAVICTI, fixed-sequence, switchover
`clinical studies [see Adverse Reactions (6.1), Clinical Studies (14.2)].
`Patients 2 Months to Less Than 2 Years of Age
`The safety and efficacy of RAVICTI in patients with UCDs, 2 months to less than 2 years of
`age were established in 3 open-label studies. Pharmacokinetics and pharmacodynamics
`(plasma ammonia), and safety were studied in 17 patients between 2 months and less than 2
`years of age [see Adverse Reactions (6.1), Clinical Studies (14.3)].
`Patients Less Than 2 Months of Age
`RAVICTI is contraindicated in patients less than 2 months of age [see Contraindications
`(4)]. Pediatric patients less than 2 months of age may have immature pancreatic exocrine
`
`Reference ID: 4091177
`
`Par Pharmaceutical, Inc. Ex. 1013
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 9 of 26
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`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 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
`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)].
`
`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 [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.
`
`Reference ID: 4091177
`
`Par Pharmaceutical, Inc. Ex. 1013
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 10 of 26
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`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 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:
`
`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.
`
`Reference ID: 4091177
`
`Par Pharmaceutical, Inc. Ex. 1013
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 11 of 26
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`Figure 1:
`
`RAVICTI Mechanism of Action
`
`NH/
`
`cx-Ketoglutarate i
`NH/ i
`Glutamine !
`
`Glutamate
`
`Glycerol Phenylbutyrate
`I Ester Hydrolysis/
`t Pancreatic lipases
`t Beta Oxidation
`Phenylbutyric Acid
`
`Phenylacetate
`
`I Phenylacetylglutamine I
`l
`
`Urine Excretion
`
`12.2 Pharmacodynamics
`Pharmacological Effects
`In clinical studies, total 24-hour area under the plasma concentration-time curve (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.
`
`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 concentra