`
`
`
`
`
`
`•
`
`•
`
`
`•
`
`
`
` ______________
` _____________
`DOSAGE FORMS AND STRENGTHS
`Oral liquid: 1.1 g/mL of glycerol phenylbutyrate. (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%) are: diarrhea, flatulence, and
`
`
`
`
`
`headache. (6)
`
`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 to the
`
`
`concomitant drug; monitor for decreased efficacy of the narrow
`
`
`
`therapeutic index drug (7.3)
`
`
`
`• Midazolam: decreased exposure with concomitant use; monitor
`
`
`
`for suboptimal effect of midazolam if used concomitantly with
`
`
`
`RAVICTI. (7.3)
`
`
`
` _______________
` ______________
`USE IN SPECIFIC POPULATIONS
`Lactation: Breastfeeding is not recommended. (8.2)
`
`
`
`•
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide.
`
`
`Revised: 09/2016
`
`
`
`
`
`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 with UCDs
`
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`PATIENT COUNSELING INFORMATION
`17
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
`
` RAVICTI safely and effectively. See full prescribing information for
`
`
` RAVICTI.
`
`
`RAVICTI® (glycerol phenylbutyrate) oral liquid
`
`
`
`
`
`Initial U.S. Approval: 1996
`
` __________________
` _________________
`INDICATIONS AND USAGE
`
`
`
`
`
`RAVICTI (glycerol phenylbutyrate) is a nitrogen-binding agent indicated for
`
`
`
`
`chronic management of patients 2 years 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). (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. (2.1)
`
`
`
`Instruct patients to take with food and to administer directly into
`
`•
`
`mouth via oral syringe or dosing cup.
`
`
`
`Total daily dosage is given in 3 equally divided dosages, rounded
`
`up to nearest 0.5 mL.
`
`• Maximum daily dosage is 17.5 mL (19 g).
`
`
`• Must be used with dietary protein restriction.
`
`
`Switching From Sodium Phenylbutyrate to RAVICTI:
`
`
`Daily dosage of RAVICTI (mL) = daily dosage of sodium
`
`•
`
`
`
`phenylbutyrate tablets (g) x 0.86. (2.2)
`
`Daily dosage of RAVICTI (mL) = daily dosage of sodium
`
`phenylbutyrate powder (g) x 0.81 (2.2)
`Initial Dosage in Phenylbutyrate-Naïve Patients:
`
`Recommended dosage range is 4.5 to 11.2 mL/m2/day (5 to
`
`
`
`
`
`•
`12.4 g/m2/day). (2.3)
`
`
`For patients with some residual enzyme activity who are not
`
`
`
`adequately controlled with dietary restriction, recommended
`starting dose is 4.5 mL/m2/day. (2.3)
`
`
`
`
`Take into account patient's estimated urea synthetic capacity,
`
`
`dietary protein intake, and diet adherence. (2.3)
`
`Dosage Modifications in Patients With Hepatic Impairment:
`Start dosage at lower end of range. (2.5, 8.6)
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`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
`
`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
`
`
`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
`
`
`
`6
`
`
`7
`
`
`8
`
`Reference ID: 3983369
`
`Page 1 of 23
`
`LUPIN EX. 1017
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` 1
`
` INDICATIONS AND USAGE
`
` RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of
`
`
`
`
`
`
` patients 2 years 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 and to administer directly into the mouth via
` oral syringe or dosing cup. See the instructions on the use of RAVICTI by nasogastric tube
`
`
` or g-tube [see Dosage and Administration (2.6)].
`
`
`
` The recommended dosages for patients switching from sodium phenylbutyrate to RAVICTI
`
` and patients naïve to phenylbutyric acid are different [see Dosage and Administration (2.2,
`
` 2.3)]. For both subpopulations:
`
` • Give RAVICTI in 3 equally divided dosages, each rounded up to the nearest 0.5 mL.
`
` • The maximum total daily dosage is 17.5 mL (19 g).
`
`
`
` • RAVICTI must be used with dietary protein restriction and, in some cases, dietary
`
`supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie
`supplements).
`
`
`
`
`
`
` 2.2 Switching From Sodium Phenylbutyrate to RAVICTI
`
`
`
` Patients switching from sodium phenylbutyrate to RAVICTI should receive the dosage of
` RAVICTI that contains the same amount of phenylbutyric acid. The conversion is as follows:
`
`
`
`
`
`
`
` Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate tablets (g) x 0.86
`
` Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate powder (g) x 0.81
`
`
`
`
`
`
`
`Reference ID: 3983369
`
`Page 2 of 23
`
`LUPIN EX. 1017
`
`

`

` Initial Dosage in Phenylbutyrate-Naïve Patients
` 2.3
`
`
` The recommended dosage range, based upon body surface area, in patients naïve to
`
`
` phenylbutyrate (PBA) is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day). For patients with some
`
`
` residual enzyme activity who are not adequately controlled with protein restriction, the
`
`
`recommended starting dosage is 4.5 mL/m2/day.
`
`
`In determining the starting dosage of RAVICTI in treatment-naïve patients, consider the
`
`
`patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence.
`
`
`Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of
`
`
`
`dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose
`
`will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated
`
`
`RAVICTI dose for a 24-hour period is 0.6 mL RAVICTI per gram of dietary protein ingested
`
`per 24-hour period. The total daily dosage should not exceed 17.5 mL.
`
`
`
` 2.4 Dosage Adjustment and Monitoring
`
`
` Adjustment Based on Plasma Ammonia: Adjust the RAVICTI dosage to produce a fasting
`
`
` plasma ammonia level that is less than half the upper limit of normal (ULN) according to
`
` age.
` Adjustment Based on Urinary Phenylacetylglutamine: If available, U-PAGN measurements
`
`
`
`
`may be used to help guide RAVICTI dose adjustment. Each gram of U-PAGN excreted over
`
`24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN
`
`excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is
`
`greater than half the ULN, the RAVICTI dose should be adjusted upward. The amount of
`
`dose adjustment should factor in the amount of dietary protein that has not been covered, as
`
`
`indicated by the 24-h U-PAGN level and the estimated RAVICTI dose needed per gram of
`dietary protein ingested and the maximum total daily dosage (i.e., 17.5 mL).
`
`
`
`
`Consider a patient’s use of concomitant medications, such as probenecid, when making
`
`
`dosage adjustment decisions based on U-PAGN. Probenecid may result in a decrease of the
`
`urinary excretion of PAGN [see Drug Interactions (7.2)].
`
`
`Adjustment Based on Plasma Phenylacetate: If available, measurements of the plasma
`
`
`
`
`
`phenylacetate (PAA) levels may be useful to guide dosing if symptoms of vomiting, nausea,
`
`
`
`headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia
`
`
`or intercurrent illness. Ammonia levels must be monitored closely when changing the dose of
`
`RAVICTI. The ratio of PAA to PAGN in plasma may provide additional information to
`
`
`assist in dose adjustment decisions. In patients with a high PAA to PAGN ratio, a further
`
`increase in RAVICTI dose may not increase PAGN formation, even if plasma PAA
`concentrations are increased, due to saturation of the conjugation reaction. The PAA to
`
`
`
`PAGN ratio has been observed to be generally less than 1 in patients without significant PAA
`
`accumulation [see Warnings and Precautions (5.1)].
`
`
`
`
` 2.5 Dosage Modifications in Patients with Hepatic Impairment
`
`
`
`
` For patients with moderate to severe hepatic impairment, the recommended starting dosage is
` at the lower end of the range [see Warnings and Precautions (5.1), Use in Specific
`
`
`
`
` Populations (8.6)].
`
`
`
`
`
`
`Reference ID: 3983369
`
`Page 3 of 23
`
`LUPIN EX. 1017
`
`

`

`
`
`
`
`
`
` 2.6 Preparation for Nasogastric Tube or Gastrostomy Tube
`
`
` Administration
`
` For patients who have a nasogastric tube or gastrostomy tube in place, administer RAVICTI
`
` as follows:
`
` • Utilize an oral syringe to withdraw the prescribed dosage of RAVICTI from the
`
`
`bottle.
`
` • Place the tip of the syringe into the tip of the gastrostomy/nasogastric tube.
`
` • Utilizing the plunger of the syringe, administer RAVICTI into the tube.
`
`
` • Flush once with 30 mL of water and allow the flush to drain.
`
`
`
` • Flush a second time with an additional 30 mL of water to clear the tube.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3
`
`
`
` 4
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
` Oral liquid: colorless to pale yellow, 1.1 g/mL of glycerol phenylbutyrate (delivers 1.02
`
` g/mL of phenylbutyrate).
`
`
`
` CONTRAINDICATIONS
`
`
` RAVICTI is contraindicated in patients
` • Less than 2 months of age. 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 cancer patients who were administered IV PAA. 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.
`
`
`
`
`Reference ID: 3983369
`
`Page 4 of 23
`
`LUPIN EX. 1017
`
`

`

` In clinical trials in UCD patients who had been on sodium phenylbutyrate prior to
`
`
`
` administration of RAVICTI, peak PAA concentrations after dosing with RAVICTI ranged
` from 1.6 to 178 micrograms/mL (mean: 39 micrograms/mL) in adult patients and from 7 to
`
`
`
` 480 micrograms/mL (mean: 90 micrograms/mL) in pediatric patients. Some UCD patients
` experienced headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor and/or
`
` dizziness. No correlation between PAA levels and neurotoxicity symptoms was identified but
`
`
`
` PAA levels were generally not measured at the time of neurotoxicity symptoms.
` If symptoms of vomiting, nausea, headache, somnolence, or confusion, are present in the
`
`
` absence of high ammonia or other intercurrent illnesses, reduce the RAVICTI dosage.
`
`
`
`
`
`
`
` 5.2
`
`
`
`
`
` Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or
`
` Intestinal Malabsorption
`Exocrine pancreatic enzymes hydrolyze RAVICTI in the small intestine, separating the
`
`
` active moiety, phenylbutyrate, from glycerol. This process allows phenylbutyrate to be
` absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease
`
`
` resulting in fat malabsorption may result in reduced or absent digestion of RAVICTI and/or
`
` absorption of phenylbutyrate and reduced control of plasma ammonia. Monitor ammonia
`
`
` levels closely in patients with pancreatic insufficiency or intestinal malabsorption.
`
`
`
`
`
`
` 6
`
`
`
` ADVERSE REACTIONS
`
`
`
`
`
`
`
` 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 UCD Patients (at least 4%
`Table 1:
`
`
`in Either Treatment Arm) in Study 1
`
`
`
`
`
`Diarrhea
`
`
`Reference ID: 3983369
`
`
`
` Number (%) of Patients in Study 1
`
`
` Sodium Phenylbutyrate
`RAVICTI
`
`
` (N = 44)
` (N = 45)
`
`
` 3 (7)
` 7 (16)
`
`
`
`Page 5 of 23
`
`LUPIN EX. 1017
`
`

`

`
`
`
`
` Number (%) of Patients in Study 1
`
`
` Sodium Phenylbutyrate
`RAVICTI
`
`
` (N = 44)
` (N = 45)
`
` 6 (14)
`
` 4 (9)
`
` 6 (14)
`
` 1 (2)
` 3 (7)
`
`
` 2 (4)
`
` 3 (7)
`
` 2 (4)
`
` 3 (7)
`
` 2 (4)
`3 (7)
`
` 1 (2)
`
`2 (5)
`
` 3 (7)
`
`2 (5)
`
` 1 (2)
`
`1 (2)
`
` 3 (7)
`
`0
`
` 4 (9)
`
`0
`
` 3 (7)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Headache
`
` Flatulence
` Abdominal pain
`
` Vomiting
` Decreased appetite
`
` Fatigue
` Dyspepsia
`
` Ammonia increased
`
` Nausea
` Dizziness
`
` Abdominal discomfort
`
` Other Adverse Reactions
`
` RAVICTI has been evaluated in 77 UCD patients (51 adult and 26 pediatric) in 2 open-label
`
`
` long-term studies, in which 69 patients completed 12 months of treatment with RAVICTI
`
`(median exposure = 51 weeks). During these studies there were no deaths.
` Adverse reactions occurring in at least 10% of adult patients were nausea, vomiting, diarrhea,
`
`
`
`
`
` decreased appetite, hyperammonemia, dizziness, headache, and fatigue.
` Adverse reactions occurring in at least 10% of pediatric patients were upper abdominal pain,
`
`
`
` rash, nausea, vomiting, diarrhea, decreased appetite, hyperammonemia, and headache.
`
`
`
` 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
`
`
`
`Reference ID: 3983369
`
`Page 6 of 23
`
`LUPIN EX. 1017
`
`

`

`
`
` Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia
`
` levels closely when use of valproic acid or haloperidol is necessary in UCD patients.
`
`
`
`
`
` 7.2 Potential for Other Drugs to Affect RAVICTI
`
`
` Probenecid
` Probenecid may inhibit the renal excretion of metabolites of RAVICTI including PAGN and
`
` PAA.
` 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].
`
`
`Reference ID: 3983369
`
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`

`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 to Less Than 18 Years of Age
`
`
`
`
` The safety and efficacy of RAVICTI in patients 2 to less than 18 years of age were
`
` established in 2 open-label, sodium phenylbutyrate to RAVICTI, fixed-sequence, switchover
`
`
` clinical trials [see Adverse Reactions (6) and Clinical Studies (14.2)].
`
`
` Patients 2 Months to Less Than 2 Years of Age
`
`
`The safety and efficacy of RAVICTI in patients 2 months to less than 2 years of age has not
`
`
`
`been established. PK and ammonia control were studied in only 4 patients between 2 months
`
`and less than 2 years of age, providing insufficient data to establish a safe and effective dose
`
`
`in this age range.
`
`
`Reference ID: 3983369
`
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` 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
`
`function, which could impair hydrolysis of RAVICTI. Pancreatic lipases may be necessary
`
`
`for intestinal hydrolysis of RAVICTI, allowing release of phenylbutyrate and subsequent
`
`
`formation of PAA, the active moiety. It is not known whether pancreatic and extrapancreatic
`
`
`lipases are sufficient for hydrolysis of RAVICTI. If there is inadequate intestinal hydrolysis
`
`
`
`of RAVICTI, impaired absorption of phenylbutyrate and hyperammonemia could occur.
`
`Juvenile Animal Study
`
`In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating
`
`
`and pregnancy after maturation, terminal body weight was dose-dependently reduced by up
`to 16% in males and 12% in females. Learning, memory, and motor activity endpoints were
`
`not affected. However, fertility (number of pregnant rats) was decreased by up to 25% at 650
`
`
`
` mg/kg/day or greater (2.6 times the dose of 6.87 mL/m2/day in adult patients, based on
`
`
`combined AUCs for PBA and PAA). Embryo toxicity (increased resorptions) occurred at 650
`mg/kg/day (2.6 times the dose of 6.87 mL/m2/day in adult patients, based on combined
`
`AUCs for PBA and PAA) and litter size was reduced at 900 mg/kg/day (3 times the dose of
`
`
` 6.87 mL/m2/day in adult patients, based on combined AUCs for PBA and PAA).
`
`
`
`
`
`
`
` 8.5 Geriatric Use
`
`
`
` Clinical studies of RAVICTI did not include sufficient numbers of subjects 65 years of age
`
`
` 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 UCD patients with hepatic impairment. Because conversion of
`PAA to PAGN occurs in the liver, patients with hepatic impairment may have reduced
`conversion capability and higher plasma PAA and PAA to PAGN ratio. Therefore, dosage
`
`
`
`for patients with moderate to severe hepatic impairment should be started at the lower end of
`
`the recommended dosing range and should be kept on the lowest dose necessary to control
`
`their ammonia levels [see Dosage and Administration (2.5)].
`
`
`
`
`
`Reference ID: 3983369
`
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`
`
` 10
`
`
`
` 11
`
` 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 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.
`
`
`
`RAVICTI Mechanism of Action
`Figure 1:
`
`
`
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`
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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 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 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,
`
`
`
`
`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.
`
`
`
`
`
`Reference ID: 3983369
`
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`
`
`In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose-
`dependent manner. Following 4 mL of RAVICTI 3 times a day for 3 days, the mean Cmax
`
`
`
` and AUC were 66 micrograms/mL and 930 micrograms•h/mL for PBA and 28
`
` micrograms/mL and 942 micrograms•h/mL for PAA, respectively. In the same study,
`
`
` following 6 mL of RAVICTI three times a day for 3 days, mean Cmax and AUC were 100
`
`
`
`
`
`micrograms/mL and 1400 micrograms•h/mL for PBA and 65 µg/mL and 2064
`
`
`micrograms•h/mL for PAA, respectively.
`
`In adult UCD patients receiving multiple doses of RAVICTI, maximum plasma
`
`concentrations at steady state (Cmaxss) of PBA, PAA, and PAGN occurred at 8 hours, 12
`
`hours, and 10 hours, respectively, after the first dose in the day. Intact glycerol
`
`phenylbutyr