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` MEDICATION GUIDE
`
`
`
` RAVICTI (rah-VIK- tee)
`(glycerol phenylbutyrate)
`
`
` oral liquid
` What is the most important information I should know about RAVICTI?
`
`
` RAVICTI may cause serious side effects, including:
` Nervous system problems (Neurotoxicity). Phenylacetate (PAA), a breakdown product of RAVICTI, may cause
`
`
`
`
`
`
` nervous system side effects. Call your doctor or get medical help right away if you get any of these symptoms while taking
` RAVICTI:
`
` • worsening of numbness, tingling, or burning in
`
`
` • sleepiness
`
`
`
`
` your hands or feet
`
`lightheadedness
`
`•
`
` • headache
`
` • change in taste
`
`
`
` feeling very tired (fatigue)
`
` • problems with hearing
`•
`
`
` • nausea
`
`
` • confusion
`
`
`
` vomiting
`
` • problems with memory
`•
`
` Your doctor may do blood tests to measure the amount of PAA in your blood during your treatment with RAVICTI.
`
`
` What is RAVICTI?
`
` • RAVICTI is a prescription medicine used in adults and in children 2 months of age and older for long-term
`
`
`
`
`
`
`
` management of high blood levels of ammonia (hyperammonemia) caused by a condition called a urea cycle disorder
` (UCD). RAVICTI should be used if the UCD cannot be managed with a low protein diet and dietary supplements
`
`
`
` alone. RAVICTI must be used along with a low protein diet and in some cases dietary supplements.
`
`
`
` • RAVICTI is not used for the acute treatment of hyperammonemia in people with UCD.
` It is not known if RAVICTI is safe and effective for the treatment of N-acetylglutamate synthase (NAGS) deficiency.
`
`
`•
`
` Who should not take RAVICTI?
` • Children less than 2 months of age should not take RAVICTI because it may not be digested in children less than 2
`
`
` months of age.
` • Do not take RAVICTI if you are allergic to phenylbutyrate. Call your doctor or go to the nearest hospital emergency
`
`
`
`
`
`
`
`
`
` room if you have wheezing, shortness of breath, cough, low blood pressure, flushing, nausea or a rash while taking
` RAVICTI.
`
`
`
` Before taking RAVICTI, tell your doctor about any medical conditions and if you:
`
` • Have liver or kidney problems.
`
`
`
` • Have pancreas or bowel (intestine) problems.
`
`
`
`
`
`
` • Are pregnant or plan to become pregnant. It is not known if RAVICTI will harm your unborn baby.
`
`
`
` • Pregnancy Registry: There is a Pregnancy Registry for women who take RAVICTI just before becoming pregnant or
`
`
`
` who become pregnant during treatment with RAVICTI. The purpose of this registry is to collect information about the
` health of you and your baby. Talk to your doctor about how you can join the Pregnancy Registry. For more information
`
`
`
`
`
` about this registry, call 1-855-823-2595 or visit www.ucdregistry.com.
`
`
`
`
` • Are breastfeeding or plan to breastfeed. It is not known if RAVICTI passes into your breast milk. Breastfeeding is not
`
` recommended during treatment with RAVICTI. Talk to your doctor about the best way to feed your baby if you take
`
`
`
`
`
` RAVICTI.
`
` Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins,
` dietary and herbal supplements.
`
`
` Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
`
` How should I take RAVICTI?
`
`
`
`
` • Take RAVICTI exactly as your doctor tells you.
`
`
`
` • Your doctor will tell you how much RAVICTI to take and when to take it.
`
`
`
`
` • Your doctor may change your dose if needed.
`
`
`
` • Take RAVICTI with food or formula.
`
`
`
`
` • RAVICTI is an oral liquid that is taken by mouth using an oral syringe or dosing cup. Ask your pharmacist for an oral
`
` syringe or dosing cup if you do not have one.
`
`
` If you have a nasogastric or gastrostomy tube in place and can swallow, you should take RAVICTI by mouth.
`
`
`•
`
` • Stay on the diet that your doctor gives you.
`
`
`
`
` If you take too much RAVICTI, call your doctor or your poison control center at 1-800-222-1222 or go to the nearest
`
`
`•
` hospital emergency room right away.
`
`
` For people who cannot swallow and who have a nasogastric or gastrostomy tube in place, RAVICTI should be
`
` given as follows:
`
`
` • Use an oral syringe to withdraw the prescribed dose of RAVICTI from the bottle.
`
`
` • Place the tip of the syringe into the nasogastric or gastrostomy tube and push the plunger of the syringe to give
`
`
`
` RAVICTI into the tube.
` • Add 10 mL of water or formula to the syringe and push the plunger of the syringe to flush any remaining medicine
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4091177
`
`

`

`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`
`
`
`
`
`
`
`
` from the nasogastric or gastrostomy tube into the stomach.
` If needed, flush the nasogastric or gastrostomy tube again with 10 mL of water or formula to clear the nasogastric or
`
`
`
` gastrostomy tube.
`
`
` What are the possible side effects of RAVICTI?
`
`
`
` RAVICTI may cause serious side effects, including:
` • See “What is the most important information I should know about RAVICTI?”
`
`
` The most common side effects of RAVICTI in adults include:
`vomiting
`
`
` • diarrhea
`
`
`•
`tiredness
`
`
` • gas
`
`
`•
`
` • decreased appetite
`
` • headache
`
`
`
`indigestion or heartburn
`
` • abdomen (stomach) pain
`
`
`•
` The most common side effects of RAVICTI in children 2 years to 17 years of age include:
`
`
` • upper abdomen (stomach) pain
`
`
` • diarrhea
`
`
`rash
`
` • decreased appetite
`
`
`•
`
` • nausea
`
` • headache
`
`
`
` • vomiting
`
`
` The most common side effects of RAVICTI in children 2 months to less than 2 years of age include:
`
`
`
` low white blood cell count (neutropenia)
`
`
` cough
`•
`•
`
`
` • vomiting
`
`
`stuffy nose
`•
`
` runny nose
`
` • diarrhea
`
`
`•
`
`
`
`
` fever
` skin rash
`•
`•
`
`
` reduced food intake
`
`small round bumps on the skin
`
`•
`•
` Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible
`
`
` side effects of RAVICTI.
`
` Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
`
`
` How should I store RAVICTI?
`
`
`
` • Store RAVICTI between 68ºF to 77ºF (20°C to 25°C).
`
`
` Keep RAVICTI and all medicines out of the reach of children.
` General information about the safe and effective use of RAVICTI.
`
`
`
`
` Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RAVICTI for
` a condition for which it was not prescribed. Do not give RAVICTI to other people, even if they have the same symptoms
`
`
`
`
`
`
`
` you have. It may harm them.
` You can ask your doctor or pharmacist for information about RAVICTI that is written for health professionals.
`
`
` What are the ingredients in RAVICTI?
`
`
` Active ingredient: glycerol phenylbutyrate
`
`
`
`
` Distributed by: Horizon Pharma USA, Inc., Lake Forest, IL 60045.
` © Horizon Therapeutics, LLC. All rights reserved. RAVICTI is a registered trademark of Horizon Therapeutics, LLC.
`
`
`
`
` For more information, go to www.RAVICTI.com or call 1-855-823-7878.
`
`
` This Medication Guide has been approved by the U.S. Food and Drug Administration.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4091177
`
`
`
` Revised: 04/2017
`
`
`
`
`
`

`

`
`
`______________
`
`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
`
`
`
`13
`
`14
`
`
`
`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.
`
`
`
`
`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)
`
`
`
` 
`
`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
`
`Pregnancy
`8.1
`8.2 Lactation
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Renal Impairment
`
`8.7 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`
`DESCRIPTION
`11
`
`
`12
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`6
`
`
`7
`
`
`8
`
`Reference ID: 4091177
` 
`
`

`

`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
`
`

`

`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
`
`

`

`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
`
`

`

`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
`
`

`

`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
`
`
`RAVICTI
`Sodium Phenylbutyrate
`(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
`
`

`

` 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
`
`

`

`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
`
`

`

`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 contraind