RAVICTI (glycerol phenylbutyrate) liquid
 [Hyperion Therapeutics, Inc.]
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 is indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years of age with urea cycle disorders (UCDs) that 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)
The use of RAVICTI in patients <2 months of age is contraindicated (4)
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. (2.1)
Total daily dosage is given in 3 equally divided dosages, rounded up to nearest 0.5 mL. (2.1)
Maximum daily dosage is 17.5 mL (19 g). (2.1)
Must be used with dietary protein restriction. (2.1)
Switching From Sodium Phenylbutyrate to RAVICTI:

Daily dosage of RAVICTI (mL) = daily dosage of sodium phenylbutyrate (g) x 0.86. (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)

DOSAGE FORMS AND STRENGTHS
Oral liquid: 1.1 g/mL of glycerol phenylbutyrate. (3)

CONTRAINDICATIONS
Patients <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 in ≥10% of patients are diarrhea, flatulence, and headache. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hyperion 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 PAGN and PAA. (7.2)
 
 
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm. (8.1)
Nursing Mothers: Discontinue nursing or discontinue the drug. (8.3)
 
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 02/2013

Back to Highlights and Tabs
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Important Instructions
2.2 Switching From Sodium Phenylbutyrate to RAVICTI
2.3 Initial Dosage in Phenylbutyrate-Naïve Patients
2.4 Dosage Adjustment and Monitoring
2.5 Dosage Modifications in Patients with Hepatic Impairment
2.6 Preparation for Nasogastric Tube or Gastrostomy Tube Administration
3 DOSAGE FORMS AND STRENGTHS
4. CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Neurotoxicity
5.2 Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption
6 ADVERSE REACTIONS
7 DRUG INTERACTIONS
7.1 Potential for Other Drugs to Affect Ammonia
7.2 Potential for Other Drugs to Affect RAVICTI
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing mothers
8.4 Pediatric use
8.5 Geriatric use
8.6 Hepatic Impairment
8.7 Renal 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
15. REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage
17 PATIENT COUNSELING INFORMATION
*
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE
RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years of age 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.

The use of RAVICTI in patients <2 months of age is contraindicated [see Contraindications (4)].

2 DOSAGE AND ADMINISTRATION

2.1 Important Instructions
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 (g) x 0.86

2.3 Initial Dosage in Phenylbutyrate-Naïve Patients
The recommended dosage range, based upon body surface area, in patients naïve to phenylbutyrate (PBA) is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day). For patients with some residual enzyme activity who are not adequately controlled with protein restriction, the recommended starting dosage is 4.5 mL/m2/day.

In determining the starting dosage of RAVICTI in treatment-naïve patients, consider the patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated RAVICTI dose for a 24-hour period is 0.6 mL RAVICTI per gram of dietary protein ingested per 24 hour period. The total daily dosage should not exceed 17.5 mL.

2.4 Dosage Adjustment and Monitoring
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 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) and Use in Specific Populations (8.6)].

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 to 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 DOSAGE FORMS AND STRENGTHS
Oral liquid: colorless to pale yellow, 1.1 g/mL of glycerol phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate).

4. CONTRAINDICATIONS
RAVICTI is contraindicated in patients

Less than 2 months of age. Children <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 Pediatric Use (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 ≥500 µg/mL in a study of cancer patients who were administered IV PAA. In this study, adverse events 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 <100 µg/mL.

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 µg/mL (mean: 39 µg/mL) in adult patients and from 7 to 480 µg/mL (mean: 90 µg/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, confusion, or sleepiness 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
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 [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.

Table 1 summarizes adverse reactions occurring in ≥2 patients treated with RAVICTI or sodium phenylbutyrate. The most common adverse reactions (occurring in ≥10% of patients) reported during short-term treatment with RAVICTI were diarrhea, flatulence, and headache.

Table 1: Adverse Reactions Reported in ≥2 Adult UCD Patients in Study 1
  Number (%) of Patients in Study 1
Sodium Phenylbutyrate
(N = 45) RAVICTI
(N = 44)
Gastrointestinal disorders              
        Abdominal discomfort  3 (7)  0
        Abdominal pain  2 (4)  3 (7)
        Diarrhea  3 (7)  7 (16)
        Dyspepsia  3 (7)  2 (5)
        Flatulence  1 (2)  6 (14)
        Nausea  3 (7)  1 (2)
        Vomiting  2 (4)  3 (7)
General disorders and administration site conditions              
        Fatigue  1 (2)  3 (7)
Investigations              
        Ammonia increased  1 (2)  2 (5)
Metabolism and nutrition disorders              
        Decreased appetite  2 (4)  3 (7)
Nervous system disorders              
        Dizziness  4 (9)  0
        Headache  4 (9)  6 (14)
Other Adverse Reactions

RAVICTI has been eva luated 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 ≥10% of adult patients were nausea, vomiting, diarrhea, decreased appetite, hyperammonemia, dizziness, headache, and fatigue.

Adverse reactions occurring in ≥10% of pediatric patients were upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, hyperammonemia, and headache.