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Warnings 

Description 

RAVICTI™ (glycerol phenylbutyrate) oral liquid
Initial U.S. Approval: 1996

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 >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.

Clinical pharmacology

Mechanism of Action:
UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia (NH3, NH4+). Absence of these enzymes or transporters results in the 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. On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.

Indications and usage 

INDICATIONS AND USAGE:
RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients geq2 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).

Limitations of Use:
RAVICTI is not indicated for treatment of acute hyperammonemia in patients with UCDs.

Safety and efficacy for treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.

The use of RAVICTI in patients <2 months of age is contraindicated

Contraindications

Patients <2 months of age.

Known hypersensitivity to phenylbutyrate.

Precautions

WARNINGS AND PRECAUTIONS:

  1. Neurotoxicity (phenylacetate [PAA], the active moiety of RAVICTI, may be toxic): Reduce dosage for symptoms of neurotoxicity.
  2. Reduced Phenylbutyrate Absorption in Pancreatic Insufficiency or Intestinal Malabsorption: Monitor ammonia levels closely.

Adverse reactions

ADVERSE REACTIONS
Most common adverse reactions in geq10% of patients are diarrhea, flatulence, and headache.

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.

Probenecid: May affect renal excretion of metabolites of RAVICTI, including PAGN and PAA.

USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm.

Nursing Mothers: Discontinue nursing or discontinue the drug.

See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide.

Dosage and administration 

DOSAGE AND ADMINISTRATION:
RAVICTI should be prescribed by a physician experienced in management of UCDs.

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 (g) x 0.86.

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).

For patients with some residual enzyme activity who are not adequately controlled with dietary restriction, 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 Modifications in Patients With Hepatic Impairment:
Start dosage at lower end of range.

How supplied

DOSAGE FORMS AND STRENGTHS

Oral liquid: 1.1 g/mL of glycerol phenylbutyrate.

Reference

Package insert data:   [Accessed: Jan 2014].

Manufactured by:
Lyne Laboratories, Inc.
Brockton, MA 02301

Manufactured for:
Hyperion Therapeutics Inc.
601 Gateway Boulevard, Suite 200
South San Francisco, CA 94080

Issued: February 2013

© Hyperion Therapeutics, Inc.
All rights reserved.

RAVICTI is a trademark of Hyperion Therapeutics, Inc.

Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates.  A local search option of this data can be found here.

Disclaimer

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