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RAVICTI™ (glycerol phenylbutyrate) oral liquid

DESCRIPTION CLINICAL PHARMACOLOGY INDICATIONS AND USAGE
CONTRAINDICATIONS PRECAUTIONS ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION HOW SUPPLIED WARNINGS
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Drug Updates:  RAVICTI ® (glycerol phenylbutyrate) Oral Liquid
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2013

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.

WARNINGS  top of page

See warnings and precautions below.

DESCRIPTION  top of page

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: top of page

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  top of page

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 top of page

Patients <2 months of age.

Known hypersensitivity to phenylbutyrate.

PRECAUTIONS top of page

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 top of page

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  top of page

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 top of page

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.
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