Glycerol phenylbutyrate

RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of patients 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.

UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia (NH 3, NH 4 + ). 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 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. Figure 1: RAVICTI Mechanism of Action Figure 1

RAVICTI should be prescribed by a physician experienced in management of UCDs. For administration and preparation, see full prescribing information. 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. Initial Dosage in Phenylbutyrate-Naïve Patients: Recommended dosage range is 4.5 to 11.2 mL/m 2 /day (5 to 12.4 g/m 2 /day). For patients with some residual enzyme activity not adequately controlled with dietary restriction, the recommended starting dose is 4.5 mL/m 2 /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.

RAVICTI is contraindicated in patients with known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Known hypersensitivity to phenylbutyrate.

Neurotoxicity: Phenylacetate (PAA), the active moiety of RAVICTI, may be toxic, reduce dosage for symptoms of neurotoxicity. Pancreatic Insufficiency or Intestinal Malabsorption: Monitor ammonia levels closely.

The following clinically significant adverse reactions are described elsewhere in the labeling: Neurotoxicity Pancreatic insufficiency or Intestinal Malabsorption Most common adverse reactions (≥ 10%) in adults are: diarrhea, flatulence, and headache.

Corticosteroids, valproic acid, or haloperidol: May increase plasma ammonia level, monitor ammonia levels closely. Probenecid: May affect renal excretion of metabolites of RAVICTI, including phenylacetylglutamine (PAGN) and PAA. 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. Midazolam: Decreased exposure, monitor for suboptimal effect of midazolam.

Store at 20°-25°C (68°-77°F) with excursions permitted to 15°-30°C (59°-86°F).