General Information

Ravicti (glycerol phenylbutyrate) is a nitrogen-binding agent. Urea cycle disorders result from deficiencies in the enzymes responsible for clearing toxic ammonia from the blood. During protein metabolism, nitrogen is produced as a waste product, which is normally converted to urea and excreted. In patients with urea cycle disorders, the nitrogen accumulates as ammonia and can cause coma, brain damage, and death. Glycerol phenylbutyrate aids in the removal of this accumulated ammonia.

Ravicti is specifically indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients over two years of age with urea cycle disorders 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.

Mechanism of Action

Ravicti (glycerol phenylbutyrate) is a nitrogen-binding agent. 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 three molecules of phenylbutyrate (PBA). PAA, the major metabolite of PBA, is the active moiety of Ravicti. PAA conjugates with glutamine, which contains two 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 two moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.

Side Effects

Adverse events associated with the use of Ravicti may include, but are not limited to, the following:

• Diarrhea
• Flatulence
• Headache

Dosing/Administration

Ravicti is supplied as a liquid for oral administration. It should be taken with food and administered directly into the mouth via oral syringe or dosing cup. The recommended dosages for patients switching from sodium phenylbutyrate to Ravicti and patients naïve to phenylbutyric acid are different.

For both subpopulations: Give Ravicti in three 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.

Please see the Ravicti drug label for specific instructions in dosing patients switching from sodium phenylbutyrate to Ravicti and patients naïve to phenylbutyric acid.

Clinical Trial Results

The FDA approval of Ravicti was based on separate studies in adults and pediatrics.

Clinical Studies in Adults

A randomized, double-blind, active-controlled, crossover, non-inferiority study enrolled 45 subjects with UCDs who had been on sodium phenylbutyrate prior to enrollment. The trial was designed to compare Ravicti to sodium phenylbutyrate by evaluating venous ammonia levels. The primary endpoint was to establish non-inferiority in the 24-hour AUC (a measure of exposure to ammonia over 24 hours) for venous ammonia on days 14 and 28, when the drugs were expected to be at steady state. The subjects were randomized to sodium phenylbutyrate for two weeks, followed by Ravicti for 2twoweeks or Ravicti for two weeks followed by Sodium phenylbutyrate for two weeks. The dose of Ravicti was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dose the patients were taking when they entered the trial. Both treatments were administered three times daily with meals. Forty-four subjects were evaluable for analysis. Ravicti was noninferior to sodium phenylbutyrate with respect to the 24-hour AUC for ammonia. Mean 24-hour AUCs for venous ammonia during steady-state dosing were 866 µmol/L hour and 977 µmol/L hour with Ravicti and sodium phenylbutyrate, respectively.

Long-term (12-month), uncontrolled, open-label study

This study was conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. A total of 51 adults were in the study and all but 6 had been converted from sodium phenylbutyrate to Ravicti. Venous ammonia levels were monitored monthly. Mean fasting venous ammonia values in adults were within normal limits during long-term treatment with Ravicti (range: 6-30 µmol/L). Of 51 adult, 7 (14 percent) reported a total of 10 hyperammonemic crises.

Clinical Studies in Pediatrics

Two fixed-sequence, open-label, sodium phenylbutyrate-to-Ravicti switchover studies were conducted in pediatrics ages two to 17 years. The first study was seven days in duration and the second study was 10 days in duration. A total of 26 subjects were enrolled. The dose of Ravicti was calculated to deliver the same amount of PBA as the dose of sodium phenylbutyrate patients were taking when they entered the trial. Sodium phenylbutyrate or Ravicti were administered in divided doses with meals and the subjects adhered to a low-protein diet throughout the study. After a dosing period with each treatment, all subjects underwent 24 hours of venous ammonia measurements, as well as blood and urine PK assessments. The 24-hour AUCs for blood ammonia (AUC0-24h) in 11 pediatrics six to 17 years of age (study One) and 11 pediatrics two years to 5 years of age (study Two) were similar between treatments. In children six to 17 years of age, the ammonia AUC0-24h was 604 µmol·h/L vs. 815 µmol·h/L on Ravicti vs. sodium phenylbutyrate. In the patients between two years and five years of age, the ammonia AUC0-24h was 632 µmol·h/L vs. 720 µmol·h/L on Ravicto versus sodium phenylbutyrate.

Long-term (12-month), uncontrolled, open-label studies

These studies were conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period. In two studies, one of which also enrolled adults (see above), and an extension of studyone1 above, referred to here as study 1E), a total of 26 children ages six to 17, were enrolled, and all but one had been converted from sodium phenylbutyrate to Ravicti. Mean fasting venous ammonia values were within normal limits during long-term treatment with Ravicti (range: 17-23 µmol/L). Of the 26 patients, five (19 percent) reported a total of five hyperammonemic crises. In an extension of study two, after a median time on study of 4.5 months (range 1.0-5.7 months), two of 16 pediatrics ages two to five years had experienced three hyperammonemic crises.

Additional Information

For additional information regarding Ravicti or urea cycle disorders, please visit the Hyperion Products web page.