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.

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.