What are the precautions for glyceryl phenylbutyrate oral solution (Ravicti)?

In clinical studies of Glycerol Phenylbutyrate Oral Liquid in the treatment of patients with urea cycle disorders (UCDs), warnings and precautions such as neurotoxicity, pancreatic insufficiency, or intestinal malabsorption have emerged. Discontinue and resume at reduced dose upon recovery, or permanently discontinue based on severity.

1. Neurotoxicity: Increased exposure to PAA (the main metabolite of glycerol phenylbutyrate) may be related to neurotoxicity in patients with UCDs. Signs and symptoms of potentially reversible PAA neurotoxicity have been reported when plasma PAA concentrations exceed 500 μg/mL, including drowsiness, fatigue, dizziness, headache, dysgeusia, hearing loss, disorientation, impaired memory, and exacerbation of pre-existing neuropathy. After symptom resolution, PAA concentrations were not measured.

Adverse reactions such as headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor, and/or dizziness have been reported in clinical trials in patients with UCDs who had taken sodium phenylbutyrate prior to oral administration of glycerol phenylbutyrate. No correlation was found between plasma PAA concentrations and neurological symptoms, but plasma PAA concentrations are often not continuously measured at the time of neurological symptoms. If symptoms of vomiting, nausea, headache, drowsiness, or confusion occur in the absence of hyperammonemia or other concurrent illnesses that explain the symptoms, consider the possibility of neurotoxicity from the PAA, which may require a reduction in the oral glycerol phenylbutyrin dose.

2. Pancreatic insufficiency or intestinal malabsorption: Exocrine pancreatic enzymes hydrolyze glycerol phenylbutyrate in the small intestine and separate the active part phenylbutyrate from glycerin. This process allows phenylbutyrate to be absorbed into the circulation. Low or deficient pancreatic enzyme levels or intestinal disease causing fat malabsorption may result in reduced or deficient digestion of glycerol phenylbutyrin oral solution and/or phenylbutyrate absorption and reduced control of plasma ammonia. Closely monitor ammonia levels in patients with pancreatic insufficiency or intestinal malabsorption.

Reference materials:https://www.ravicti.com/