Glycerol phenylbutyrate - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS Neurotoxicity : Phenylacetate (PAA), the active moiety of glycerol phenylbutyrate, may be toxic; reduce dosage for symptoms of neurotoxicity.

Pancreatic Insufficiency or Intestinal Malabsorption: Monitor ammonia levels closely.

5.1 Neurotoxicity Increased exposure to PAA, the major metabolite of glycerol phenylbutyrate, may be associated with neurotoxicity in patients with UCDs.

In a study of adult cancer patients, subjects received sodium phenylacetate administered as a 1-hour infusion twice daily at two dose levels of 125 and 150 mg/kg for a 2-week period.

Of 18 subjects enrolled, 7 had a history of primary central nervous system tumor.

Signs and symptoms of potential PAA neurotoxicity, which were reversible, were reported at plasma PAA concentrations above 500 micrograms/mL and included somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of preexisting neuropathy.

PAA concentrations were not measured when symptoms resolved.

In healthy subjects, after administration of 4 mL and 6 mL glycerol phenylbutyrate 3 times daily (13.2 g/day and 19.8 g/day, respectively) for 3 days, a dose-dependent increase in non-serious nervous system adverse reactions were observed.

In subjects who had nervous system adverse reactions, plasma PAA concentrations, which were measured on Day 3 per protocol and not always at onset of symptoms, ranged from 8 to 56 micrograms/mL with 4 mL glycerol phenylbutyrate 3 times daily and from 31 to 242 micrograms/mL with 6 mL glycerol phenylbutyrate 3 times daily.

In clinical trials in patients with UCDs who had been on sodium phenylbutyrate prior to administration of glycerol phenylbutyrate, adverse reactions of headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor and/or dizziness were reported.

No correlation between plasma PAA concentration and neurologic symptoms was identified but plasma PAA concentrations were generally not consistently measured at the time of neurologic symptom occurrence [see Clinical Pharmacology ] .

If symptoms of vomiting, nausea, headache, somnolence or confusion are present in the absence of high ammonia or other intercurrent illness which explains these symptoms, consider the potential for PAA neurotoxicity which may need reduction in the glycerol phenylbutyrate dosage [see Dosage and Administration ] .

5.2 Pancreatic Insufficiency or Intestinal Malabsorption Exocrine pancreatic enzymes hydrolyze glycerol phenylbutyrate 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 glycerol phenylbutyrate and/or absorption of phenylbutyrate and reduced control of plasma ammonia.

Monitor ammonia levels closely in patients with pancreatic insufficiency or intestinal malabsorption.