Special Warning : אזהרת שימוש

4.4       Special warnings and precautions for use

Even while on treatment with glycerol phenylbutyrate, acute hyperammonaemia including hyperammonaemic encephalopathy may occur in a proportion of patients.

Reduced phenylbutyrate absorption in pancreatic insufficiency or intestinal malabsorption 
Exocrine pancreatic enzymes hydrolyse 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. Ammonia levels should be closely monitored in patients with pancreatic insufficiency or intestinal malabsorption.

Neurotoxicity

Reversible clinical manifestations suggestive of neurotoxicity (e.g., nausea, vomiting, somnolence) have been reportedly associated with phenylacetate levels ranging from 499-1,285 mcg/ml in cancer patients who received PAA intravenously. Although these have not been seen in clinical trials involving UCD patients, high PAA levels should be suspected in patients (particularly in children<2months) with unexplained somnolence, confusion, nausea and lethargy who have normal or low ammonia.

If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or other intercurrent illnesses, measure plasma PAA and plasma PAA to 
Ravicti-SPC-0423-V1
PAGN , it should be considered to reduce the glycerol phenylbutyrate dose or increase the frequency of dosing if the PAA level exceeds 500 mcg/L and the plasma PAA to PAGN ratio exceeds 2.5.

Monitoring and laboratory tests

The daily dose should be individually adjusted according to the patient’s estimated urea synthetic capacity, if any, amino acid profile, protein tolerance and the daily dietary protein intake needed to promote growth and development. Supplemental amino acid formulations may be necessary to maintain essential amino acids and branched chain amino acids within normal range. Further adjustment may be based on monitoring of plasma ammonia, glutamine, U-PAGN and/or plasma PAA and PAGN as well as the ratio of plasma PAA to PAGN (see section 4.2).

Potential for other medicinal products to affect ammonia

Corticosteroids
Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels.
Monitor ammonia levels closely when corticosteroids and glycerol phenylbutyrate are used concomitantly.

Valproic acid and haloperidol

Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia levels closely when use of valproic acid or haloperidol is necessary in UCD patients.


Probenecid

Probenecid may inhibit the renal excretion of metabolites of glycerol phenylbutyrate including PAGN.

Women of childbearing potential/contraception in males and females
Effective contraceptive measures must be taken by women of child-bearing potential (see section 4.6).

Pregnancy

RAVICTI should not be used during pregnancy and in women of childbearing potential not using contraception unless the clinical condition of the woman requires treatment with glycerol phenylbutyrate, see section 4.6.

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Effects on Driving

4.7   Effects on ability to drive and use machines
RAVICTI may have major influence on the ability to drive and use machines given that treatment with glycerol phenylbutyrate may cause dizziness or headaches (see section 4.8). Patients should not drive or use machines whilst experiencing these adverse reactions.