Safety and tolerability of RAVICTI®1,2

RAVICTI® (glycerol phenylbutyrate) is comprehensively documented for the treatment of Urea Cycle Disorders.

Assessment of adverse reactions with RAVICTI was in the study program based on exposure in 114 UCD patients (65 adults and 49 children between the ages of 2 months and 17 years) with deficiencies in CPS, OTC, ASS, ASL, ARG, or HHH. Additional adverse reactions have been evaluated in a clinical study including 16 UCD patients less than 2 months of age.
 
At the beginning of the treatment, abdominal pain, nausea, diarrhoea, and/or headache may occur; these reactions usually disappear within a few days even if treatment is continued.
 

The most common adverse reactions reported in clinical trials (at least 10% of patients) were:

  • Adult patients: diarrhoea, flatulence, headache, nausea, vomiting, decreased appetite, dizziness, and fatigue
  • Paediatric patients ages 2 to 17 years: upper abdominal pain, rash, nausea, vomiting, diarrhoea, decreased appetite, and headache
  • Paediatric patients ages 2 months to less than 2 years: neutropenia, vomiting, constipation, diarrhoea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhoea, rash, and papule
  • Paediatric patients less than 2 months of age: vomiting, rash, gastroesophageal reflux, increased hepatic enzymes, feeding disorder (decreased appetite, hypophagia), anaemia, cough, dehydration, metabolic acidosis, thrombocytosis, thrombocytopenia, neutropenia, lymphocytosis, diarrhoea, flatulence, constipation, pyrexia, lethargy, and irritability/agitation

Treatment associated adverse events – RAVICTI vs NaPBA

One hundred patients or their caregivers responded to a non-validated UCD-specific questionnaire including a pre-defined list of common symptoms associated with nitrogen scavengers. Baseline values (while patients were receiving sodium phenylbutyrate [NaPBA]) were compared with values after three months treatment with glycerol phenylbutyrate (GPB).3

Major patient

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.
  • Hypersensitivity to the active substance 
  • Treatment of acute hyperammonaemia

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.

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 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.

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 in SPC).

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
Hyperammonaemia 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

Effective contraceptive measures must be taken by women of child-bearing potential (see section 4.6 in SPC).

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 in SPC.

Safety reporting and product complaints

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Immedica by email: safety@immedica.com

If you would like to report a product complaint, this should be reported according to national requirements and primarily to your local pharmacy. You may also contact Immedica Quality at: complaints@immedica.com

References:
1. RAVICTI European Assessment Report.
2. Summary of Product Characteristics RAVICTI.
3. Nagamani SC et al. Mol Genet Metab. 2015;116:29–34.