Ravicti

RAVICTI should be prescribed by a physician experienced in the management of UCDs. , essential amino acids, arginine, citrulline, protein-free calorie supplements) depending on the daily dietary protein intake needed to promote growth and development.

The daily dose should be individually adjusted according to the patient’s protein tolerance and the daily dietary protein intake needed. RAVICTI therapy may be required life long unless orthotopic liver transplantation is elected. Adults and children The recommended dose for patients naïve to phenylbutyric acid and for patients switching from sodium phenylbutyrate or from sodium phenylacetate/sodium benzoate injection to RAVICTI are different.

g. three times to six times per day). 5 ml for patients 2 years of age and older. 3 m2 Initial dose in patients switching from sodium phenylbutyrate to RAVICTI Patients switching from sodium phenylbutyrate to RAVICTI should receive the dose of RAVICTI that contains the same amount of phenylbutyric acid.

2 ml/m2/day) with measurements of plasma ammonia to guide further dosing. 2 ml/m2/day over a period of up to 24 hours for patients stabilised with no further hyperammonaemia is as follows: • Step 1: 100% dose sodium phenylacetate/sodium benzoate and 50% dose of RAVICTI for 4-8 hours; • Step 2: 50% dose sodium phenylacetate/sodium benzoate and 100% RAVICTI for 4-8 hours; • Step 3: sodium phenylacetate/sodium benzoate discontinued and full dose RAVICTI continued according to feeding schedule for 4-8 hours.

2. Dose adjustment and monitoring in adults and children The daily dose should be individually adjusted according to the patient’s estimated urea synthetic capacity, if any, protein tolerance and the daily dietary protein intake needed to promote growth and development.

Dietary protein is approximately 16% nitrogen by weight. 6 ml glycerol phenylbutyrate per gram of dietary protein ingested per 24 hour period assuming all the waste nitrogen is covered by glycerol phenylbutyrate and excreted as phenylacetylglutamine (PAGN).

Adjustment based on plasma ammonia The dose of glycerol phenylbutyrate should be adjusted to produce a fasting plasma ammonia level that is less than half the upper limit of normal (ULN) in patients 6 years and older. In infants and young children (generally below 6 years of age) where obtaining fasting ammonia is problematic due to frequent feedings, the first ammonia of the morning should be kept below the ULN.

Summary of the safety profile Assessment of adverse reactions was 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 across 4 short term and 3 long term clinical studies, in which 90 patients completed 12 months duration (median exposure = 51 weeks).

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. 3% each). Additional adverse reactions have been evaluated in a clinical study including 16 UCD patients less than 2 months of age.

The median exposure was 10 months (range 2 to 20 months). Tabulated list of adverse reactions The adverse reactions are listed below, by system organ class and by frequency. Frequency is defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Any adverse reaction reported in one patient met the uncommon criteria. Due to the rarity of the UCD population, and the small size of the medicinal product safety population database (N=114), the adverse reaction frequency for rare and very rare is not known.

Table 1. 1%] versus 0 of 51 adults [0%]. In an additional long term (24 month), uncontrolled, open-label clinical study the safety of RAVICTI has been evaluated in 16 UCD patients less than 2 months of age and 10 paediatric patients with UCDs aged 2 months to less than 2 years.

3 months). Adverse reactions are summarized below. Table 2. 3%) Table 3. List of adverse reactions in patients 2 months to less than 2 years of age System Organ Class Preferred Term Total (N=10) Gastrointestinal disorders 2 (20%) Constipation 1 (10%) Diarrhoea 1 (10%) Skin and subcutaneous tissue disorders 2 (20%) Eczema 1 (10%) Nail ridging 1 (10%) Rash 1 (10%) Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

6 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. , 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.

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. 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.

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