Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Immedica Pharma AB, SE-113 29, Stockholm, Sweden
RAVICTI is indicated for use as adjunctive therapy for chronic management of patients with urea cycle disorders (UCDs) including deficiencies of carbamoyl phosphate synthetase I (CPS), ornithine carbamoyltransferase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), arginase I (ARG) and ornithine translocase deficiency hyperornithinaemia-hyperammonaemia homocitrullinuria syndrome (HHH) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone.
RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (e.g. essential amino acids, arginine, citrulline, protein-free calorie supplements).
RAVICTI should be prescribed by a physician experienced in the management of UCDs.
RAVICTI must be used with dietary protein restriction and sometimes dietary supplements (e.g. 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.
The recommended dosages for patients naïve to phenylbutyric acid and for patients switching from sodium phenylbutyrate or from sodium phenylacetate/sodium benzoate injection to RAVICTI are different.
The recommended total daily dose of RAVICTI is based on body surface area and ranges from 4.5 ml/m²/day to 11.2 ml/m²/day [5.3 g/m²/day to 12.4 g/m²/day) and should take into account the following:
The total daily dose should be divided into equal amounts and given with each meal or feeding (e.g. three times to six times per day). Each dose should be rounded up to the nearest 0.1 ml for patients less than 2 years of age and 0.5 ml for patients 2 years of age and older.
Recommended starting dosage in phenylbutyrate-naïve patients:
Initial dosage in patients switching from sodium phenylbutyrate to RAVICTI:
Patients switching from sodium phenylbutyrate to RAVICTI should receive the dosage of RAVICTI that contains the same amount of phenylbutyric acid. The conversion is as follows:
Initial dosage in patients switching from sodium phenylacetate/sodium benzoate injection to RAVICTI:
Once stable with controlled ammonia, patients switching from sodium phenylacetate/sodium benzoate to RAVICTI should receive a dose of RAVICTI at the higher end of the treatment range (11.2 ml/m²/day) with measurements of plasma ammonia to guide further dosing.
The recommended daily dose schedule of 8.5 ml/m²/day-11.2 mL/m²/day over a period of up to 24 hours for patients stabilised with no further hyperammonaemia is as follows:
For data regarding pharmacodynamic and pharmacokinetic properties in this age group, see sections 5.1 and 5.2.
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. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered 4-phenylbutyric acid (PBA) dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated glycerol phenylbutyrate dose for a 24-hour period is 0.6 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).
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.
U-PAGN measurements may be used to help guide glycerol phenylbutyrate dose adjustment and assess compliance. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the recommended ULN, the glycerol phenylbutyrate dose should be adjusted upward. The amount of dose adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-h U-PAGN level and the estimated glycerol phenylbutyrate dose needed per gram of dietary protein ingested.
Spot U-PAGN concentrations below the following levels may indicate improper medicinal product administration and/or lack of compliance:
If spot U-PAGN concentrations fall below these levels, assess compliance with medicinal product and/or effectiveness of medicinal product administration (e.g. via feeding tube) and consider increasing the glycerol phenylbutyrate dose in compliant patients to achieve optimal ammonia control (within normal limit for patients under 2 years of age and less than half ULN in older patients when fasted).
Symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness in the absence of high ammonia or intercurrent illness may be signs of phenylacetic acid (PAA) toxicity (see section 4.4, PAA toxicity). Therefore, measurement of plasma PAA and PAGN levels may be useful to guide dosing. The plasma PAA to PAGN (both measured in mcg/ml) ratio has been observed to be generally less than 1 in patients without PAA accumulation. In patients with a PAA to PAGN ratio exceeding 2.5, a further increase in glycerol phenylbutyrate dose may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction. In such cases, increasing the dosing frequency may result in a lower plasma PAA level and PAA to PAGN ratio. Ammonia levels must be monitored closely when changing the dose of glycerol phenylbutyrate.
The safety and efficacy of RAVICTI for the treatment of patients with N-acetylglutamate synthase (NAGS) and CITRIN (citrullinaemia type 2) deficiency have not been established.
Posology is the same for adult and paediatric patients.
Clinical studies of RAVICTI did not include sufficient numbers of subjects ≥65 years of age to determine whether they respond differently than younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other medicinal product therapy.
Because conversion of PAA to PAGN occurs in the liver, patients with severe hepatic impairment may have reduced conversion capability and higher plasma PAA and plasma PAA to PAGN ratio. Therefore, dosage for adult and paediatric patients with mild, moderate or severe hepatic impairment should be started at the lower end of the recommended dosing range (4.5 ml/m²/day) and kept at the lowest dose necessary to control the patient’s ammonia levels. A plasma PAA to PAGN ratio exceeding 2.5 may indicate saturation of PAA to PAGN conversion capacity and the need for reduced dosing and/or increased frequency of dosing. The plasma PAA to PAGN ratio may be useful in dosage monitoring. (see section 5.2).
No studies were conducted in UCD patients with renal impairment; the safety of glycerol phenylbutyrate in patients with renal impairment is unknown. RAVICTI should be used with caution in patients with severe renal impairment. Preferably such patients should be started and maintained at the lowest dose necessary to control the blood ammonia levels.
Oral or gastroenteral use.
RAVICTI should be taken with meals and administered directly into the mouth via an oral syringe. Do not add and stir the medicinal product into a large volume of other liquid, as glycerol phenylbutyrate is heavier than water and this may result in incomplete administration. Compatibility studies have been conducted (see section 4.5). RAVICTI may be added to a small amount of apple sauce, ketchup, or squash puree and should be used within 2 hours when stored at room temperature (25°C). The medicinal product may be mixed with medical formulas (Cyclinex-1, Cyclinex-2, UCD-1, UCD-2, Polycose, Pro Phree and Citrulline) and used within 2 hours when stored at 25°C, or up to 24 hours, refrigerated.
The RAVICTI pack contains the medicinal product and a reclosable bottle cap adapter. CE marked oral syringes compatible with the reclosable bottle cap adapter can be obtained from a pharmacy.
Open the bottle of RAVICTI by pushing down on the cap and twisting to the left. Twist the reclosable bottle cap adapter onto the bottle. Place the tip of the oral syringe into the reclosable bottle cap adapter. Turn the bottle upside down with the oral syringe still inserted. Fill the oral syringe by pulling the plunger back until the syringe is filled with the amount of medicinal product. Tap the oral syringe to remove air bubbles, making sure you have filled it with the correct amount of liquid. Swallow the liquid from the oral syringe or attach the oral syringe to a gastrostomy or nasogastric tube. The same oral syringe should be used for all doses taken each day. It is important to ensure that the oral syringe is kept clean and dry between the dosing intervals. Do not rinse the reclosable bottle cap or the oral syringe between daily doses, as the presence of water causes glycerol phenylbutyrate to degrade. Tightly close the tethered tab on the reclosable bottle adapter after use. After the last dose of the day, the oral syringe should be discarded. The reclosable bottle cap should be discarded when the bottle is empty or after 14 days following opening even if the bottle is not empty. A new reclosable bottle cap should be used for each new bottle that is opened.
RAVICTI may also be administered by CE marked medical grade silicone nasogastric or gastrostomy tube for those patients unable to take the medicinal product by mouth.
For additional information regarding method of administration and compatibility/in-use stability studies please refer to section 6.6.
In vitro studies evaluating the percent recovery of total dose delivered with nasogastric, nasojejunal or gastrostomy tubes demonstrated the percent of dose recovered was >99% for doses >1 ml and 70% for a 0.5 ml dose. For patients who can swallow liquids take RAVICTI should be taken orally, even those with a nasogastric and/or gastrostomy tube. However, for patients who cannot swallow liquids, a nasogastric tube or gastrostomy tube may be used to administer RAVICTI as follows:
It is not recommended to administer a dose of 0.5 ml or less with nasogastric, gastrostomy or nasojejunal tubes, given the low drug recovery in dosing.
PAA, the active metabolite of glycerol phenylbutyrate, is associated with signs and symptoms of neurotoxicity (see section 4.4) and could accumulate in patients who receive an overdose. In case of overdose, the medicinal product should be discontinued and the patient monitored for any signs or symptoms of adverse reactions.
Shelf life: 2 years.
After the first opening of the bottle, the medicinal product must be used within 14 days and the bottle and its contents discarded, even if not empty.
This medicinal product does not require any special storage conditions.
Clear, Type III glass, bottle with a high density polyethylene (HDPE) child-resistant closure.
Each bottle contains 25 ml of liquid.
Each bottle should be discarded after 14 days. Based on prescribed dosing volume, patients should be advised to obtain CE marked oral syringes with suitable size for the dosage and compatible with the reclosable bottle cap adapter from the pharmacy. Patients should be advised to have a sufficient quantity of syringes on hand.
Standard pack size: 1 bottle and 1 reclosable bottle cap adapter per carton.
Any unused product or waste material should be disposed of in accordance with national requirements.
One oral syringe should be used each day. Do not rinse the reclosable bottle cap adapter or the oral syringe between daily doses as the introduction of water causes glycerol phenylbutyrate to degrade. After the last dose of each day, the oral syringe should be discarded. The same reclosable bottle cap adapter can be used until a bottle is empty. A new reclosable bottle cap adapter should be used for each new bottle that is opened.
Chemical compatibility of glycerol phenylbutyrate with medical grade silicone nasogastric, gastrostomy, and nasojejunal tubes has been demonstrated. In vitro studies evaluating the percent recovery of total dose delivered with nasogastric or gastrostomy tubes demonstrated the percent of dose recovered was >99% for doses >1 ml and 70% for a 0.5 ml dose. Therefore, it is recommended that nasogastric, nasojejunal or gastrostomy tubes only be used to administer doses >1 ml. If there is a need to administer a dose of 0.5 ml or less with such nasogastric, gastrostomy or nasojejunal tubes, consideration should be given to the low drug recovery in dosing.
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