Posology : מינונים

4.2   Posology and method of administration

RAVICTI should be prescribed by a physician experienced in the management of UCDs.
Posology

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.

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.

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.

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Recommended starting dose in phenylbutyrate-naïve patients

• 8.5 ml/m2/day (9.4 g/m2/day) in patients with a body surface area (BSA) < 1.3 m2 
• 7 ml/m2/day (8 g/m2/day) in patients with a BSA ≥ 1.3 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. The conversion is as follows: 
• Total daily dose of RAVICTI (ml) = total daily dose of sodium phenylbutyrate tablets (g) x 0.86 
• Total daily dose of RAVICTI (ml) = total daily dose of sodium phenylbutyrate powder (g) x 0.81 

Initial dose 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: 
•   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.

For data regarding pharmacodynamic and pharmacokinetic properties in this age group, see sections 5.1 and 5.2.



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. 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).

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 

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(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.

Adjustment based on urinary phenylacetylglutamine

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:

• 9,000 microgram (mcg/ml) for patients under 2 years of age

• 7,000 microgram (mcg/ml) for patients >2 years of age with a BSA of ≤1.3 
• 5,000 microgram (mcg/ml) for patients >2 years of age with a BSA of >1.3 
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).

Adjustment based on plasma phenylacetate and phenylacetylglutamine

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.

N-acetylglutamate synthase (NAGS) and CITRIN (citrullinaemia type 2) deficiency 
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.

Paediatric population

Posology is the same for adult and paediatric patients.

Missed dose

Any missed dose should be taken as soon as recognised. However, if the next scheduled dose is within 2 hours for adults and within 30 minutes for children, the missed dose should be omitted and the usual dosing schedule resumed. The dose should not be doubled to make up for a missed dose.


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Special populations
Elderly (65 years or older)

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.

Hepatic impairment

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, dose 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 dose monitoring. (see section 5.2).

Renal impairment

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.

Method of administration

Oral or gastroenteral use.
RAVICTI should be taken with meals and administered directly into the mouth via an oral syringe. The medicinal product should not be added or stirred 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.


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The RAVICTI bottle should be opened by pushing down on the cap and twisting to the left. The tip of the oral syringe should be placed into the syringe insert and the bottle should be turned upside down with the syringe still inserted. The oral syringe should then be filled by pulling the plunger back until the syringe is filled with the prescribed amount of medicinal product. The oral syringe should be tapped to remove air bubbles, while making sure it is filled with the correct amount of liquid. The liquid can be swallowed from the oral syringe or the oral syringe can be attached 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. The oral syringe should not be rinsed between daily doses, as the presence of water causes glycerol phenylbutyrate to degrade.
The bottle should be closed tightly after use. The oral syringe should be discarded after the last dose of the day.
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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.

Preparation for nasogastric tube or gastrostomy tube administration

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: 
•    An oral syringe should be utilised to withdraw the prescribed dose of RAVICTI from the bottle.
•    The tip of the oral syringe should be placed onto the tip of the gastrostomy/nasogastric tube.
•    The plunger of the oral syringe should be used to administer RAVICTI into the tube.
•    10 ml of water or medical formula should be used to flush the tube once, and the flush should be allowed to drain after administration.

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.