Posology : מינונים

4.2   Posology and method of administration

NITYR tablets treatment should be initiated and supervised by a physician experienced in the treatment of HT-1 patients.

Posology
Treatment of all genotypes of the disease should be initiated as early as possible to increase overall survival and avoid complications such as liver failure, liver cancer and renal disease.
Adjunct to the NITYR tablets treatment, a diet deficient in phenylalanine and tyrosine is required and should be followed by monitoring of plasma amino acids (see sections 4.4 and 4.8) 
The recommended initial dose in the pediatric and adult population is 1mg/kg body weight administered orally. The dose of NITYR tablets should be adjusted individually. It is recommended to administer the dose once daily. However, due to the limited data in patients with body weight <20 kg, it is recommended to divide the total daily dose into two daily administrations in this patient population.

Dose adjustment
During regular monitoring, it is appropriate to follow urine succinylacetone, liver function test values and alpha-fetoprotein levels (see section 4.4). If urine succinylacetone is still detectable one month after the start of NITYR tablets treatment, the NITYR tablets dose should be increased to 1.5 mg/kg body weight/day divided in 2 doses. A dose of 2 mg/kg body weight/day may be needed based on the evaluation of all biochemical parameters. This dose should be considered as a maximal dose for all patients.
If the biochemical response is satisfactory, the dose should be adjusted only according to body weight gain.
However, in addition to the tests above, during the initiation of therapy, switch from twice daily to once daily dosing or if there is a deterioration, it may be necessary to follow more closely all available biochemical parameters (i.e. plasma succinylacetone, urine 5- aminolevulinate (ALA) and erythrocyte porphobilinogen (PBG)-synthase activity).
Special populations

There are no dosage adjustments provided in the manufacturer's labeling for renal or liver impaired patients

Pediatric population
The dose recommendation in mg/kg body weight is the same in children and adults. However, due to the limited data in patients with body weight <20 kg, it is recommended to divide the total daily dose into two daily administrations in this patient population.


Method of administration
Tablets may be disintegrated in water and administered using an oral syringe or crushed and mixed with applesauce

It is recommended that if NITYR tablets treatment is initiated with food, this should be maintained on a routine basis, see section 4.5.


•    Maintain dietary restriction of tyrosine and phenylalanine when taking NITYR tablets.
•    NITYR tablets can be taken with or without food.
•    For patients, including pediatric patients, who have difficulty swallowing intact tablets, NITYR tablets can be disintegrated in water and administered using an oral syringe. If patients can swallow semi-solid foods, NITYR tablets can be crushed and mixed with applesauce. Administration of NITYR tablets with other liquids or foods has not been studied and is not recommended.


Preparation and Administration of NITYR tablets with Water in an Oral Syringe: A 5-mL oral syringe with a cap will be provided by a pharmacist.
Follow the instructions below for one or two intact tablets, depending on the number of tablets needed to achieve the patient’s individual dosage.
Do not prepare more than two tablets at once within the same oral syringe.
If patient’s dosage requires more than two tablets, follow the steps below using multiple oral syringes to achieve the required dose.


One Tablet
1. Remove the plunger from the 5-mL oral syringe and insert a single, intact tablet.
2. Replace the plunger and draw up 2.6 mL of room temperature water.
3. Cap the oral syringe and leave the oral syringe for at least 60 minutes.
4. After 60 minutes, turn the oral syringe up and down for at least 30 seconds to suspend the material.
5. Inspect the syringe to ensure the tablet has disintegrated prior to administration to the patient. Administer immediately. However, do not administer unless the tablet has fully disintegrated.
6. If the tablet is not fully disintegrated, leave the oral syringe for an additional 10 minutes.
Before administration of the suspension to the patient, turn the oral syringe up and down for 30 seconds to re-suspend the particles. Inspect the syringe again to ensure the tablet has disintegrated prior to administration to the patient. Do not administer unless the tablet has fully disintegrated.
7. Administer immediately. However, if this is not possible, the suspension can be stored at room temperature in the capped oral syringe, protected from direct sunlight for up to 24 hours after adding water to the tablets. Discard after 24 hours.
8. Uncap the oral syringe and administer the suspension into the patient's mouth. To facilitate full administration, avoid depressing the plunger to the end of the oral syringe and leave a gap between the plunger and the oral syringe.
9. Rinse the oral syringe by drawing up 2 mL of water. Cap the oral syringe and shake well for 10 seconds to suspend any remaining particles.
10. Uncap the oral syringe and administer the suspension into the patient’s mouth, this time fully depressing the plunger. If particles are still present in the syringe, repeat steps 9-10.

Two Tablets

1.  Remove the plunger from the 5-mL oral syringe and insert two intact tablets.
2.  Replace the plunger and draw up 5 mL of room temperature water.
3.  Cap the oral syringe and leave it for at least 60 minutes.
4.  After 60 minutes, turn the oral syringe up and down for at least 30 seconds to suspend the material.
5. Inspect the syringe to ensure the tablets have disintegrated prior to administration to the patient. Administer immediately. However, do not administer unless the tablet has fully disintegrated.
6. If the tablet is not fully disintegrated, leave the oral syringe for an additional 10 minutes.
Before administration of the suspension to the patient, turn the oral syringe up and down for 30 seconds to re-suspend the particles. Inspect the syringe again to ensure the tablet has disintegrated prior to administration to the patient. Do not administer unless the tablet has fully disintegrated.
7. Administer immediately. However, if this is not possible, the suspension can be stored at room temperature in the capped oral syringe, protected from direct sunlight for up to 24 hours after adding water to the tablets. Discard after 24 hours.
8. Uncap the oral syringe and administer the suspension into the patient's mouth. To facilitate full administration, avoid depressing the plunger to the end of the oral syringe and leave a gap between the plunger and the oral syringe.
9. Rinse the oral syringe by drawing up 2 mL of water. Cap the oral syringe and shake well for 10 seconds to suspend any remaining particles.
10. Uncap the oral syringe and administer the suspension into the patient’s mouth, this time fully depressing the plunger and ensuring the syringe is empty. If particles are still present in the syringe, repeat steps 9-10.

Preparation and Administration of NITYR Mixed in Applesauce
For patients who can swallow semi-solid food, NITYR tablets can be crushed and mixed with applesauce:

1. Measure around one teaspoon of applesauce and transfer it into a clean container (e.g., clean glass).
2. Always crush one tablet at a time. Position the tablet between two metal teaspoons and apply light pressure on the top spoon. The two teaspoons should overlap each other to form a fine powder.
3. Press and rotate the two teaspoons against each other repeatedly until all of the tablet is in a fine powder.
4. Carefully transfer the resulting powder to the applesauce container ensuring all the powder is transferred, and no powder residue remains on the teaspoons.
5. If more than one tablet is needed, repeat the procedure starting from Step 2 and collect all the resulting powder together in the applesauce container.
6. Mix the powder into the applesauce until the powder is well dispersed.
7. Administer the entire NITYR-applesauce mixture to the patient’s mouth using a teaspoon.
Administer immediately. However, if this is not possible, the mixture can be stored at room temperature, out of direct sunlight, for up to 2 hours after adding the crushed tablets to the applesauce. Discard any mixture that has not been given within 2 hours.
8. To assure that any leftover applesauce mixture from the container is recovered, add around one teaspoon of applesauce to the same container and mix the fresh applesauce with the remaining mixture.
9. Administer the additional NITYR-applesauce mixture immediately to the patient’s mouth using a teaspoon.