​2.1 Dosage

​Starting Dosage

​The recommended starting dosage of NITYR is 0.5 mg/kg administered orally twice daily.

​Maintenance Regimen
In patients 5 years of age and older who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone, the total daily dose of NITYR may be given once daily (e.g., 1 to 2 mg/kg once daily) [see Clinical Pharmacology (12.2)]​.

​Dosage Titration

​Titrate the dosage in each individual patient based on biochemical and/or clinical response.

• ​Monitor plasma and/or urine succinylacetone concentrations, liver function parameters and alphafetoprotein levels.
• ​If succinylacetone is still detectable in blood or urine 4 weeks after the start of nitisinone treatment, increase the NITYR dosage to 0.75 mg/kg twice daily. A maximum total daily dosage of 2 mg/kg may be needed based on the evaluation of all biochemical parameters.
• ​If the biochemical response is satisfactory (undetectable blood and/or urine succinylacetone), the dosage should be adjusted only according to body weight gain and not according to plasma tyrosine levels.
• ​During initiation of therapy, when switching from twice daily to once daily dosing, or if there is a deterioration in the patient’s condition, it may be necessary to follow all available biochemical parameters more closely (i.e. plasma and/or urine succinylacetone, urine 5-aminolevulinate (ALA) and erythrocyte porphobilinogen (PBG)-synthase activity).
• Maintain plasma tyrosine levels below 500 micromol/L by dietary restriction of tyrosine and phenylalanine intake [see Warnings and Precautions (5.1)]​. In patients who develop plasma tyrosine levels above 500 micromol/L, assess dietary tyrosine and phenylalanine intake. Do not adjust the NITYR dosage in order to lower the plasma tyrosine concentration.

Preparation and Administration Instructions

• Maintain dietary restriction of tyrosine and phenylalanine when taking NITYR.
• NITYR can be taken with or without food.
• For patients, including pediatric patients, who have difficulty swallowing intact tablets, NITYR 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 with other liquids or foods has not been studied and is not recommended.

Preparation and Administration of NITYR 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 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.