ORFADIN Capsule / Oral suspension Ref.[10890] Active ingredients: Nitisinone

Starting Dosage

The recommended starting dosage of ORFADIN 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 ORFADIN 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 alpha-fetoprotein levels.
• If succinylacetone is still detectable in blood or urine 4 weeks after the start of nitisinone treatment, increase the nitisinone 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 ORFADIN dosage in order to lower the plasma tyrosine concentration.

2.2 Preparation and Administration Instructions

Preparation of the Oral Suspension

The oral suspension will be dispensed with an oral syringe of appropriate size and a bottle adaptor provided by a pharmacist or other healthcare provider.

Preparing a Bottle Without the Adapter Already Inserted:

• Store the bottle in the refrigerator prior to first use.
• Remove the bottle from the refrigerator. Calculate 60 days from when the bottle is removed from the refrigerator. Write this date as the “Discard after” date on the bottle label.
• Allow the bottle to warm to room temperature (30 to 60 minutes).
• Shake the bottle vigorously for at least 20 seconds until the solid cake at the bottom of the bottle is completely dispersed. Check that there are no particles left at the bottom of the bottle. Foam will form in the bottle.
• Insert the bottle adapter.

Preparing a Bottle With the Adapter Inserted:

• Shake the bottle vigorously for at least 5 seconds. Check that there are no particles left at the bottom of the bottle. Foam will form in the bottle.

Measuring and Administering the Dose

Once the bottle is prepared with the adapter:

• Use the oral syringe to measure the dose.
• Keep the bottle upright and insert the oral syringe into the adapter.
• Carefully turn the bottle upside down with the oral syringe in place. Wait for the foam to rise to the top of the bottle.
• Pull back on the syringe plunger to withdraw the dose.
• Leave the syringe in the adapter and turn the bottle upright.
• Remove the syringe from the adapter by gently twisting it out of the bottle.
• Dispense the dose into the patient’s mouth.
• Do not remove the bottle adapter.
• Store the bottle at room temperature (not above 25°C).

Administration of ORFADIN Capsules and Oral Suspension:

• Maintain dietary restriction of tyrosine and phenylalanine when taking ORFADIN.
• Capsules: Take at least one hour before, or two hours after a meal [see Clinical Pharmacology (12.3)]. For patients who have difficulty swallowing the capsules and who are intolerant to the oral suspension [see Warnings and Precautions (5.3)], the capsules may be opened and the contents suspended in a small amount of water, formula or apple sauce immediately before use.
• Oral suspension: Take without regard to meals [see Clinical Pharmacology (12.3)].

Accidental ingestion of ORFADIN by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. In healthy subjects given a single 1 mg/kg dose of nitisinone, the plasma tyrosine level reached a maximum of 1200 micromol/L at 48 to 120 hours after dosing. After a washout period of 14 days, the mean value of plasma tyrosine was still 808 micromol/L. Fasted follow-up samples obtained from volunteers several weeks later showed tyrosine values back to normal. There were no reports of changes in vital signs or laboratory data of any clinical significance. One patient reported sensitivity to sunlight. Hyper-tyrosinemia has been reported with ORFADIN treatment [see Warnings and Precautions (5.1)].

Capsules:

Store refrigerated at 2° to 8°C (36° to 46°F). Alternatively, patients/caregivers may store ORFADIN capsules at room temperature up to 25°C (77°F) for up to 45 days. If not used within 45 days, discard ORFADIN capsules.

Oral suspension:

• Store refrigerated at 2°C to 8°C (36°F to 46°F) prior to first use. Do not freeze. Store upright.
• After first opening, store the product at room temperature (up to 25°C (77°F)) for up to 60 days. If not used within 60 days, discard unused portion. The discard after date should be noted on the bottle