Usual Adult Dose for Hereditary Tyrosinemia Type 1

Dosing should be individualized based on biochemical and/or clinical response; monitor plasma and/or urine succinylacetone concentrations, liver function parameters and alphafetoprotein levels

Initial dose 0.5 mg/kg orally twice a day for 4 weeks, then

• If succinylacetone is still detectable in blood or urine, increase dose to 0.75 mg/kg orally twice a day
• Once succinylacetone concentrations are undetectable, dose adjustments should be based on body weight

Alternative Maintenance Regimen: For patients with undetectable succinylacetone concentrations after a minimum of 4 weeks on a stable dose, the total daily dose may be given once a day
Maintenance Dose: 1 to 2 mg/day
Maximum Dose: 2 mg/day

Comments:

• Tablet dose should be rounded up to the nearest dose that can be administered using the available tablet strengths.
• During initiation of therapy, when switching from twice a day to once daily dosing, or if a patient's condition deteriorates, it may be necessary to follow all available biochemical parameters more closely (i.e, plasma and/or succinylacetone, urine 5-aminolevulinate [ALA], and erythrocyte porphobilinogen [PBG]-synthase activity).
• Plasma tyrosine levels should be maintained below 500 micromol/L by tyrosine and phenylalanine dietary restriction; the dose of this drug should not be adjusted to lower plasma tyrosine concentration.

Use: For the treatment of patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

Usual Pediatric Dose for Hereditary Tyrosinemia Type 1

Dosing should be individualized based on biochemical and/or clinical response; monitor plasma and/or urine succinylacetone concentrations, liver function parameters and alphafetoprotein levels

Initial dose 0.5 mg/kg orally twice a day for 4 weeks, then

• If succinylacetone is still detectable in blood or urine, increase dose to 0.75 mg/kg orally twice a day
• If succinylacetone is undetectable in blood and/or urine, dose adjustments should be based on body weight gain

Maintenance Dose: 1 to 2 mg/day
Maximum Dose: 2 mg/day

5 years or older:
Alternative Maintenance Regimen: For patients with undetectable succinylacetone concentrations after a minimum of 4 weeks on a stable dose, the total daily dose may be given once a day

Comments:

• Tablet dose should be rounded up to the nearest dose that can be administered using the available tablet strengths.
• During initiation of therapy, when switching from twice a day to once daily dosing, or if a patient's condition deteriorates, it may be necessary to follow all available biochemical parameters more closely (i.e, plasma and/or succinylacetone, urine 5-aminolevulinate [ALA], and erythrocyte porphobilinogen [PBG]-synthase activity).
• Plasma tyrosine levels should be maintained below 500 micromol/L by tyrosine and phenylalanine dietary restriction; the dose of this drug should not be adjusted to lower plasma tyrosine concentration.

Use: For the treatment of patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

Renal Dose Adjustments

No adjustment recommended

Liver Dose Adjustments

No adjustment recommended

Precautions

CONTRAINDICATIONS: None

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:
Capsules: Take orally at least 1 hour before or 2 hours after a meal
Tablets and Suspension: Take orally without regards to meals

Preparation Techniques:
CAPSULES: May be opened and contents suspended in a small amount of water, formula, or applesauce; take immediately

ORAL SUSPENSION:

• Prior to first use, store in refrigerator; allow 30 to 60 minutes to warm to room temperature prior to first use
• Shake bottle vigorously to allow solid cake at bottom of the bottle to completely disperse (first use: 20 seconds; subsequent use: 5 seconds); foam will form in bottle
• Insert syringe into adapter in bottle; turn bottle upside down and wait for foam to rise to top of the bottle
• Pull back on plunger to withdraw dose; measure dose with oral syringe; administer immediately
• Store bottle at room temperature with bottle adapter in bottle

TABLETS: Mix with applesauce OR disintegrate in water and administer using oral syringe
With Applesauce (administration with other foods/liquids has not been studied and is not recommended):

• Measure 1 teaspoon of applesauce into clean container
• Crush 1 tablet at a time by positioning tablet between 2 metal teaspoons and apply light pressure on top spoon; should yield a fine powder; transfer to applesauce container
• Mix powder until well dispersed; administer immediately
• To ensure all drug has been administered, add 1 teaspoon of applesauce to container and mix, administer applesauce mixture
• This mixture may be stored at room temperature (protected from light) for 2 hours after adding applesauce to tablet; discard after 2 hours

With Water: Disintegrate in water and administer using an oral syringe:

• Prepare 1 or 2 tablets at once within same oral syringe; if more tablets are needed use multiple oral syringes
• Remove plunger from a 5-mL oral syringe and insert 1 or 2 intact tablets
• Replace plunger and draw up 2.6 mL (1 tablet) or 5 mL (2 tablets) of room temperature water
• Cap oral syringe and leave for at least 60 minutes
• After 60 minutes, turn the oral syringe up and down for at least 30 seconds to suspend material
• Inspect syringe to ensure the tablet has disintegrated, if so, administer immediately
• If not fully disintegrated, leave the oral syringe for an additional 10 minutes, then turn the oral syringe up and down for at least 30 seconds, inspect the syringe and if fully disintegrated, administer immediately; do not administer unless tablet(s) has fully disintegrated
• To administer: Uncap syringe and administer into mouth; avoid depressing the plunger to the end of the oral syringe, rinse by drawing up 2 mL water, cap the syringe and shake well for 10 seconds; uncap and administer this time depressing the plunger and ensuring the syringe is empty; repeat rinsing of oral syringe to remove any remaining particles
• This suspension may be stored at room temperature in the capped oral syringe (protected from light) for up to 24 hours after adding water to the tablets; discard after 24 hours

Storage requirements:

• Capsules: Store refrigerated 2C to 8C (36F to 46F); capsules may be stored at room temperature (up to 25C [77F]) for up to 45 days; discard if not used within 45 days
• Oral suspension: Prior to use: Store refrigerated 2C to 8C (36F to 46F); store upright; do not freeze
• Oral suspension: After first opening, store at room temperature for up to 60 days; discard unused portion
• Tablets: Store at room temperature; protect from light and moisture

General:

• Maintain dietary restriction of tyrosine and phenylalanine during therapy.
• Doses should be titrated individually based on biochemical and/or clinical response.
• If a patients condition deteriorates during therapy, it may be necessary to follow all available biochemical parameters more closely (i.e, plasma succinylacetone, urine 5-aminolevulinate (ALA), and erythrocyte porphobilinogen (PBG)-synthase activity).

MONITORING RECOMMENDATIONS:

• Routinely monitor plasma and/or urine succinylacetone concentrations, liver function parameters and alphafetoprotein levels; if patient deteriorates, monitor plasma succinylacetone, urine 5-aminolevulinate (ALA), and erythrocyte porphobilinogen (PBG)-synthase activity
• HEMATOLOGIC: Monitor platelet and white blood cell count regularly
• HEPATIC: Regularly monitor for porphyric crisis, hepatic neoplasms and liver failure by hepatic imaging (ultrasound, computerized tomography, magnetic resonance imaging) and laboratory tests (including serum alpha-fetoprotein concentration)
• METABOLIC: Maintain plasma tyrosine levels below 500 micromole/L; perform an assessment of dietary tyrosine intake in patients who develop elevated tyrosine levels; monitor blood and urine succinylacetone levels in the children to ensure adequate control
• NERVOUS SYSTEM: Perform a clinical laboratory assessment including plasma tyrosine levels in patients who exhibit abrupt changes in neurological status
• OCULAR: Perform an ophthalmologic exam including slit-lamp prior to starting treatment and regularly thereafter; assess plasma tyrosine levels and perform slit-lamp reexamination if photophobia, eye pain, signs of inflammation (redness, welling, burning) or tyrosine levels exceed 500 micromol/L during therapy

Patient advice:

• Read the US FDA-approved patient labeling (Instructions for Use).
• Patient should understand that inadequate tyrosine and phenylalanine dietary restrictions may be associated with ocular symptoms, intellectual disability and developmental delay, and painful hyperkeratotic plaques on soles and palms.
• Patients should be instructed to report any unexplained ocular or neurologic symptoms, or any other unexplained symptoms to their healthcare provider promptly.
• Patients receiving the oral suspension should report headaches, upset stomach, and diarrhea to their healthcare provider as this may be due to glycerol content of suspension.