Orfadin
(Nitisinone)Dosage & Administration
The recommended starting dosage of ORFADIN is 0.5 mg/kg administered orally twice daily.
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)
Titrate the dosage in each individual patient based on biochemical and/or clinical response.
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.
Once the bottle is prepared with the adapter:
Take ORFADIN oral suspension without regard to meals.
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Orfadin Prescribing Information
Warnings and Precautions (Nitisinone is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway [see Clinical Pharmacology ] . Therefore, treatment with ORFADIN may cause an increase in plasma tyrosine levels in patients with HT-1. Maintain concomitant reduction in dietary tyrosine and phenylalanine while on ORFADIN treatment. Do not adjust ORFADIN dosage in order to lower the plasma tyrosine concentration. Maintain plasma tyrosine levels below 500 micromol/L. Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine levels and levels greater than 500 micromol/L may lead to the following:
In patients with HT-1 treated with dietary restrictions and ORFADIN who develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake. | 05/2019 |
ORFADIN® is indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.
The recommended starting dosage of ORFADIN is 0.5 mg/kg administered orally twice daily.
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)
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 ]. 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.
- The recommended starting dosage is 0.5 mg/kg orally twice daily.
- 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 may be given once daily.
- Titrate the dosage based on biochemical and/or clinical response, as described in the full prescribing information.
- The maximum total daily dosage is 2 mg/kg orally.
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.
- 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.
- 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.
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).
- 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 ]. For patients who have difficulty swallowing the capsules and who are intolerant to the oral suspension[see Warnings and Precautions ], 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 ].
- For instructions on preparing, measuring and administering the oral suspension, see the full prescribing information.
- Maintain dietary restriction of tyrosine and phenylalanine
- Take ORFADIN capsules at least one hour before, or two hours after a meal
- For patients who have difficulties swallowing capsules and who are intolerant to the oral suspension, the capsules may be opened and the contents suspended in a small amount of water, formula or apple sauce immediately before use.
Take ORFADIN oral suspension without regard to meals.
- Capsules: 2 mg, 5 mg, 10 mg and 20 mg white capsules imprinted with “NTBC” followed by “2 mg”, “5 mg”, “10 mg” or ”20 mg”, indicating the actual amount of nitisinone in each capsule.
- Oral suspension: 4 mg/mL, a white, slightly viscous opaque suspension.
Limited available data with nitisinone use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. Animal reproduction studies have been conducted for nitisinone. In these studies, nitisinone was administered to mice and rabbits during organogenesis with oral doses of nitisinone up to 20 and 8 times respectively, the recommended initial dose of 1 mg/kg/day. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended initial dose, and increased gestational length at doses 4 times the recommended initial dose. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 1.6 times the recommended initial dose
Reproduction studies have been performed in mice at oral doses of about 0.4, 4 and 20 times the recommended initial dose (1 mg/kg/day) and in rabbits at oral doses of about 1.6, 4 and 8 times the recommended initial dose based on the body surface area. In mice, nitisinone has been shown to cause incomplete skeletal ossification of fetal bones at 0.4, 4 and 20 times the recommended initial dose, increased gestational length at 4 and 20 times the recommended initial dose, and decreased pup survival at 0.4 times the recommended initial dose based on the body surface area. In rabbits, nitisinone caused incomplete skeletal ossification of fetal bones at 1.6, 4 and 8 times the recommended initial dose based on the body surface area.
The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
None.