ORFADIN

ORFADIN- nitisinone suspension
Swedish Orphan Biovitrum AB (publ)

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

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:

  1. Use the oral syringe to measure the dose.
  2. Keep the bottle upright and insert the oral syringe into the adapter.
  3. Carefully turn the bottle upside down with the oral syringe in place. Wait for the foam to rise to the top of the bottle.
  4. Pull back on the syringe plunger to withdraw the dose.
  5. Leave the syringe in the adapter and turn the bottle upright.
  6. Remove the syringe from the adapter by gently twisting it out of the bottle.
  7. Dispense the dose into the patient’s mouth.
  8. Do not remove the bottle adapter.
  9. 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)] .

3 DOSAGE FORMS AND STRENGTHS

  • 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.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques

Nitisinone is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway [see Clinical Pharmacology ( 12.1)] . 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:

  • Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia have been reported in patients treated with ORFADIN [see Adverse Reactions ( 6.1)] . In a clinical study in a non HT-1 population without dietary restriction and reported tyrosine levels >500 micromol/L both symptomatic and asymptomatic keratopathies have been observed. Therefore, perform a baseline ophthalmologic examination including slit-lamp examination prior to initiating ORFADIN treatment and regularly thereafter. Patients who develop photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning of the eyes or tyrosine levels are > 500 micromol/L during treatment with ORFADIN should undergo slit-lamp reexamination and immediate measurement of the plasma tyrosine concentration.
  • Variable degrees of intellectual disability and developmental delay. In patients treated with ORFADIN who exhibit an abrupt change in neurologic status, perform a clinical laboratory assessment including plasma tyrosine levels.
  • Painful hyperkeratotic plaques on the soles and palms

In patients with HT-1 treated with dietary restrictions and ORFADIN who develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake.

5.2 Leukopenia and Severe Thrombocytopenia

In clinical trials, patients treated with ORFADIN and dietary restriction developed transient leukopenia (3%), thrombocytopenia (3%), or both (1.5%) [see Adverse Reactions ( 6.1)] . No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Monitor platelet and white blood cell counts during ORFADIN therapy.

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