Nitisinone (Generic) (Orfadin - Brand) is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase. It is used to slow the effects of hereditary tyrosinemia type 1 in patients with the disease.

Nitisinone Uses:

• Hereditary tyrosinemia type 1:

  • As an adjunct to dietary restriction of tyrosine & phenylalanine, treatment of hereditary tyrosinemia type 1 (HT-1)  in adult & pediatric patients.

Nitisinone (Orfadin) Dose in Adults

Note:

• Must be used in conjunction with a diet restricted in tyrosine & phenylalanine.
• Titrate dose as required based on biochemical & clinical response.
• The dosage should be adjusted only according to body weight gain if the biochemical response is satisfactory.
• Do not adjust the dose according to plasma tyrosine concentration.

Nitisinone (Orfadin) Dose in the treatment of Hereditary tyrosinemia type 1 (HT-1):

• 0.5 milligram per kilogram orally twice a day initially
• If succinylacetone is detectable 4 weeks after initiation, Increase to 0.75 milligrams per kilogram twice a day.
• Based on the evaluation of all biochemical parameters, a further increase may be needed (max dose: 2 milligrams per kilogram per day).
• If serum and urine succinylacetone is undetectable after ≥4 weeks of therapy, the dose may be administered once daily (eg, 1-2 mg per kg once daily)

Nitisinone (Orfadin) Dose in Children

Note:

• It must be used in conjunction with a diet restricted in tyrosine & phenylalanine.
• Round calculated dose up to the nearest available tablet strength if using tablets

Nitisinone (Orfadin) Dose in the treatment of Hereditary tyrosinemia type 1 (HT-1):

• Infants, Children, and Adolescents:

  • 0.5 milligram per kg per dose orally twice daily initially.
  • Based on biochemical markers (eg, plasma and/or urine succinylacetone concentrations, liver function parameters and alpha-fetoprotein concentrations) and clinical response, titrate dose individually.
  • If succinylacetone concentrations are still detectable after 1 month of therapy, may increase dose to 0.75 milligrams/kilogram/dose twice daily.
  • May further increase as needed up to a max of one milligram/kilogram/dose twice daily.
  • max daily dose: 2 milligram/kilogram/day.
  • Further dosage adjustments should be only according to body weight gain, once the biochemical response is satisfactory.
  • In patients ≥5 years using capsules or oral suspension, the daily dose may be transitioned to once daily (eg, 1 to 2 milligram/kilogram/dose once daily) if serum & urine succinylacetone is undetectable after ≥4 weeks of stable therapy.

Pregnancy Risk Category: C

• In animal reproduction studies, adverse events have been observed.

Nitisinone use during breastfeeding:

• It is not known if nitisinone is present in breast milk or not.
•  The decision to continue or discontinue breastfeeding during therapy should take into account the risk of exposure to the infant, the benefits of breastfeeding to the infant, & the benefits of treatment to the mother, according to the manufacturer.

Nitisinone (Orfadin) Dose in Kidney Disease:

In the manufacturer's labeling, there are no dosage adjustments provided.

Nitisinone (Orfadin) Dose in Liver disease:

In the manufacturer's labeling, there are no dosage adjustments provided.

Common Side Effects of Nitisinone (Orfadin):

• Endocrine & metabolic:

  • Increased plasma tyrosine

Less Common Side Effects of Nitisinone (Orfadin):

• Dermatologic:

  • Alopecia
  • Exfoliative Dermatitis
  • Maculopapular Rash
  • Pruritus
  • Xeroderma

• Endocrine & Metabolic:

  • Porphyria

• Hematologic & Oncologic:

  • Leukopenia
  • Thrombocytopenia
  • Granulocytopenia

• Hepatic:

  • Hepatic Failure
  • Hepatic Neoplasm

• Ophthalmic:

  • Conjunctivitis
  • Corneal Opacity
  • Keratitis
  • Photophobia
  • Blepharitis
  • Cataract
  • Eye Pain

• Respiratory:

  • Epistaxis

Contraindication to Nitisinone (Orfadin):

• In the manufacturer's labeling, there are no contraindications listed.

Canadian labeling:

• Hypersensitivity to nitisinone or any component of the formulation.
• Breastfeeding.

Warnings and Precautions

• Dermatologic effects:

  • Non-success to adequately restrict dietary tyrosine & phenylalanine may lead to hyperkeratotic plaques on the soles & palms.

• Hematologic effects:

  • Leukopenia & thrombocytopenia have been reported.
  • May improve with a reduced dose.
  • Rather than drug-related, maybe it is due to underlying liver disease.
  • During therapy examine platelets & WBC regularly.

• Neurological effects:

  • Non-success to adequately restrict dietary tyrosine & phenylalanine may lead to variable degrees of intellectual disability & developmental delay.
  • While on therapy, Clinical laboratory assessment including tyrosine levels is recommended for any patient exhibiting abrupt changes in neurological status.

• Ocular effects:

  • Failure to adequately restrict dietary tyrosine and phenylalanine may lead to ocular toxicities (eg, conjunctivitis, corneal ulcers, corneal opacities, eye pain, keratitis, photophobia).
  • Slit-lamp examination of the eyes is recommended prior to initiation of therapy and regularly thereafter & in patients who develop photophobia, eye pain, tyrosine levels >500 micromol/L, or signs of inflammation (eg, redness, swelling, burning of the eyes).
  • Immediate measurement of plasma tyrosine concentration is also recommended in patients who develop ocular symptoms.

Nitisinone: Drug Interaction

Monitoring parameters:

• Dietary tyrosine & phenylalanine (assess dietary intake with tyrosine concentrations greater than 500 micromol/L).
• Urine & plasma succinylacetone, liver function parameters, and alpha-fetoprotein levels (in addition, at initiation or if there is a deterioration of the patient's clinical condition, may also examine urine 5-aminolevulinate and erythrocyte porphobilinogen-synthase activity).
• Bodyweight.
• Slit-lamp examination (prior to initiation of therapy and regularly thereafter, and in patients who develop symptoms of ocular toxicity).
• Plasma tyrosine (as clinically indicated with side effects; concentrations should be kept <500 micromol/L to avoid toxicity).
• Regularly during therapy, Platelet & white blood cell counts.

Note:

•  After the start of therapy, Plasma succinylacetone may take up to three months to normalize.

How to administer Nitisinone (Orfadin)?

Capsules:

• After a meal, administer at least 1 hour prior to, or 2 hours. Capsules may be opened & contents suspended in a small quantity of water, formula, or apple sauce.
• Administer immediately.

Suspension:

• Administer without regard to meals.
• Prior to preparation, allow the suspension to warm to room temperature (30-60 mins).

Tablets:

• Administer without regard to meals.
• Refer to the manufacturer's labeling for detailed instructions.
• Tablets may be disintegrated in water and administered using an oral syringe or crushed and mixed with applesauce (administration with other liquids or foods is not recommended [has not been studied]).

Mechanism of action of Nitisinone (Orfadin):

• In patients with HT-1, tyrosine metabolism is interrupted due to a lack of the enzyme (fumarylacetoacetate hydrolase) required in the last step of tyrosine degradation.
• Liver & kidney toxicity is due to the accumulation of toxic metabolites of tyrosine.
• Preventing the build-up of the toxic metabolites,  Nitisinone competitively inhibits 4hydroxyphenyl-pyruvate dioxygenase, an enzyme present early in the tyrosine degradation pathway.

Protein binding:

• >95 percent

Metabolism:

• Minor metabolism possibly via CYP3A4

Half-life elimination:

• Healthy volunteers: Terminal half-life: Capsule, suspension: 54 hours; Tablet: 59.3 hours

Time to peak:

• Healthy volunteers:
• Capsule:
• Single 30-milligram dose: Median: 3.5 hours (range: 0.8-8 hours)
• Multiple 80-milligram doses: Median: 4 hours (range: 0-16 hours)

Suspension:

• Single 30-milligram dose: Median: 0.4 hours (range: 0.2-4 hours)

Tablet:

• Single 10-milligram dose: Median: 3.5 hours (range: 1-4 hours)

Excretion:

• Healthy volunteers: Urine (3 percent unchanged).

International Brands of Nitisinone:

• Orfadin
• MDK-Nitisinone
• Nityr

Nitisinone Brand Names in Pakistan:

No Brands Available in Pakistan.