What are NITYR (nitisinone) Tablets?

INDICATIONS

NITYR® (nitisinone) Tablets are a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase 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.

IMPORTANT SAFETY INFORMATION

Do not prescribe NITYR to patients allergic to nitisinone or any other ingredients.

WARNINGS AND PRECAUTIONS:

Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques Due to Elevated Plasma Tyrosine Levels:

Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine and levels above 500 micromol/L may lead to ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia; intellectual disability and developmental delay; or painful hyperkeratotic plaques on the soles and palms.

Do not adjust the NITYR dosage in order to lower the plasma tyrosine concentration.
Obtain slit-lamp examination prior to treatment and regularly thereafter. Reexamine patients if symptoms develop or tyrosine levels are > 500 micromol/L. Assess plasma tyrosine levels in patients with an abrupt change in neurologic status.
Perform a clinical laboratory assessment, including plasma tyrosine levels, in patients with an abrupt change in neurologic status.

Leukopenia and Severe Thrombocytopenia:

Monitor platelet and white blood cell counts.

ADVERSE REACTIONS:

The most common adverse reactions (≥1%) reported in patients with HT-1 taking nitisinone in the clinical trials are elevated tyrosine levels, thrombocytopenia, leukopenia, conjunctivitis, corneal opacity, keratitis, photophobia, eye pain, blepharitis, cataracts, granulocytopenia, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash, and alopecia.
Adverse reactions reported in less than 1% of the patients, included death, seizure, brain tumor, encephalopathy, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastrointestinal hemorrhage, melena, elevated hepatic enzymes, liver enlargement, hypoglycemia, septicemia, and bronchitis.

DRUG INTERACTIONS:

Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer and an inhibitor of OAT1/OAT3.
Potential clinical impact of concomitant administration with CYP2C9 Substrates: increased systemic exposure of co-administered drugs metabolized by CYP2C9. Prevention or Management: reduce the dosage of the of co-administered drugs metabolized by CYP2C9 by half. Additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs.
Potential clinical impact of concomitant administration with OAT1/OAT3 Substrates: increased exposure of these co-administered drugs. Prevention or Management: monitor for potential adverse reactions.

USE IN SPECIFIC POPULATIONS:

Pregnancy: Limited available data with nitisinone use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes.

Lactation: The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NITYR and any potential adverse effects on the breastfed infant from NITYR or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of nitisinone have been established for the treatment of HT-1 in combination with dietary restriction of tyrosine and phenylalanine in pediatric patients. Use of NITYR for this indication is supported by evidence from one open-label, uncontrolled clinical study conducted with another oral formulation of nitisinone in 207 patients with HT-1 ages 0 to 22 years (median age 9 months).

Geriatric Use: Clinical studies of nitisinone did not include any subjects aged 65 and over. No pharmacokinetic studies of nitisinone have been performed in geriatric patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this patient population.

For more detailed information, please refer to the full Prescribing Information at www.nityr.com/pi.

To report SUSPECTED ADVERSE REACTIONS contact Cycle Pharmaceuticals Ltd at: 1-855-831-5413, or the FDA at: 1-800-FDA-1088 or www.fda.gov/medwatch.