Nitisinone (Monograph)

Drug class:

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Nitisinone is a synthetic, reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme in the tyrosine catabolic pathway.

Uses for Nitisinone

Hereditary Tyrosinemia

Nitisinone is used as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of tyrosinemia type 1 (hereditary tyrosinemia). Tyrosinemia type 1 is caused by a deficiency of fumarylacetoacetase, the final enzyme in the tyrosine catabolic pathway, and is characterized by progressive liver failure, increased risk of hepatocellular carcinoma, coagulopathy, painful neurologic crises, and renal tubular dysfunction that can result in rickets. Nitisinone is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.

In a multicenter, open-label study in approximately 200 pediatric patients (median age: 9 months, range: birth to 21 years) with tyrosinemia type 1, nitisinone reduced urine succinylacetone concentrations to undetectable levels and normalized plasma succinylacetone concentrations and erythrocyte porphobilinogen-synthase activity. Among patients presenting with tyrosinemia type 1 before 2 months of age, nitisinone in conjunction with dietary restrictions produced 2- and 4-year survival rates of 88% each; historical data indicate that 2- and 4-year survival rates for such patients are about 29% each with dietary restrictions alone. Among those presenting with tyrosinemia type 1 before 6 months of age, nitisinone in conjunction with dietary restrictions produced 2- and 4-year survival rates of 94% each; historical data indicate that 2- and 4-year survival rates for such patients are about 74 and 60%, respectively, with dietary restrictions alone. Results from the open-label study also showed substantial reductions in the incidence of early-onset liver failure and of porphyria-like neurologic crises. In a subgroup of patients with renal impairment prior to initiation of nitisinone therapy, indicators of renal function (e.g., urinary excretion of amino acids, serum phosphate concentrations, urinary α₁-microglobulin) were within normal ranges following 1 year of therapy with the drug.

Related/similar drugs

Orfadin, Nityr

Nitisinone Dosage and Administration

General

Nitisinone should be used under the supervision of a qualified clinician experienced in the treatment of tyrosinemia type 1. In addition, dietary management (i.e., a low-protein diet deficient in tyrosine and phenylalanine) should be initiated by an individual experienced in the management of children with inborn errors of metabolism.

Nitisinone is administered orally twice daily in the morning and evening at least 1 hour before meals. The manufacturer states that nitisinone capsules may be opened and the entire contents sprinkled on a small amount of applesauce or suspended in a small amount of water or infant formula immediately prior to administration.

The recommended initial dosage of nitisinone for adults and pediatric patients is 1 mg/kg daily administered in 2 divided doses. Administration of the total daily dosage as 2 unequal doses may be considered as a means of limiting the number of capsules given per dose. If the biochemical parameters (except plasma succinylacetone) (see Laboratory Monitoring under Dosage and Administration: General) are not normalized within 1 month following initiation of nitisinone therapy, the dosage should be increased to 1.5 mg/kg daily. Higher dosages (up to a maximum of 2 mg/kg daily) may be required, especially in infants, once liver function has improved.

Laboratory Monitoring

Plasma nitisinone concentrations, urine and plasma succinylacetone concentrations, urine 5-aminolevulinic acid concentrations, and erythrocyte porphobilinogen-synthase activity were monitored during clinical trials to guide nitisinone dosage adjustments; however, with the exception of urine succinylacetone, these laboratory tests are not routinely available in most clinical settings. Therefore, the manufacturer states that urine succinylacetone concentrations, liver function test results, and plasma concentrations of α-fetoprotein, tyrosine, and phenylalanine may be followed for routine monitoring; however, during initiation of nitisinone therapy and acute exacerbations of tyrosinemia type 1, it may be necessary to monitor more closely all available biochemical parameters.

Plasma α-fetoprotein concentrations should decrease gradually during therapy with nitisinone; increases in α-fetoprotein concentrations may be a sign of inadequate treatment. If exponential increases in plasma α-fetoprotein concentrations occur, the patient should be evaluated promptly for potential liver neoplasm. Platelet and leukocyte counts also should be monitored regularly; serum phosphate concentration should be measured initially in patients with renal involvement to screen for secondary hypophosphatemia and rickets. Plasma tyrosine concentrations should be maintained below 500 µmol/L to reduce the likelihood of adverse effects. (See Plasma Tyrosine Concentrations under Warnings/Precautions: Warnings, in Cautions.)

Special Populations

No special population dosage recommendations at this time.

Cautions for Nitisinone

Contraindications

The manufacturer states that there are no known contraindications to use of nitisinone.

Warnings/Precautions

Warnings

Plasma Tyrosine Concentrations

Elevation of plasma tyrosine concentrations can result from inadequate restriction of tyrosine and phenylalanine intake in patients receiving nitisinone; plasma tyrosine concentrations should be maintained below 500 µmol/L to avoid toxic effects to the eyes, skin, and nervous system. If plasma tyrosine concentrations exceed 500 µmol/L, a more-restricted diet should be implemented; nitisinone dosage should not be adjusted to reduce plasma tyrosine concentrations.

Hematologic Effects

Transient thrombocytopenia and/or leukopenia have been reported in patients receiving nitisinone. Most cases have resolved without nitisinone dosage reduction or interruption of therapy. Platelet and leukocyte counts should be monitored regularly during nitisinone therapy.

General Precautions

Ocular Effects

Corneal ulcers, corneal opacities, keratitis, conjunctivitis, ocular pain, and photophobia have been reported in patients receiving nitisinone. Slit-lamp examination should be performed prior to initiation of nitisinone therapy; patients who develop photophobia, ocular pain, or signs of ocular inflammation (e.g., ocular redness, swelling, burning) during therapy with the drug should be promptly evaluated by slit-lamp examination and by measurement of plasma tyrosine concentration.

Hepatic Effects

Liver failure or hepatic neoplasms may occur in patients with tyrosinemia type 1. Periodic monitoring with imaging studies (ultrasound, computerized tomography, magnetic resonance imaging) and laboratory tests (serum α-fetoprotein) should be performed in patients receiving nitisinone for treatment of tyrosinemia type 1. (See Laboratory Monitoring under Dosage and Administration: General.)

Porphyria

Three episodes of porphyria-like neurologic crises, including one fatality, have been reported in clinical studies in patients receiving nitisinone; an annual incidence of 5–20% has been reported in patients with tyrosinemia type 1.

Specific Populations

Pregnancy

Category C.

Lactation

Nitisinone is distributed into milk in rats. It is not known whether nitisinone is distributed into milk in humans; caution if used in nursing women.

Pediatric Use

Safety and efficacy of nitisinone were evaluated in pediatric patients from birth to 21 years of age.

Geriatric Use

Safety and efficacy of nitisinone have not been established in adults 65 years of age or older.

Common Adverse Effects

Adverse effects occurring in 1% or more of patients receiving nitisinone include hepatic neoplasms, liver failure, thrombocytopenia, leukopenia, conjunctivitis, corneal opacity, keratitis, photophobia, blepharitis, ocular pain, cataracts, porphyria, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash, and alopecia.

Drug Interactions

The manufacturer states that no drug interaction studies have been conducted to date.

Description

Nitisinone is a synthetic competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with tyrosinemia type 1, nitisinone prevents the formation and accumulation of toxic metabolites that directly affect the liver and kidneys and indirectly (i.e., through inhibition of the porphyrin synthesis pathway) affect the peripheral nerves. The drug is rapidly adsorbed following oral administration. The mean terminal plasma half-life of nitisinone in healthy men is 54 hours. The elimination characteristics of nitisinone, including possible metabolic pathways and/or excretion mechanisms, have not been fully elucidated.

Advice to Patients

Importance of maintaining dietary restriction of tyrosine and phenylalanine during nitisinone therapy for tyrosinemia type 1. Importance of reporting unexplained ocular symptoms, rash, jaundice, or excessive bleeding immediately. Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Reload page with references included

Medical Disclaimer