Nitisinone

Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate.

• 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. ORFADIN is a hydroxy-phenylpyruvate dioxygenase inhibitor 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.

• None.contraindicated

Recommended Dosage ( 2.1 ) : 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. Preparation and Administration Instructions ( 2.2 ) : 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. 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 )] .

Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques : Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine, which at levels above 500 micromol/L can result in symptoms, intellectual disability and developmental delay or painful hyperkeratotic plaques on the soles and palms; do not adjust ORFADIN dosage in order to lower the plasma tyrosine concentration. Obtain slit-lamp examination prior to treatment, regularly during treatment; 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. ( 5.1 ) Leukopenia and Severe Thrombocytopenia : Monitor platelet and white blood cell counts. ( 5.2 ) Risk of Adverse Reactions Due to Glycerol Content of ORFADIN Oral Suspension : Doses of 20 mL of ORFADIN oral suspension may cause headache, upset stomach and diarrhea due to the glycerol content. Consider switching patients to ORFADIN capsules. ( 5.3 ) 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.

Most common adverse reactions (>1%) 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Swedish Orphan Biovitrum at 1-866-773-5274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ORFADIN was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of ORFADIN was 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, biochemical, and enzyme markers. The recommended starting dosage of ORFADIN is 0.5 mg/kg twice daily [see Dosage and Administration ( 2.1 )] . Median duration of treatment was 22 months (range 0.1 to 80 months). The most serious adverse reactions reported during ORFADIN treatment were thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels [see Warnings and Precautions ( 5.1 , 5.2 )] .

8.1 Pregnancy Risk Summary 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 [see Data ] . 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. Data Animal Data 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.

Metabolism

The single-dose pharmacokinetics of nitisinone have been studied for both ORFADIN capsules and ORFADIN oral suspension in healthy adult subjects and the multiple-dose pharmacokinetics have been studied for ORFADIN capsules in healthy subjects. Absorption The pharmacokinetic characteristics following single oral administration of ORFADIN 30 mg under fasting conditions are shown in Table 3 .

Accidental ingestion of ORFADIN by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. In healthy subjects given a single 1 mg/kg dose of nitisinone, the plasma tyrosine level reached a maximum of 1200 micromol/L at 48 to 120 hours after dosing. After a washout period of 14 days, the mean value of plasma tyrosine was still 808 micromol/L. Fasted follow-up samples obtained from volunteers several weeks later showed tyrosine values back to normal. There were no reports of changes in vital signs or laboratory data of any clinical significance. One patient reported sensitivity to sunlight. Hyper-tyrosinemia has been reported with ORFADIN treatment [see Warnings and Precautions ( 5.1 )] .

• Jan 18, 2002NDANDA021232Swedish Orphan
• Apr 22, 2016NDANDA206356Swedish Orphan
• Jul 26, 2017NDANDA209449Cycle
• Aug 26, 2019ANDAANDA211041Novitium Pharma
• May 26, 2022ANDAANDA212390Medunik
• May 25, 2023ANDAANDA216201Eton

1. 1Amino Acid Level Increased13314%
2. 2Liver Transplant11813%
3. 3Hepatocellular Carcinoma616.5%
4. 4Alpha 1 Foetoprotein Increased525.5%
5. 5Treatment Noncompliance505.3%
6. 6Off Label Use485.1%
7. 7Cataract475.0%
8. 8Hepatic Failure454.8%
9. 9Death394.1%
10. 10Hepatic Cirrhosis373.9%
11. 11Vomiting373.9%
12. 12Succinylacetone Increased353.7%
13. 13Lenticular Opacities343.6%
14. 14Abdominal Pain293.1%
15. 15Drug Ineffective242.5%

The 10 most recently updated of 17 ClinicalTrials.gov registrations naming Nitisinone as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• A Non-interventional, Post-Marketing Study to Describe Outcome of Nitisinone Treatment in HT-1 Patients
  Withdrawn · Observational · 0 enrolled · Swedish Orphan Biovitrum
  NCT06227429updated 2025-12-23
• Long Term Safety Study of Orfadin Treatment in HT-1 Patients in Standard Clinical Care
  Completed · Observational · 315 enrolled · Swedish Orphan Biovitrum
  NCT02320084updated 2024-09-19
• Bioequivalence of Orfadin 20 mg Compared to Orfadin 10 mg Capsules.
  Completed · Phase 1 · Interventional · 12 enrolled · Swedish Orphan Biovitrum
  NCT01857362updated 2021-10-12
• Long-Term Study of Nitisinone to Treat Alkaptonuria
  Completed · Phase 2 · Interventional · 40 enrolled · National Human Genome Research Institute (NHGRI)
  NCT00107783updated 2021-08-26
• Nitisinone (NTBC) In Different Age Groups Of Patients With Alkaptonuria
  Completed · Phase 2 · Phase 3 · Interventional · 8 enrolled · University of California, San Diego
  NCT01390077updated 2021-04-22
• Bio Equivalency 20 Mgm Orfadin and 20 Mgm of Nitisonine
  Unknown · Interventional · 4 enrolled · Sutphin Drugs
  NCT04113772updated 2019-10-03
• Nitisinone for Type 1B Oculocutaneous Albinism
  Completed · Phase 1 · Phase 2 · Interventional · 5 enrolled · National Eye Institute (NEI)
  NCT01838655updated 2019-02-26
• Suitability of Nitisinone in Alkaptonuria 2
  Unknown · Phase 3 · Interventional · 140 enrolled · University of Liverpool
  NCT01916382updated 2018-05-31
• A Study to Investigate the Potential Influence of Nitisinone on the Metabolism and the Transport of Other Drugs in Healthy Volunteers
  Completed · Phase 1 · Interventional · 36 enrolled · Swedish Orphan Biovitrum
  NCT03103568updated 2017-08-10
• Bioequivalence Study of Two Oral Nitisinone Formulations to Treat Hereditary Tyrosinemia (HT-1)
  Completed · Phase 1 · Interventional · 24 enrolled · Cycle Pharmaceuticals Ltd.
  NCT02750345updated 2017-06-14

Frequently asked questions

How does Nitisinone work?

Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate.

What is Nitisinone used for?

According to FDA labeling, Nitisinone carries indications including: 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. ORFADIN is a hydroxy-phenylpyruvate dioxygenase inhibitor 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.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Nitisinone?

Nitisinone is classified as Various alimentary tract and metabolism products, 4-Hydroxyphenyl-Pyruvate Dioxygenase Inhibitor, Cytochrome P450 2C9 Inhibitors, Cytochrome P450 2E1 Inducers, Hydroxyphenylpyruvate Dioxygenase Inhibitors, Organic Anion Transporter 1 Inhibitors, Organic Anion Transporter 3 Inhibitors, Decreased Amino Acid Synthesis.

What are the brand names for Nitisinone?

Nitisinone is marketed under brand names including Harliku, Nityr, Orfadin.

What are the contraindications for Nitisinone?

Nitisinone labeling lists contraindications including: None.. Always consult the full prescribing information and a clinician.