Nitisinone

A16A - Other alimentary tract and metabolism products ATC A16AX04 Small molecule approved 2002 Oral First-in-class

JFDA label: Orfadin 5mg Hard Capsules

Mechanism of Action

Inhibitor of 4-hydroxyphenylpyruvate dioxygenase — 4-hydroxyphenylpyruvate dioxygenase inhibitor

Target	Action	Gene / class
4-hydroxyphenylpyruvate dioxygenase efficacy	INHIBITOR	HPD

Indications

Approved

Hereditary tyrosinemia type 1

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Hypersensitivity to nitisinone or any component of the formulation Absolute
There are no contraindications listed in the manufacturer's labeling Absolute
breastfeeding Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Hepatobiliary disorders (2)

Common Hepatic failure · hepatic neoplasm

Blood and lymphatic system disorders (3)

Common granulocytopenia · Leukopenia · thrombocytopenia

Metabolism and nutrition disorders (2)

Very Common Increased plasma tyrosine

Common Porphyria

Skin and subcutaneous tissue disorders (5)

Common Alopecia · exfoliative dermatitis · maculopapular rash · pruritus · xeroderma

Eye disorders (7)

Common blepharitis · cataract · Conjunctivitis · corneal opacity · eye pain · keratitis · photophobia

Respiratory, thoracic and mediastinal disorders (1)

Common Epistaxis

Dosing

Source: Lexicomp

Note: Must be used in conjunction with a diet restricted in tyrosine and phenylalanine. Titrate dose as needed based on biochemical and/or clinical response. If the biochemical response is satisfactory, the dosage should be adjusted only according to body weight gain. Do not adjust dose according to plasma tyrosine concentration. Hereditary tyrosinemia type 1 (HT-1): Oral: Initial: 0.5 mg/kg twice daily. Increase to 0.75 mg/kg twice daily if succinylacetone is detectable 4 weeks after initiation. Further increase may be needed based on the evaluation of all biochemical parameters (maximum dose: 2 mg/kg/day); dose may be administered once daily (eg, 1 to 2 mg/kg once daily) if serum and urine succinylacetone is undetectable after ≥4 weeks of therapy.

(For additional information see "Nitisinone: Pediatric drug information") Note: Must be used in conjunction with a diet restricted in tyrosine and phenylalanine. Titrate dose as needed based on biochemical and/or clinical response. If the biochemical response is satisfactory, the dosage should be adjusted only according to body weight gain. Do not adjust dose according to plasma tyrosine concentration. Hereditary tyrosinemia type 1 (HT-1): Oral: Infants and Children Children ≥5 years and Adolescents: Refer to adult dosing.

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer's labeling.

Warnings & Precautions

Source: Lexicomp

Dermatologic effects

Failure to adequately restrict dietary tyrosine and phenylalanine may lead to hyperkeratotic plaques on the soles and palms.

Hematologic effects

Leukopenia and/or thrombocytopenia have been reported; may improve with dose reduction. May be due to underlying liver disease rather than drug-related (McKiernan 2006). Monitor platelets and WBC regularly during therapy.

Neurological effects

Failure to adequately restrict dietary tyrosine and phenylalanine may lead to variable degrees of intellectual disability and developmental delay; clinical laboratory assessment including tyrosine levels is recommended for any patient exhibiting abrupt changes in neurological status while on therapy.

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 in patients who develop photophobia, eye pain, 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. Dosage form specific issues:

Glycerol

Oral suspension contains 500 mg/mL of glycerol; oral doses of glycerol ≥10 g may cause headache, upset stomach, and diarrhea. Patients receiving single doses >20 mL are at increased risk for these adverse reactions; consider switching patients unable to tolerate the oral suspension to nitisinone capsules. Other warnings/precautions:

Dietary restrictions

Must be used with dietary restriction of tyrosine and phenylalanine; inadequate restriction can result in toxic effects to the eyes, skin, and nervous system. Evaluate plasma tyrosine concentrations in patients who develop signs and symptoms of toxicity. Nutritional consultation is recommended.

Pregnancy & Lactation

Pregnancy

Adverse events have been observed in animal reproduction studies.

Lactation

It is not known if nitisinone is present in breast milk. According to the manufacturer, 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, and the benefits of treatment to the mother.

Monitoring

Clinical pearl	Dietary tyrosine and phenylalanine (assess dietary intake with tyrosine concentrations >500 micromole/L); urine and/or 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 monitor urine 5-aminolevulinate and erythrocyte porphobilinogen-synthase activity); body weight; slit-lamp examination (prior to initiation of therapy and in patients who develop symptoms of ocular toxicity); plasma tyrosine (as clinically indicated with side effects; concentrations should be kept Note: Plasma succinylacetone may take up to 3 months to normalize after start of therapy.

Clinical pearl

Dietary tyrosine and phenylalanine (assess dietary intake with tyrosine concentrations >500 micromole/L); urine and/or 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 monitor urine 5-aminolevulinate and erythrocyte porphobilinogen-synthase activity); body weight; slit-lamp examination (prior to initiation of therapy and in patients who develop symptoms of ocular toxicity); plasma tyrosine (as clinically indicated with side effects; concentrations should be kept Note: Plasma succinylacetone may take up to 3 months to normalize after start of therapy.

Chemistry & Properties

Formula	C14H10F3NO5
Molecular weight	329.23 g/mol
IUPAC name	2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione
CAS	104206-65-7
PubChem CID	115355
InChIKey	`OUBCNLGXQFSTLU-UHFFFAOYSA-N`
logP	2.73 (XLogP 2.3)
Polar surface area	94.35 Å²
H-bond acceptors / donors	5 / 0
Drug-likeness (QED)	0.37
Lipinski violations	0

SMILES

O=C1CCCC(=O)C1C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OAT1 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Siponimod	major
Abametapir (topical)	moderate
Abiraterone	moderate
Acetohexamide	moderate
Aldesleukin	moderate
Aminoglutethimide	moderate
Amiodarone	moderate
Amlodipine	moderate
Amobarbital	moderate
Amprenavir	moderate
Apalutamide	moderate
Aprepitant	moderate
Atazanavir	moderate
Avatrombopag	moderate
Baricitinib	moderate
Berotralstat	moderate
Bexarotene	moderate
Bicalutamide	moderate
Boceprevir	moderate
Bosentan	moderate
Brigatinib	moderate
Bromocriptine	moderate
Butabarbital	moderate
Butalbital	moderate
Carbamazepine	moderate
Carvedilol	moderate
Celecoxib	moderate
Cenobamate	moderate
Ceritinib	moderate
Chloramphenicol	moderate
Chlorpropamide	moderate
Cimetidine	moderate
Ciprofloxacin	moderate
Clarithromycin	moderate
Clofarabine	moderate
Clotrimazole	moderate
Cobicistat	moderate
Conivaptan	moderate
Crizotinib	moderate
Cyclophosphamide	moderate

Showing 40 of 100+.

Registered Products (4)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Orfadin 20mg Hard Capsule	Capsule 20 mg	60 cap	Horizon Drug Store	—
Orfadin 5mg Hard Capsules	Capsule 5 mg	60 cap	Horizon Drug Store	—
Tisinon	Capsule 5 mg	60 cap	Ibn Rushd Drug Store	—
Tisinon	Capsule 10 mg	60 cap	Ibn Rushd Drug Store	—