Nitisinone

Nitisinone is a prescription medication used for the treatment of hereditary tyrosinemia type 1 (HT-1) as an adjunct to dietary restriction of tyrosine and phenylalanine.

• Nitisinone is available under the following different brand names: Orfadin, Nityr

Common side effects of Nitisinone include:

• vision changes,
• light sensitivity,
• eye pain,
• red or puffy eyes,
• nosebleeds,
• increased sensitivity of the eyes to light,
• rash,
• itching,
• dry or peeling skin, and
• thinning hair

Serious side effects of Nitisinone include:

• hives,
• difficulty breathing,
• swelling of the face, lips, tongue, or throat,
• sudden change in behavior, ability, or development (sitting up, crawling, walking, talking),
• easy bruising,
• unusual bleeding (nose, mouth, vagina, or rectum),
• purple or red pinpoint spots under the skin,
• nausea,
• diarrhea,
• upper stomach pain,
• itching,
• loss of appetite,
• dark urine,
• clay-colored stools,
• yellowing of the skin or eyes (jaundice),
• vision problems,
• eye pain,
• redness or swelling, burning, white or yellow patches on the eyes, and
• calluses, peeling, or hardened skin on the palms of the hands or the soles of the feet

Rare side effects of Nitisinone include:

• none

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors;
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out. 

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult and pediatric dosage

Capsule (Orfadin)

• 2 mg
• 5 mg
• 10 mg
• 20 mg

Oral suspension (Orfadin)

• 4 mg/mL

Tablet (Nityr)

• 2 mg
• 5 mg
• 10 mg

Hereditary Tyrosinemia Type 1

Adult and pediatric dosage

• Starting dose: 0.5 mg/kg orally every 12 hours (morning and evening); titrate dose based on biochemical and/or clinical response, as described in the full prescribing information  
• Succinylacetone detectable in blood or urine 4 weeks after initiating: May increase to 0.75 mg/kg every 12 hours; maximum total daily dose (TDD) of 2 mg/kg may be needed based on evaluation of all biochemical parameters
• Undetectable serum and urine succinylacetone concentrations after at least 4 weeks on stable dose: TDD may be given once daily (eg, 1-2 mg/kg every day

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Nitisinone has severe interactions with no other drugs.
• Nitisinone has serious interactions with the following drugs:
  • erdafitinib
  • siponimod
• Nitisinone has moderate interactions with at least 32 other drugs.
• Nitisinone has minor interactions with no other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all your products. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• None

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Nitisinone?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Nitisinone?”

Cautions

• May develop transient leukopenia, thrombocytopenia, or both; monitor CBC during therapy
• Increase tyrosine levels
• May cause an increase in plasma tyrosine levels in patients with HT-1
• Maintain concomitant reduction in dietary tyrosine and phenylalanine during treatment
• Inadequate restriction of tyrosine and phenylalanine may lead to elevated plasma levels of tyrosine
• Do not adjust dosage in order to lower plasma tyrosine concentration; maintain plasma tyrosine levels below 500 micromol/L
• In patients with HT-1 treated with dietary restrictions and receive therapy who develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake
• Tyrosine levels more than 500 mmol/L may lead to:
  • Variable degrees of intellectual disability and developmental delay; perform a clinical assessment if abrupt changes in neurologic status occur OR
  • Painful hyperkeratotic plaques on the soles and palms OR
  • Ocular signs and symptoms (e.g., corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, photophobia); rerform a baseline ophthalmologic examination including slit-lamp examination prior to initiating treatment and regularly thereafter; if photophobia, eye pain, or signs of inflammation develops or tyrosine levels are more than 500 micromol/L during treatment, undergo slit-lamp reexamination and immediately measure plasma tyrosine concentration
• Glycerol content in oral suspension
  • Doses of 20 mL of oral suspension (10 g glycerol) may cause headache, upset stomach and diarrhea due to glycerol content
  • Oral suspension contains 500 mg/mL of glycerol
    • Consider switching patients who are unable to tolerate the oral suspension to the oral capsules (see Administration)
• Drug interaction overview
  • Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer, and an OAT1/OAT3 inhibitor
  • Sensitive CYP2C9 substrates or CYP2C9 substrates with a narrow therapeutic index
  • Nitisinone increases exposure of CYP2C9 substrates
  • Reduce dose of coadministered CYP2C9 substrates drug by half
  • Additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs; see prescribing information for those drugs
  • OAT1/OAT3 substrates
    • Nitisinone increases exposure of OAT1/OAT3 substrate Monitor for potential adverse reactions related to coadministered drug

Pregnancy and Lactation

• Limited data on use in pregnant women insufficiently informs a drug-associated risk of major birth defects and miscarriage
• Lactation
  • No data on the presence of enasidenib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production
  • Data suggest that nitisinone may be present in rat milk due ocular toxicity and lower body weight seen in drug naïve pups; consult women of the risk versus benefits for nitisinone and any potential adverse effects on breastfed infant from nitisinone