Nitisinone is a medication primarily used for the treatment of a rare genetic disorder called hereditary tyrosinemia type 1 (HT-1). This condition affects the body's ability to break down the amino acid tyrosine, leading to a buildup of toxic byproducts which can cause liver and kidney damage, as well as other serious health issues.

Nitisinone works by inhibiting an enzyme called 4-hydroxyphenylpyruvate dioxygenase (HPPD), which is involved in the production of toxic byproducts from tyrosine metabolism. By inhibiting this enzyme, nitisinone helps reduce the buildup of toxic metabolites and can improve the symptoms and outcomes of HT-1.

Nitisinone (Generic) (Orfadin - Brand) is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase. It is used to slow the effects of hereditary tyrosinemia type 1 in patients with the disease.

Nitisinone Uses:

• Hereditary tyrosinemia type 1:
  • As an adjunct to dietary restriction of tyrosine & phenylalanine, treatment of hereditary tyrosinemia type 1 (HT-1)  in adult & pediatric patients.

Nitisinone (Orfadin) Dose in Adult

Note:

• Nitisinone is a medicine used for treating a rare condition called hereditary tyrosinemia type 1 (HT-1).
• HT-1 makes it hard for the body to break down a certain amino acid, which can cause liver and kidney problems.
• Nitisinone helps by stopping the production of harmful substances from this amino acid.
• It's important to follow a special diet low in certain amino acids while taking nitisinone.
• Your doctor will adjust the dose based on how well it's working for you, especially by watching your body weight.
• Don't change the dose based on your blood test results alone.

Nitisinone (Orfadin) Dose in the treatment of Hereditary tyrosinemia type 1 (HT-1):

• In treating Hereditary tyrosinemia type 1 (HT-1) with Nitisinone, the initial dose is 0.5 milligrams per kilogram of body weight taken orally twice a day.
• If a substance called succinylacetone is still detectable in the body after 4 weeks, the dose may be increased to 0.75 milligrams per kilogram twice daily.
• Depending on how the body responds to treatment, further adjustments may be necessary, but the maximum dose should not exceed 2 milligrams per kilogram per day.
• In some cases, the dose may be given just once a day (for example, 1 to 2 milligrams per kilogram once daily) if succinylacetone is undetectable in both blood and urine after at least 4 weeks of therapy.

Nitisinone (Orfadin) Dose in Children

Note:

• It must be used in conjunction with a diet restricted in tyrosine & phenylalanine.
• Round calculated dose up to the nearest available tablet strength if using tablets

Nitisinone (Orfadin) Dose in the treatment of Hereditary tyrosinemia type 1 (HT-1):

• In treating Hereditary tyrosinemia type 1 (HT-1) with Nitisinone, the initial dose for infants, children, and adolescents is 0.5 milligrams per kilogram of body weight taken orally twice daily.
• Doctors will adjust the dose based on various factors such as biochemical markers and the patient's response to treatment.
• If succinylacetone, a specific marker, is still detectable after 1 month, the dose may be increased to 0.75 milligrams per kilogram twice daily, and further increases may be done as needed, but not exceeding 1 milligram per kilogram twice daily, with a maximum daily dose of 2 milligrams per kilogram.
• Once a satisfactory response is achieved, dose adjustments should primarily be based on body weight gain.
• For patients aged 5 years and older using capsules or oral suspension, the daily dose may be shifted to once daily if succinylacetone is undetectable in both blood and urine after at least 4 weeks of stable therapy.

Pregnancy Risk Category: C

• Adverse events have been noted in animal reproduction studies of Nitisinone.
• This suggests potential risks to pregnant individuals and their developing fetuses.
• It's essential for pregnant individuals or those planning to become pregnant to discuss the potential risks and benefits of using Nitisinone with their healthcare provider.
• Alternative treatment options may be considered to minimize potential harm during pregnancy.

Nitisinone use during breastfeeding:

• The presence of Nitisinone in breast milk is not confirmed.
• According to the manufacturer, the decision regarding breastfeeding during therapy should carefully consider the potential risk of exposing the infant to the medication, the benefits of breastfeeding for the infant, and the advantages of treatment for the mother.

Nitisinone (Orfadin) Dose in Kidney Disease:

• The manufacturer's labeling for Nitisinone does not include specific dosage adjustments for individuals with renal impairment.
• This suggests that no dose modifications are recommended based solely on kidney function.

Nitisinone (Orfadin) Dose in Liver disease:

• The manufacturer's labeling for Nitisinone does not include specific dosage adjustments for individuals with hepatic impairment.
• This implies that no dose modifications are recommended based solely on liver function.

Common Side Effects of Nitisinone (Orfadin):

• Endocrine & metabolic:
  • Increased plasma tyrosine

Less Common Side Effects of Nitisinone (Orfadin):

• Dermatologic:
  • Alopecia
  • Exfoliative Dermatitis
  • Maculopapular Rash
  • Pruritus
  • Xeroderma
• Endocrine & Metabolic:
  • Porphyria
• Hematologic & Oncologic:
  • Leukopenia
  • Thrombocytopenia
  • Granulocytopenia
• Hepatic:
  • Hepatic Failure
  • Hepatic Neoplasm
• Ophthalmic:
  • Conjunctivitis
  • Corneal Opacity
  • Keratitis
  • Photophobia
  • Blepharitis
  • Cataract
  • Eye Pain
• Respiratory:
  • Epistaxis

Contraindication to Nitisinone (Orfadin):

• In the manufacturer's labeling, there are no reasons stated where you can't use the medication.
• However, in Canada, they add some extra reasons you shouldn't use it, like if you're allergic to nitisinone or any part of the medicine, or if you're breastfeeding.

Warnings and Precautions

Dermatologic effects:

• If you don't follow the diet that limits tyrosine and phenylalanine while taking nitisinone, you might develop thickened patches on the soles of your feet and palms of your hands, called hyperkeratotic plaques.
• It's essential to stick to the prescribed diet to avoid these skin problems.

Hematologic effects:

• Some people taking nitisinone may experience low levels of white blood cells (leukopenia) and/or low levels of platelets (thrombocytopenia).
• If this happens, reducing the dose of nitisinone might help improve these blood cell counts.
• It's important to monitor your platelet and white blood cell counts regularly while you're on this medication.
• However, it's worth noting that these effects might be related to liver issues rather than the medication itself.

Neurological effects:

• If you don't follow the diet that limits tyrosine and phenylalanine while taking nitisinone, it could cause different levels of intellectual disability and developmental delay.
• If you notice sudden changes in your neurological status while on this therapy, it's essential to get your tyrosine levels checked along with other clinical assessments.

Ocular effects:

• If you don't follow the diet that limits tyrosine and phenylalanine while taking nitisinone, it could lead to eye problems like conjunctivitis, corneal ulcers, and sensitivity to light (photophobia).
• Before starting the treatment and regularly afterwards, your doctor may check your eyes using a special microscope called a slit lamp.
• If you experience eye pain, sensitivity to light, or signs of inflammation, it's important to let your doctor know.
• They may also measure your tyrosine levels in the blood right away if you have any eye symptoms.
• This helps your doctor monitor your eye health and adjust your treatment as needed.

Nitisinone: Drug Interaction

Monitoring parameters:

• Dietary Intake of Tyrosine and Phenylalanine
  • Check the amount of tyrosine in your diet, especially if it's higher than 500 mcmol/L.
• Succinylacetone Levels
  • Monitor urine and/or plasma succinylacetone regularly.
• Liver Function and Alpha-fetoprotein Levels
  • Keep an eye on liver function parameters and alpha-fetoprotein levels.
  • Consider monitoring urine 5-aminolevulinate and erythrocyte porphobilinogen-synthase activity at initiation or if the patient's condition worsens.
• Body Weight
  • Keep track of your body weight regularly.
• Eye Examination
  • Before starting treatment and regularly thereafter, get your eyes checked with a slit-lamp examination.
  • If you develop symptoms of eye problems, see your doctor promptly.
• Plasma Tyrosine Levels
  • Measure plasma tyrosine levels if you experience side effects.
  • Aim to keep concentrations below 500 mcmol/L to avoid toxicity.
• Platelet and White Blood Cell Counts
  • Monitor these counts regularly during therapy.

Note: It may take up to 3 months for plasma succinylacetone levels to normalize after starting therapy.

How to administer Nitisinone (Orfadin)?

• Capsules
  • Take capsules at least 1 hour before or 2 hours after a meal.
  • If needed, open capsules and mix the contents with a small amount of water, formula, or applesauce. Administer immediately.
• Suspension
  • Administer suspension without considering meals.
  • Allow the suspension to warm to room temperature (30 to 60 minutes) before preparation.
• Tablets
  • Administer tablets without considering meals.
  • Tablets may be dissolved in water and given with an oral syringe or crushed and mixed with applesauce. Avoid mixing with other liquids or foods.

Refer to the manufacturer's labeling for detailed instructions.

Mechanism of action of Nitisinone (Orfadin):

• In patients with Hereditary tyrosinemia type 1 (HT-1), the breakdown of tyrosine is disrupted because they lack an enzyme called fumarylacetoacetate hydrolase, which is crucial in the last step of tyrosine degradation.
• This interruption leads to the accumulation of harmful substances from tyrosine, causing damage to the liver and kidneys.
• Nitisinone works by competitively inhibiting an enzyme called 4-hydroxyphenylpyruvate dioxygenase, which is involved early in the tyrosine breakdown process.
• By doing so, it prevents the buildup of these toxic substances, helping to alleviate the liver and kidney toxicity associated with HT-1.
• It's important to note that there are limited studies on how nitisinone behaves in children or patients with HT-1 from a pharmacokinetic standpoint.

Volume of Distribution (V):

• In healthy volunteers, it's about 8.2 liters.

Protein Binding:

• More than 95% of nitisinone is bound to proteins in the blood.

Metabolism:

• It undergoes minor metabolism, possibly through the CYP3A4 enzyme.

Elimination Half-Life:

• In healthy volunteers, the terminal half-life is approximately 54 hours for capsules and suspension, and 59.3 hours for tablets.

Time to Peak Concentration:

• For healthy volunteers, after taking a single 30 mg dose:
  • Capsule: Median time to peak is 3.5 hours.
  • Suspension: Median time to peak is 0.4 hours.
  • Tablet: Median time to peak is 3.5 hours after taking a single 10 mg dose.

Excretion:

• In healthy volunteers, approximately 3% of the drug is excreted unchanged in urine.

These details help understand how nitisinone is distributed, metabolized, and eliminated in the body, as well as the time it takes to reach peak concentration after administration.

International Brands of Nitisinone:

• Orfadin
• MDK-Nitisinone
• Nityr

Nitisinone Brand Names in Pakistan:

No Brands Available in Pakistan.