Nitisinone

For the treatment of Hereditary Tyrosinemia Type 1 (HT-1), the standard starting dose for adults is typically 1 mg/kg body weight per day, divided into two doses (morning and evening). Depending on the clinical response and the levels of succinylacetone in the blood or urine, the dose may be titrated upward. The maximum recommended dose is generally 2 mg/kg/day.

For Alkaptonuria (AKU), the dosage used in clinical trials (such as the SONIA 2 study) and approved by the EMA is 10 mg once daily. This is a much lower dose than that used for HT-1 because the goal is to reduce homogentisic acid without causing the extreme tyrosinemia seen at higher doses.

Nitisinone is approved for use in pediatric patients of all ages, including neonates. The dosing is strictly weight-based:

• Initial Dose: 1 mg/kg/day divided into two oral doses.
• Titration: If succinylacetone is still detectable after one month of treatment, the dose may be increased to 1.5 mg/kg/day. If it remains detectable after another month, the dose may be increased to a maximum of 2 mg/kg/day.
• Administration: For infants, the oral suspension is preferred. If capsules are used, they can be opened and the contents mixed with a small amount of water or formula immediately before administration.

Renal Impairment

There are no specific dosage adjustment guidelines provided by the manufacturer for patients with renal impairment. However, since nitisinone is used to prevent renal damage in HT-1, and its primary clearance is not purely renal, standard doses are usually employed with close monitoring of kidney function markers.

Hepatic Impairment

Nitisinone has not been specifically studied in patients with pre-existing hepatic impairment unrelated to HT-1. In patients with HT-1 who have severe liver cirrhosis or failure, the drug is still used as it is the primary treatment for the underlying cause, but these patients require intensive monitoring by a hepatologist.

Elderly Patients

Clinical studies of nitisinone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

Nitisinone should be taken exactly as prescribed by a specialist in metabolic diseases.

1. 1Consistency: It can be taken with or without food, but the patient should be consistent. If the patient starts taking it with meals, they should continue that way.
2. 2Capsules vs. Tablets: Capsules should generally be swallowed whole. However, for patients who cannot swallow, capsules may be opened and mixed with a small amount of water, formula, or applesauce. The Nityr tablet brand is often small and can be taken with or without food.
3. 3Suspension: Always shake the oral suspension well before measuring a dose. Use the oral syringe provided by the pharmacy to ensure accurate measurement.
4. 4Storage: Most formulations should be refrigerated (2°C to 8°C / 36°F to 46°F), although some brands allow for short-term storage at room temperature. Check the specific product insert for your brand.

If a dose is missed, it should be taken as soon as the patient remembers. However, if it is nearly time for the next scheduled dose, the missed dose should be skipped. Do not double the dose to make up for a missed one, as this could lead to a temporary spike in tyrosine levels.

Data on nitisinone overdose in humans is limited. The most likely consequence of an acute overdose would be a significant increase in blood tyrosine levels, which could lead to eye irritation or skin lesions. In the event of an overdose, the patient should be monitored closely, and a low-tyrosine diet should be strictly enforced. Contact a Poison Control Center or seek emergency medical care immediately if an overdose is suspected.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose without medical guidance. Regular blood tests are the only way to ensure the dose is correct.

The most common side effects associated with nitisinone are actually related to the elevation of tyrosine levels rather than the drug itself.

• Elevated Tyrosine Levels (Hypertyrosinemia): This occurs in almost all patients if the diet is not strictly followed.
• Eye Disorders: These include conjunctivitis (pink eye), corneal opacity (clouding of the cornea), keratitis (inflammation of the cornea), and photophobia (sensitivity to light). Patients often describe a 'gritty' feeling in the eyes or sharp pain. These symptoms are usually caused by tyrosine crystals forming in the eye tissue.
• Skin Reactions: Some patients may develop a painful rash or thickening of the skin on the palms and soles (palmoplantar keratoderma).

These side effects may occur in up to 10% of patients:

• Hematologic Changes: Leukopenia (low white blood cell count) and thrombocytopenia (low platelet count) have been reported. This can increase the risk of infection or bruising.
• Gastrointestinal Issues: Abdominal pain, diarrhea, and nausea are occasionally reported, though they are often transient.
• Nervous System: Headaches or irritability may occur, particularly during the initiation phase of treatment.

• Severe Neutropenia: A dangerously low level of neutrophils (a type of white blood cell), which requires immediate medical intervention.
• Cataracts: Prolonged, uncontrolled high tyrosine levels can lead to the development of permanent cataracts.
• Liver Failure: While nitisinone is used to treat liver disease, there have been rare reports of hepatic changes that require differentiation from the underlying HT-1 progression.

> Warning: Stop taking Nitisinone and call your doctor immediately if you experience any of these.

• Visual Changes: Any sudden blurring of vision, eye pain, or extreme redness. This may indicate corneal scarring which can lead to permanent vision loss.
• Infection Signs: Fever, sore throat, or unusual tiredness, which may indicate a drop in white blood cell counts (leukopenia).
• Unusual Bleeding: Nosebleeds, bleeding gums, or easy bruising, which may indicate low platelets (thrombocytopenia).
• Severe Skin Peeling: While rare, any widespread skin blistering or peeling requires an immediate dermatological evaluation.

The long-term use of nitisinone has been studied for over two decades. The primary long-term risk is the development of ocular complications if tyrosine levels are not kept within the recommended range (typically 200–500 micromol/L). There is also a theoretical risk of developmental delays if tyrosine levels are allowed to fluctuate wildly during critical periods of brain development in early childhood. However, when the diet is managed well, nitisinone is generally considered safe for lifelong use. Some studies have looked at the risk of cognitive impairment, but it is difficult to separate the effects of the underlying disease from the effects of the medication.

No FDA black box warnings for Nitisinone. However, the FDA-approved labeling includes a 'Precautions' section that is nearly as stringent, emphasizing the absolute necessity of dietary tyrosine restriction and regular ophthalmic examinations.

Report any unusual symptoms to your healthcare provider. Monitoring is a lifelong commitment for patients on nitisinone therapy.

Nitisinone is a highly specialized medication that must only be prescribed by physicians experienced in the treatment of Hereditary Tyrosinemia Type 1 or Alkaptonuria. The most critical safety point is that nitisinone is NOT a cure; it is a metabolic block that requires a strict, lifelong low-protein diet. Failure to adhere to the diet while taking nitisinone can lead to toxic levels of tyrosine in the blood, causing irreversible damage to the eyes.

No FDA black box warnings for Nitisinone.

• Ocular Toxicity: High plasma tyrosine levels (above 500 micromol/L) are toxic to the eyes. Patients must have a baseline eye exam before starting treatment and regular follow-ups. If any eye symptoms occur, tyrosine levels must be checked immediately, and the diet must be adjusted.
• Hematologic Monitoring: Nitisinone can cause a decrease in white blood cell and platelet counts. This usually occurs within the first few weeks of treatment or following a dose increase. Regular blood counts are required.
• Hepatotoxicity and Liver Cancer: While nitisinone reduces the risk of liver cancer in HT-1 patients, it does not eliminate it. Patients must undergo regular liver imaging (ultrasound, CT, or MRI) and alpha-fetoprotein (AFP) testing to monitor for the development of nodules or hepatoma.
• Dietary Compliance: Nitisinone must never be used without a tyrosine- and phenylalanine-restricted diet. Using the drug while eating a normal protein diet is dangerous and can lead to rapid-onset eye pain and skin lesions.

Patients on nitisinone require intensive laboratory monitoring, especially during the first six months of life or the first few months of treatment:

1. 1Succinylacetone: Should be measured in blood or urine; it should become undetectable shortly after starting treatment.
2. 2Plasma Tyrosine: Monitored frequently to ensure it stays within the 200-500 micromol/L range.
3. 3Liver Function Tests (LFTs): To monitor the health of the liver.
4. 4Complete Blood Count (CBC): To check for leukopenia or thrombocytopenia.
5. 5Alpha-fetoprotein (AFP): Monitored every 3-6 months as a screen for liver cancer.

Nitisinone itself does not typically cause drowsiness or impairment. However, if a patient develops eye symptoms (photophobia or blurred vision) due to high tyrosine levels, they should not drive or operate heavy machinery until the symptoms resolve and their vision is cleared by an ophthalmologist.

There is no known direct chemical interaction between nitisinone and alcohol. However, many alcoholic beverages (like beer) contain significant amounts of protein or amino acids that could interfere with the strict dietary management required for HT-1 patients. Alcohol should be discussed with a metabolic specialist.

Nitisinone should never be stopped suddenly without medical supervision. In patients with HT-1, stopping the medication will lead to the immediate return of toxic succinylacetone production, which can trigger an acute 'tyrosinemia crisis' characterized by liver failure and neurological crises (similar to porphyria). There is no 'withdrawal' in the traditional sense, but the return of the disease state is rapid and life-threatening.

> Important: Discuss all your medical conditions with your healthcare provider before starting Nitisinone.

There are currently no drugs that are strictly contraindicated for use with nitisinone based on chemical incompatibility alone. However, any medication that is known to be highly hepatotoxic (damaging to the liver) should be avoided if possible, as the liver in HT-1 patients is already compromised and sensitive.

Nitisinone is a moderate inhibitor of the enzyme CYP2C9. This enzyme is responsible for breaking down several common medications. Taking nitisinone with these drugs can cause their levels to rise, increasing the risk of toxicity:

• Warfarin: Nitisinone may increase the blood-thinning effects of warfarin, leading to a higher risk of bleeding. Frequent INR (International Normalized Ratio) monitoring is essential.
• Phenytoin: Levels of this anti-seizure medication may increase, leading to dizziness, ataxia, or confusion.
• Glyburide and Glipizide: These diabetes medications may have an enhanced effect, potentially causing hypoglycemia (low blood sugar).

Nitisinone also inhibits transporters known as OAT1 and OAT3 (Organic Anion Transporters). These transporters help the kidneys clear certain drugs from the blood. Interactions may occur with:

• NSAIDs (e.g., Ibuprofen, Naproxen): The renal clearance of these drugs may be reduced.
• Furosemide: A common diuretic whose levels might be affected.
• Methotrexate: A high-risk drug used for autoimmune diseases or cancer; its levels could increase to toxic ranges if OAT transporters are blocked.
• Statins (e.g., Atorvastatin): Some statins are substrates for these transporters and may require monitoring for muscle pain (myopathy).

Food is the most significant 'interaction' for nitisinone patients.

• High-Protein Foods: Meat, dairy, nuts, and beans are essentially 'interactants' that cause nitisinone to become toxic to the eyes by flooding the system with tyrosine.
• Tyrosine/Phenylalanine-Free Formula: These medical foods are necessary to provide essential amino acids without the ones the patient cannot process.

• St. John's Wort: While nitisinone is not primarily cleared by CYP3A4, St. John's Wort can affect liver enzymes generally and should be used with caution.
• Protein Supplements: Standard protein powders or amino acid supplements are strictly forbidden unless they are the specific medical-grade, tyrosine-free versions prescribed by a metabolic dietitian.

• Succinylacetone Testing: Nitisinone will cause succinylacetone to disappear from the urine and blood. This is the intended effect, but it means that testing for the disease must be done before starting the drug or using genetic testing.
• Liver Function Tests: Nitisinone may cause a transient increase in LFTs during the first few weeks of treatment as the liver chemistry stabilizes.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. The inhibition of CYP2C9 is the most clinically significant pathway for drug interactions with nitisinone.

• Hypersensitivity: Nitisinone is absolutely contraindicated in patients with a known severe hypersensitivity (allergy) to nitisinone or any of the inactive ingredients (excipients) in the formulation. Symptoms of a severe reaction include angioedema (swelling of the face/throat), difficulty breathing, or anaphylaxis.
• Untreated HT-1: While this is the indication, using nitisinone without the ability to monitor the patient or provide the necessary medical diet is considered a relative contraindication because the risk of ocular damage is nearly 100% in such scenarios.

• Severe Pre-existing Ocular Disease: In patients with existing corneal scarring or severe keratitis, the start of nitisinone must be handled with extreme caution. The resulting increase in tyrosine could exacerbate these conditions rapidly.
• Pregnancy: While not an absolute contraindication (as the benefit to the mother's liver often outweighs the risk), it is a condition requiring a careful risk-benefit analysis by a specialist team.
• Hepatic Cirrhosis with Portal Hypertension: In very advanced stages of liver disease where a transplant is already imminent, the initiation of nitisinone may not provide sufficient benefit, though it is still generally used to stabilize the patient.

There are no other drugs in the 4-hydroxyphenylpyruvate dioxygenase inhibitor class commonly used in humans, so cross-sensitivity with other medications is not well-documented. However, patients should be cautious if they have had reactions to other 'triketone' herbicides, as nitisinone was originally developed from this chemical family.

> Important: Your healthcare provider will evaluate your complete medical history before prescribing Nitisinone. Dietary compliance is the most important factor in the safe use of this drug.

Nitisinone is classified as Pregnancy Category C (under the old FDA system). There are no adequate and well-controlled studies in pregnant women. Animal reproduction studies have shown that nitisinone is embryotoxic and can cause fetal abnormalities in rabbits and mice at doses similar to human clinical doses. However, in women with HT-1, untreated disease poses a significant risk of liver failure and death during pregnancy. Therefore, nitisinone is typically continued during pregnancy under the strict supervision of a metabolic specialist and an obstetrician specializing in high-risk pregnancies. Tyrosine levels must be monitored even more frequently to protect the developing fetus from hypertyrosinemia.

It is not known whether nitisinone is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants (specifically the risk of high tyrosine levels affecting the infant's development), a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Most experts recommend against breastfeeding while taking nitisinone.

Nitisinone is approved for use in the pediatric population, from birth onwards. It is the standard of care for children with HT-1. The safety and effectiveness have been well-established in clinical trials and long-term registries. The primary concern in children is ensuring that the dose is adjusted frequently as the child grows and that the restrictive diet does not lead to protein malnutrition, which can stunt growth. Specialized 'medical formulas' are used to ensure these children receive adequate nutrition.

There is very little data on the use of nitisinone in patients over age 65. Most patients with HT-1 are in the pediatric or young adult demographic. For older adults with Alkaptonuria, nitisinone is used, but clinicians should be mindful of the increased likelihood of decreased renal function and the presence of other comorbidities that might increase the risk of drug interactions (especially with CYP2C9 substrates like Warfarin).

No specific dose adjustments are provided for patients with renal impairment. However, succinylacetone causes 'Fanconi Syndrome' (a type of kidney tubule damage). Nitisinone typically improves renal function in HT-1 patients by stopping the production of this toxin. If a patient has end-stage renal disease, nitisinone is not known to be cleared by dialysis, and dosing should be managed by a specialist.

In HT-1, hepatic impairment is a feature of the disease. Nitisinone is used to treat this. However, if hepatic impairment is so severe that the liver's synthetic function is lost (e.g., very low albumin), the protein binding of nitisinone may be affected, potentially increasing the free fraction of the drug. These patients require close monitoring in a transplant center.

> Important: Special populations require individualized medical assessment and frequent laboratory monitoring.

Nitisinone is a competitive inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD). HPPD is a copper-containing oxygenase that catalyzes the conversion of 4-hydroxyphenylpyruvate (4-HPP) to homogentisic acid (HGA) in the catabolic pathway of tyrosine. By binding to the active site of HPPD, nitisinone prevents the formation of HGA. In Tyrosinemia Type 1, this prevents the subsequent formation of maleylacetoacetate and fumarylacetoacetate, which would otherwise spontaneously convert to the toxic succinylacetone. In Alkaptonuria, the inhibition of HPPD directly reduces the accumulation of HGA, which is the primary driver of ochronotic pathology.

The primary pharmacodynamic marker for nitisinone efficacy in HT-1 is the concentration of succinylacetone. In effective treatment, succinylacetone should become undetectable in both plasma and urine. This effect is usually achieved within 24 to 48 hours of the first dose. The secondary effect is the elevation of plasma tyrosine, which is a direct consequence of the metabolic block. The relationship between nitisinone concentration and HPPD inhibition is very potent; even low plasma concentrations are sufficient to achieve near-complete enzymatic blockade.

| Parameter | Value |

|---|---|

| Bioavailability | ~90% (estimated) |

| Protein Binding | >95% (primarily Albumin) |

| Half-life | ~54 hours (range 30-86h) |

| Tmax | 1-4 hours |

| Metabolism | Minimal hepatic CYP metabolism |

| Excretion | Primarily Renal (slow) |

• Molecular Formula: C14H10F3NO5
• Molecular Weight: 329.23 g/mol
• Solubility: Practically insoluble in water; soluble in 2M NaOH and methanol.
• Chemical Name: 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione.
• Structure: It is a triketone derivative. The structure consists of a cyclohexane-1,3-dione ring linked to a nitro-trifluoromethylbenzoyl group.

Nitisinone is the first and primary member of the 4-hydroxyphenylpyruvate dioxygenase inhibitor [EPC] class used in human medicine. It is therapeutically categorized as an 'Alimentary Tract and Metabolism' product (ATC code: A16AX04). There are currently no other drugs in this specific class approved for these indications, making it a unique orphan medication.