Nitisinone - Indications, Contraindications, Adverse Effects, Dosage, Warnings, and Precautions.

Overview

Nitisinone, originally used for killing weed, was approved by the Food and Administration (FDA) in 2002 to treat hereditary tyrosinemia type 1 (HT-1) which is a rare genetic disease. HT-1 results from a missing enzyme in the body, leading to harmful buildups of tyrosine and other substances, causing liver and kidney damage. Nitisinone (NTBC) was FDA-approved in 2002 to treat a rare genetic disease called hereditary tyrosinemia type 1 (HT-1). Without treatment, it can be fatal. It is also explored for other conditions like alkaptonuria (a rare genetic condition impairing the breakdown of specific amino acids in the body), where it might be more effective, and it is being studied for improving skin and hair pigmentation in some forms of albinism.

Indications:

• Nitisinone is used alongside a special diet that limits certain amino acids like tyrosine and phenylalanine to treat hereditary tyrosinemia type 1.

• HT-1 is a condition caused by a missing enzyme (FAH) needed to break down the amino acid tyrosine, leading to dangerous buildups of tyrosine and related chemicals in the body.

• Untreated HT-1 poses life-threatening risks, leading to symptoms like jaundice, vomiting, developmental issues, and the potential for liver cancer, but nitisinone can prevent harmful substance accumulation.

• HT-1 can be diagnosed through specific markers in the blood, and before nitisinone, liver transplants were the primary treatment.

• Nitisinone is sometimes used off-label for other conditions like alkaptonuria, where it may be more effective.

• Research is ongoing to explore whether Nitisinone can help improve skin and hair color in people with a certain type of albinism called OCA-1B.

Contradictions:

1. Regarding the Use of Nitisinone in Hereditary Tyrosinemia Type 1 (HT-1):

• There are no known situations where Nitisinone should not be used to treat HT-1.

2. Exploratory Studies on Nitisinone:

1. Ongoing experiments are exploring potential situations where Nitisinone should not be used.

2. One study found that Nitisinone can affect certain enzymes in the body that break down drugs.

3. It can increase the activity of CYP2E1 enzyme and decrease the activities of CYP2C9 enzyme.

3. Implications for Drug Use with Nitisinone:

1. Nitisinone may interact with drugs metabolized by specific enzymes (CYP2C9).

2. This could lead to higher drug levels in the body, potentially causing toxicity and more side effects.

3. Examples of drugs metabolized by CYP2C9 include Amitriptyline, Diclofenac, Ibuprofen, and Warfarin.

4. If someone is taking one of these drugs and also using Nitisinone, their doctor may need to adjust their drug doses to ensure safety.

Side Effects:

When people take Nitisinone, some common side effects can happen:

1. Metabolic Reactions:

1. The levels of a substance called tyrosine in the blood can become too high.

2. Seizures may occur.

2. Blood Reactions:

1. Counts of certain blood cells might drop, including white blood cells and platelets.

2. This can lead to conditions like leukopenia (low white blood cells), granulocytopenia (deficiency of granulocytes), and thrombocytopenia (low platelet count).

3. Eye Reactions:

1. Redness.

2. Eye pain.

3. Cloudy corneas.

4. Sensitivity to light.

5. Eye inflammation.

6. The development of cataracts.

4. Skin Reactions:

1. Skin-related issues may show up, like nosebleeds, skin inflammation with flaking, itching, dry skin, rashes, and hair loss.

2. The most common problem is having too much tyrosine in the blood, which is often the main cause of these side effects, especially eye-related ones.

3. Some people taking Nitisinone might also experience headaches or diarrhea, especially if they are using the liquid form of the medication.

For Patients

How Nitisinone Is Used in Hereditary Tyrosinemia Type 1?

Nitisinone is a medication that helps people with a rare genetic condition called hereditary tyrosinemia type 1 (HT-1) better tolerate foods that contain tyrosine. It works by blocking an enzyme in the body that is involved in processing tyrosine. This medication is used alongside a special diet to manage the condition. Nitisinone is a man-made drug that can temporarily stop the action of a specific enzyme called 4-hydroxyphenylpyruvate dioxygenase. It is prescribed to help manage a rare genetic disorder known as hereditary tyrosinemia type 1 (HT-1).

What Are the Uses of Nitisinone?

• Nitisinone is a medication used to treat hereditary tyrosinemia type 1 (HT-1), a rare genetic disorder.

• HT-1 is typically diagnosed in infants and requires lifelong treatment.

• HT-1, a rare genetic disorder, results from an inadequate supply of the essential enzyme needed to metabolize dietary tyrosine, causing the accumulation of harmful tyrosine byproducts in the liver, kidneys, and nervous system; Nitisinone functions to obstruct the production and accumulation of these toxic compounds, safeguarding these vital organs.

• To manage HT-1 effectively, Nitisinone must be combined with a special diet low in protein, tyrosine, and phenylalanine.

What Are the Warnings and Precautions of Nitisinone?

• Taking Nitisinone can lead to higher levels of tyrosine in the blood for people with HT-1. So, they need to follow a special diet to limit their tyrosine and phenylalanine intake. The goal is to keep the tyrosine level in the blood below a certain limit (500 mol/L).

• Some people who use Nitisinone have reported eye problems like corneal ulcers, pain, and sensitivity to light. Others experienced sudden changes in their nervous system, and some had painful skin conditions on their hands and feet.

• There have been cases where people taking Nitisinone and dietary changes had lower counts of certain blood cells (white blood cells and platelets). In one case, reducing the Nitisinone dose helped improve these counts. So, it is important to check the levels of blood cells while using Nitisinone regularly.

For Doctors

Pharmacodynamics:

Hereditary tyrosinemia type 1 results from a deficiency in the enzyme fumarylacetoacetase (FAH), essential for breaking down tyrosine. Nitisinone prevents the breakdown of tyrosine by blocking certain chemical steps. In patients with HT-1, this blockage leads to the formation of harmful substances called succinylacetone and succinyl acetoacetate, which can damage the liver and kidneys. Succinylacetone can also interfere with the production of porphyrins, leading to the buildup of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises seen in HT-1.

Pharmacokinetics:

There have been no pharmacokinetic studies conducted on Nitisinone in children or individuals with HT-1 (hereditary tyrosinemia type 1).

Absorption:

• Nitisinone was administered at a dose of 1 mg per kilogram of body weight as both a capsule and a liquid.

• The median time it took to reach the highest concentration in the blood was 3 hours for the capsule and 15 minutes for the liquid.

• Analysis indicated that Nitisinone's capsule and liquid forms had equivalent bioavailability based on the area under the plasma concentration-time curve and maximum plasma concentration (Cmax).

Metabolism:

Currently, more information is needed regarding how Nitisinone is metabolized in humans.

Excretion:

In healthy male volunteers, Nitisinone exhibited an average terminal plasma half-life of approximately 54 hours.

Effect of Food Not Studied:

The impact of food on the pharmacokinetics of Nitisinone has not been investigated.

Mechanism of Action:

Nitisinone operates by obstructing the second phase of the tyrosine degradation pathway, specifically targeting 4-hydroxyphenylpyruvate dioxygenase (HPPD), a step occurring before the onset of hereditary tyrosinemia type 1 (HT-1) due to the deficient FAH (Fumarylacetoacetate Hydrolase) enzyme. By inhibiting HPPD, Nitisinone effectively halts the metabolism of tyrosine in the region of the FAH enzyme, thereby averting the buildup of harmful metabolites within the tyrosine degradation pathway. It is important to note that HPPD also exists upstream of homogentisate oxidase, which is another enzyme within the same tyrosine degradation pathway and is deficient in alkaptonuria. Consequently, by inhibiting HPPD using Nitisinone before the enzymatic step associated with homogentisate oxidase in alkaptonuria, the medication prevents the accumulation of homogentisic acid, a key factor in the pathogenesis of alkaptonuria.

Indications:

• Nitisinone (NTBC) received FDA approval in 2002 for the management of hereditary tyrosinemia type 1 (HT-1), an uncommon genetic disorder.

• Nitisinone's mechanism of action involves inhibiting the accumulation of these toxic metabolites by impeding the tyrosine degradation pathway.

• HT-1 can be diagnosed through specific biochemical markers in the blood.

• Nitisinone is occasionally used off-label for managing other conditions like alkaptonuria, where it may demonstrate greater efficacy.

• Ongoing research is exploring the potential utility of Nitisinone in improving pigmentation in individuals with oculocutaneous albinism type 1B (OCA-1B), caused by mutations in the tyrosinase gene and reduced melanin production.

Contraindications:

A. Regarding Nitisinone Use in Hereditary Tyrosinemia Type 1 (HT-1):

1. There are currently no known contraindications for the use of Nitisinone in the treatment of HT-1.

2. Historical cases involving pregnant women with HT-1 who used Nitisinone did not result in harm to either the mothers or their infants.

3. Additional research is warranted to comprehensively assess the safety and potential risks associated with Nitisinone use during pregnancy.

B. Exploration of Nitisinone Effects:

1. Ongoing research endeavors are investigating potential scenarios where the administration of Nitisinone may not be advisable.

2. One study revealed that Nitisinone can impact specific enzymes responsible for the metabolism of drugs within the body.

3. It can induce the activity of one enzyme, CYP2E1, while concurrently inhibiting another, CYP2C9.

C. Implications for Drug Interactions with Nitisinone:

1. Nitisinone has the potential to interact with drugs that are substrates of specific enzymes, particularly CYP2C9.

2. Such interactions may result in elevated drug concentrations within the body, potentially leading to toxicity and an increased likelihood of adverse effects.

3. Examples of drugs metabolized by CYP2C9 encompass Amitriptyline, Diclofenac, Ibuprofen, and Warfarin.

4. In cases where individuals are concurrently using Nitisinone and one of these drugs, healthcare professionals should consider dose adjustments to ensure patient safety.

What Are the Side Effects of Nitisinone?

1. Metabolic Reactions:

1. Hyperaminoacidemia: Elevated levels of the amino acid tyrosine in the blood.

2. Seizures: Convulsive episodes involving abnormal electrical activity in the brain.

2. Blood Reactions:

1. Hematologic Abnormalities: Reduction in blood cell counts, specifically leukocytes (white blood cells), granulocytes (a type of white blood cell), and platelets.

2. Hematologic Disorders: Conditions characterized by lowered blood cell counts, including leukopenia (low white blood cell count), granulocytopenia (low granulocyte count), and thrombocytopenia (low platelet count).

3. Eye Reactions:

1. Ocular Symptoms: Manifestations affecting the eyes, such as conjunctival erythema (redness), ocular pain, corneal opacities (cloudy corneas), photophobia (light sensitivity), ocular inflammation, and the development of cataracts.

4. Skin Reactions:

1. Dermatological Manifestations: Skin-related issues including epistaxis (nosebleeds), exfoliative dermatitis (skin flaking), pruritus (itching), xerosis (dry skin), skin rashes with both raised and flat areas (maculopapular rash), and alopecia (hair loss).

2. The predominant factor contributing to these side effects, particularly those associated with the eyes, is the elevation of tyrosine levels in the blood, a common consequence of Nitisinone use.

3. Some individuals taking Nitisinone, particularly in oral suspension form, may also experience headaches or gastrointestinal disturbances like diarrhea.

Administration:

• Nitisinone is an approved medication for oral administration in the form of pill capsules or an oral suspension.

• It should be initiated as soon as the hereditary tyrosinemia type 1 (HT-1) diagnosis is confirmed.

• The dosage of Nitisinone is weight-dependent, with the recommended initial dose being 0.5 mg per kilogram of body weight, administered twice daily.

• For patients who continue to have detectable levels of succinylacetone in their blood and urine despite Nitisinone treatment, dose adjustments may be necessary, with ongoing monitoring of succinylacetone levels.

• The maximum approved oral dosage of Nitisinone is 2 mg per kilogram of body weight, given twice daily.

• Nitisinone in capsule form is typically taken either two hours after meals or at least an hour before eating.

• For individuals who have difficulty swallowing capsules, Nitisinone capsules can be opened, and the contents can be mixed with water just before consumption.

• The use of Nitisinone oral suspension is not restricted to specific meal times and can be taken at any time during the day.

• Nitisinone is available in oral dosage strengths of 2 mg, 5 mg, 10 mg, and 20 mg, while the oral suspension is provided at a concentration of 4 mg per milliliter.

• Some individuals receiving Nitisinone oral suspension may experience constitutional symptoms like diarrhea, headaches, or fatigue, which may be attributed to the polyol components included in the suspension.

• The excretion characteristics of Nitisinone remain unclear, and it exhibits a half-life of approximately 54 hours.

• Nitisinone functions by inhibiting the breakdown of tyrosine, resulting in elevated tyrosine levels in the bloodstream.

• Therefore, it should be administered concurrently with dietary restrictions limiting tyrosine and phenylalanine intake.

Dosages:

Capsules:

Nitisinone capsules are available in strengths of 2 milligrams (2 mg), 5 milligrams (5 mg), 10 milligrams (10 mg), and 20 milligrams (20 mg).

Oral Suspension:

Nitisinone oral suspension is 4 milligrams per milliliter (4 mg/mL).

Tablets:

Nitisinone tablets come in strengths of 2 milligrams (2 mg), 5 milligrams (5 mg), and 10 milligrams (10 mg).

Storage:

• Store the capsule in a refrigerator, and do not freeze.

• It can be stored at room temperature for up to 45 days. It shouldn’t be used within 45 days if not stored at room temperature.

• Tablets should be stored at room temperature and kept in a dry place.

• The oral suspension should be stored in a refrigerator.

• All drugs should be kept safe and out of reach of children and pets.

Special Considerations:

If someone is pregnant, becomes pregnant or is breastfeeding a baby, they should talk to their doctor before taking Nitisinone.