Nitisinone 2mg Capsules
It is used to treat hereditary tyrosinemia type 1 (HT-1).
Drug Class
Enzyme Inhibitor
Pharmacologic Class
4-Hydroxyphenylpyruvate Dioxygenase (HPPD) Inhibitor
Pregnancy Category
C
FDA Approved
Jan 1997
DEA Schedule
Not Controlled
Overview
What is this medicine?
Nitisinone is a medication used to treat a rare genetic disorder called hereditary tyrosinemia type 1 (HT-1). It works by blocking an enzyme in the body that helps break down a substance called tyrosine. In HT-1, the body can't properly break down tyrosine, leading to a buildup of harmful substances that can damage the liver, kidneys, and nervous system. Nitisinone helps prevent this buildup, but it must be used along with a special diet low in tyrosine and phenylalanine.
How to Use This Medicine
Taking Your Medication
To use this medication correctly, follow your doctor's instructions and read all the information provided. Take the medication on an empty stomach, either 1 hour before or 2 hours after meals. Continue taking the medication as directed by your doctor or healthcare provider, even if you start feeling well.
If you have trouble swallowing the capsules, you can open them and mix the contents with a small amount of water, formula, or applesauce. However, be sure to swallow the mixture immediately and do not store it for later use.
Storing and Disposing of Your Medication
The storage instructions for this medication may vary depending on the brand. Some brands require refrigeration, while others can be stored at room temperature. Do not freeze the medication. If you need to store it at room temperature, make sure it is in a cool, dry place and not in the bathroom. The medication can be stored at room temperature (up to 77°F or 25°C) for up to 45 days. If it is not used within 45 days, discard the medication.
Check the specific storage instructions for your brand and ask your pharmacist if you have any questions.
Missing a Dose
If you miss a dose, take it as soon as you remember. However, if it is close to the time for your next dose, skip the missed dose and resume your regular schedule. Do not take two doses at the same time or take extra doses to make up for the missed one.
To use this medication correctly, follow your doctor's instructions and read all the information provided. Take the medication on an empty stomach, either 1 hour before or 2 hours after meals. Continue taking the medication as directed by your doctor or healthcare provider, even if you start feeling well.
If you have trouble swallowing the capsules, you can open them and mix the contents with a small amount of water, formula, or applesauce. However, be sure to swallow the mixture immediately and do not store it for later use.
Storing and Disposing of Your Medication
The storage instructions for this medication may vary depending on the brand. Some brands require refrigeration, while others can be stored at room temperature. Do not freeze the medication. If you need to store it at room temperature, make sure it is in a cool, dry place and not in the bathroom. The medication can be stored at room temperature (up to 77°F or 25°C) for up to 45 days. If it is not used within 45 days, discard the medication.
Check the specific storage instructions for your brand and ask your pharmacist if you have any questions.
Missing a Dose
If you miss a dose, take it as soon as you remember. However, if it is close to the time for your next dose, skip the missed dose and resume your regular schedule. Do not take two doses at the same time or take extra doses to make up for the missed one.
Lifestyle & Tips
- Strict adherence to a low-tyrosine and low-phenylalanine diet is crucial for the effectiveness of nitisinone and to prevent side effects like high tyrosine levels.
- Regular follow-up appointments and blood tests are essential to monitor treatment effectiveness and adjust diet/medication as needed.
- Report any new or worsening symptoms, especially eye problems (e.g., sensitivity to light, eye pain), skin rashes, or neurological changes.
Available Forms & Alternatives
Available Strengths:
Dosing & Administration
Adult Dosing
Standard Dose:
0.5 mg/kg once daily
Dose Range:
0.5 - 1 mg
Condition-Specific Dosing:
initial:
0.5 mg/kg once daily
maintenance:
Adjust based on succinylacetone levels and clinical response, typically 0.5 to 1.0 mg/kg once daily. Max 2 mg/kg/day.
Pediatric Dosing
Neonatal:
0.5 mg/kg once daily (initial), adjust based on succinylacetone levels and clinical response.
Infant:
0.5 mg/kg once daily (initial), adjust based on succinylacetone levels and clinical response.
Child:
0.5 mg/kg once daily (initial), adjust based on succinylacetone levels and clinical response.
Adolescent:
0.5 mg/kg once daily (initial), adjust based on succinylacetone levels and clinical response.
Dose Adjustments
Renal Impairment:
Mild:
No specific dose adjustment recommended.
Moderate:
No specific dose adjustment recommended.
Severe:
No specific dose adjustment recommended, but monitor closely.
Dialysis:
Not available (Nitisinone is highly protein-bound and not expected to be significantly removed by dialysis).
Hepatic Impairment:
Mild:
No specific dose adjustment recommended.
Moderate:
No specific dose adjustment recommended.
Severe:
No specific dose adjustment recommended, but monitor closely due to underlying HT-1 pathology.
Pharmacology
Mechanism of Action
Nitisinone is a reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme involved in the catabolism of tyrosine. In patients with hereditary tyrosinemia type 1 (HT-1), the enzyme fumarylacetoacetate hydrolase (FAH) is deficient, leading to the accumulation of toxic metabolites like succinylacetone. By inhibiting HPPD, nitisinone prevents the formation of these toxic metabolites from tyrosine, thereby reducing liver and kidney damage.
Pharmacokinetics
Absorption:
Bioavailability:
Not available (well absorbed)
Tmax:
3-8 hours
FoodEffect:
Food does not significantly affect absorption.
Distribution:
Vd:
Not available (extensive distribution)
ProteinBinding:
>99% (primarily to albumin)
CnssPenetration:
Limited (low concentrations in CSF)
Elimination:
HalfLife:
54 hours (range 36-90 hours)
Clearance:
Not available
ExcretionRoute:
Primarily renal (unchanged drug), some fecal
Unchanged:
Approximately 60% (renal)
Pharmacodynamics
OnsetOfAction:
Within days (reduction in succinylacetone)
PeakEffect:
Weeks to months (stabilization of succinylacetone levels and clinical improvement)
DurationOfAction:
Due to long half-life, once-daily dosing maintains therapeutic levels.
Safety & Warnings
Side Effects
Urgent Side Effects: Seek Medical Attention Immediately
Although rare, some people may experience severe and potentially life-threatening side effects while taking this medication. If you notice any of the following symptoms, contact your doctor or seek medical help right away:
Signs of an allergic reaction, such as:
+ Rash
+ Hives
+ Itching
+ Red, swollen, blistered, or peeling skin with or without fever
+ Wheezing
+ Tightness in the chest or throat
+ Trouble breathing, swallowing, or talking
+ Unusual hoarseness
+ Swelling of the mouth, face, lips, tongue, or throat
Signs of liver problems, including:
+ Dark urine
+ Tiredness
+ Decreased appetite
+ Upset stomach or stomach pain
+ Light-colored stools
+ Vomiting
+ Yellow skin or eyes
Changes in eyesight, eye pain, or severe eye irritation
Sensitivity to bright light
Confusion, difficulty focusing, or changes in behavior
Redness, irritation, pain, or thick skin on the palms of the hands or soles of the feet
Signs of low white blood cell counts, which may increase the risk of infection, such as:
+ Fever
+ Chills
+ Sore throat
Signs of low platelet counts, which may increase the risk of bleeding, such as:
+ Unexplained bruising or bleeding
Other Possible Side Effects
Like all medications, this drug can cause side effects. Many people may not experience any side effects or may only have mild ones. If you have any side effects that bother you or do not go away, contact your doctor or seek medical help. This is not a comprehensive list of all possible side effects. If you have questions or concerns about side effects, consult your doctor.
Reporting Side Effects
You can report side effects to the FDA at 1-800-332-1088 or online at https://www.fda.gov/medwatch. Your doctor can also provide guidance on managing side effects and offer medical advice.
Although rare, some people may experience severe and potentially life-threatening side effects while taking this medication. If you notice any of the following symptoms, contact your doctor or seek medical help right away:
Signs of an allergic reaction, such as:
+ Rash
+ Hives
+ Itching
+ Red, swollen, blistered, or peeling skin with or without fever
+ Wheezing
+ Tightness in the chest or throat
+ Trouble breathing, swallowing, or talking
+ Unusual hoarseness
+ Swelling of the mouth, face, lips, tongue, or throat
Signs of liver problems, including:
+ Dark urine
+ Tiredness
+ Decreased appetite
+ Upset stomach or stomach pain
+ Light-colored stools
+ Vomiting
+ Yellow skin or eyes
Changes in eyesight, eye pain, or severe eye irritation
Sensitivity to bright light
Confusion, difficulty focusing, or changes in behavior
Redness, irritation, pain, or thick skin on the palms of the hands or soles of the feet
Signs of low white blood cell counts, which may increase the risk of infection, such as:
+ Fever
+ Chills
+ Sore throat
Signs of low platelet counts, which may increase the risk of bleeding, such as:
+ Unexplained bruising or bleeding
Other Possible Side Effects
Like all medications, this drug can cause side effects. Many people may not experience any side effects or may only have mild ones. If you have any side effects that bother you or do not go away, contact your doctor or seek medical help. This is not a comprehensive list of all possible side effects. If you have questions or concerns about side effects, consult your doctor.
Reporting Side Effects
You can report side effects to the FDA at 1-800-332-1088 or online at https://www.fda.gov/medwatch. Your doctor can also provide guidance on managing side effects and offer medical advice.
Seek Immediate Medical Attention If You Experience:
- Eye pain or redness
- Sensitivity to light (photophobia)
- Blurred vision or vision changes
- Skin rash or thickening (hyperkeratosis)
- Numbness or tingling in hands/feet
- Unexplained fever or infection
- Yellowing of skin or eyes (jaundice)
- Unusual bleeding or bruising
Before Using This Medicine
Before Taking This Medication: Important Information to Share with Your Doctor
It is essential to inform your doctor about the following:
Any allergies you have, including allergies to this medication, its components, or other substances, such as foods or drugs. Be sure to describe the symptoms you experienced.
All medications you are currently taking, including prescription and over-the-counter (OTC) drugs, natural products, and vitamins.
* Any existing health problems, as this medication may interact with other drugs or health conditions.
To ensure your safety, it is crucial to verify that this medication can be taken with all your current medications and health conditions. Always consult your doctor before starting, stopping, or changing the dose of any medication.
It is essential to inform your doctor about the following:
Any allergies you have, including allergies to this medication, its components, or other substances, such as foods or drugs. Be sure to describe the symptoms you experienced.
All medications you are currently taking, including prescription and over-the-counter (OTC) drugs, natural products, and vitamins.
* Any existing health problems, as this medication may interact with other drugs or health conditions.
To ensure your safety, it is crucial to verify that this medication can be taken with all your current medications and health conditions. Always consult your doctor before starting, stopping, or changing the dose of any medication.
Precautions & Cautions
It is essential to inform all your healthcare providers, including doctors, nurses, pharmacists, and dentists, that you are taking this medication.
Regular blood tests will be necessary, as directed by your doctor, to monitor your condition. Be sure to discuss any concerns or questions you have with your doctor.
Additionally, your doctor may require you to have your urine checked periodically. It is crucial to follow your doctor's instructions regarding urine tests.
To ensure your eye health, your doctor may recommend regular eye exams. Be sure to schedule these exams as advised by your doctor.
Adhering to the diet plan recommended by your doctor is also vital. This plan is tailored to your specific needs, and following it will help you get the most benefit from your treatment.
If you are pregnant, planning to become pregnant, or are breast-feeding, it is crucial to discuss this with your doctor. You and your doctor will need to weigh the benefits and risks of this medication to both you and your baby to make an informed decision.
Regular blood tests will be necessary, as directed by your doctor, to monitor your condition. Be sure to discuss any concerns or questions you have with your doctor.
Additionally, your doctor may require you to have your urine checked periodically. It is crucial to follow your doctor's instructions regarding urine tests.
To ensure your eye health, your doctor may recommend regular eye exams. Be sure to schedule these exams as advised by your doctor.
Adhering to the diet plan recommended by your doctor is also vital. This plan is tailored to your specific needs, and following it will help you get the most benefit from your treatment.
If you are pregnant, planning to become pregnant, or are breast-feeding, it is crucial to discuss this with your doctor. You and your doctor will need to weigh the benefits and risks of this medication to both you and your baby to make an informed decision.
Overdose Information
Overdose Symptoms:
- Exaggerated side effects, particularly very high tyrosine levels leading to eye problems (corneal opacities, photophobia), skin lesions, and neurological symptoms.
- Gastrointestinal upset (nausea, vomiting, diarrhea).
What to Do:
Seek immediate medical attention. Contact a poison control center (e.g., 1-800-222-1222). Treatment is supportive, focusing on managing symptoms and potentially reducing nitisinone dose or adjusting diet.
Drug Interactions
Moderate Interactions
- Drugs that induce or inhibit CYP450 enzymes (though nitisinone is minimally metabolized by CYP450, caution is advised)
- Drugs that affect protein binding (highly protein-bound drugs may displace nitisinone or be displaced by nitisinone, though clinical significance is low)
Monitoring
Baseline Monitoring
Succinylacetone (SA) levels
Rationale: To confirm diagnosis and establish baseline for treatment efficacy.
Timing: Prior to initiation of therapy.
Plasma tyrosine levels
Rationale: To establish baseline and guide dietary management.
Timing: Prior to initiation of therapy.
Liver function tests (ALT, AST, bilirubin, albumin, INR)
Rationale: To assess baseline liver function and monitor for potential hepatotoxicity.
Timing: Prior to initiation of therapy.
Renal function tests (BUN, creatinine)
Rationale: To assess baseline renal function.
Timing: Prior to initiation of therapy.
Complete Blood Count (CBC)
Rationale: To assess baseline hematologic status.
Timing: Prior to initiation of therapy.
Ophthalmologic exam (slit lamp)
Rationale: To establish baseline for potential corneal opacities.
Timing: Prior to initiation of therapy.
Routine Monitoring
Succinylacetone (SA) levels
Frequency: Weekly for the first month, then monthly or as clinically indicated until stable, then every 3-6 months.
Target: Undetectable or very low.
Action Threshold: If SA levels are detectable, consider dose increase or dietary adherence review.
Plasma tyrosine levels
Frequency: Weekly for the first month, then monthly or as clinically indicated until stable, then every 3-6 months.
Target: <500 micromol/L (ideally 200-400 micromol/L)
Action Threshold: If tyrosine levels are >500-700 micromol/L, consider dietary tyrosine restriction adjustment or dose reduction if very high.
Liver function tests (ALT, AST, bilirubin, albumin, INR)
Frequency: Monthly for the first few months, then every 3-6 months.
Target: Within normal limits.
Action Threshold: Significant elevations may require investigation and dose adjustment.
Renal function tests (BUN, creatinine)
Frequency: Every 3-6 months.
Target: Within normal limits.
Action Threshold: Significant changes may require investigation.
Complete Blood Count (CBC)
Frequency: Every 3-6 months.
Target: Within normal limits.
Action Threshold: Significant changes may require investigation.
Ophthalmologic exam (slit lamp)
Frequency: Every 6-12 months, or if visual symptoms occur.
Target: No corneal opacities.
Action Threshold: Development of corneal opacities may require dose adjustment or dietary review.
Symptom Monitoring
- Changes in vision (e.g., photophobia, eye pain, blurred vision)
- Skin changes (e.g., hyperkeratosis, rash)
- Neurological symptoms (e.g., peripheral neuropathy, developmental delay)
- Signs of liver dysfunction (e.g., jaundice, ascites, easy bruising)
- Signs of renal dysfunction (e.g., edema, changes in urine output)
- General well-being and growth in pediatric patients
Special Patient Groups
Pregnancy
Use during pregnancy should only be considered if the potential benefit justifies the potential risk to the fetus. Nitisinone is Pregnancy Category C. Animal studies have shown adverse effects on development.
Trimester-Specific Risks:
First Trimester:
Potential for developmental abnormalities based on animal data.
Second Trimester:
Potential for developmental abnormalities based on animal data.
Third Trimester:
Potential for developmental abnormalities based on animal data.
Lactation
Nitisinone is excreted into breast milk. Due to the potential for serious adverse reactions in the breastfed infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Lactation Risk L3 (Moderate Concern).
Infant Risk:
Potential for high tyrosine levels in the infant, leading to corneal opacities, skin lesions, and neurological effects. Monitor breastfed infant for adverse effects.
Pediatric Use
Nitisinone is indicated for pediatric patients of all ages with hereditary tyrosinemia type 1. Dosing is weight-based. Close monitoring of succinylacetone and tyrosine levels, as well as growth and development, is essential.
Geriatric Use
Hereditary tyrosinemia type 1 is typically diagnosed in infancy or early childhood. Data on nitisinone use in geriatric patients are limited, as HT-1 is rarely diagnosed in this population. No specific dose adjustments are recommended based on age alone, but monitor for age-related decline in organ function.
Clinical Information
Clinical Pearls
- Nitisinone therapy must always be accompanied by a strict low-tyrosine and low-phenylalanine diet. Without dietary restriction, high tyrosine levels can lead to severe side effects, particularly ocular and dermatological issues.
- Regular monitoring of succinylacetone (to ensure efficacy) and tyrosine levels (to prevent toxicity) is critical for optimal management.
- Patients and caregivers should be educated on the importance of dietary adherence and recognizing symptoms of high tyrosine levels.
- Early diagnosis and treatment of HT-1 with nitisinone significantly improve prognosis and prevent severe complications like liver failure and hepatocellular carcinoma.
Alternative Therapies
- Liver transplantation (for patients who fail nitisinone therapy or present with advanced liver disease)
- Dietary management alone (historically, but less effective and associated with higher morbidity/mortality than nitisinone + diet)
Cost & Coverage
Average Cost:
Highly variable, typically very expensive per 30 capsules
Generic Available:
Yes
Insurance Coverage:
Specialty Tier (requires prior authorization, often covered by medical benefit or specialty pharmacy programs)
General Drug Facts
If your symptoms or health issues persist or worsen, it is essential to contact your doctor promptly. To ensure safe and effective treatment, never share your medication with others or take someone else's medication. Some medications may come with an additional patient information leaflet, so it's a good idea to check with your pharmacist for more information. If you have any questions or concerns about this medication, don't hesitate to reach out to your doctor, nurse, pharmacist, or other healthcare provider. In the event of a suspected overdose, immediately call your local poison control center or seek emergency medical attention. When seeking help, be prepared to provide details about the overdose, including the medication taken, the amount, and the time it occurred.