Nitisinone 10mg Capsules
It is used to treat hereditary tyrosinemia type 1 (HT-1).
Drug Class
Hereditary Tyrosinemia Type 1 (HT-1) Treatment
Pharmacologic Class
4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor
Pregnancy Category
Not available
FDA Approved
Jan 2002
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 a specific enzyme in the body, which prevents the buildup of harmful substances that can damage the liver, kidneys, and nervous system. It must be used along with a very strict low-protein diet.
How to Use This Medicine
Taking Your Medication Correctly
To get the most benefit from your medication, follow your doctor's instructions carefully. Read all the information provided with your prescription and follow the instructions closely. Take your medication on an empty stomach, either 1 hour before or 2 hours after meals. Continue taking your medication as directed by your doctor or healthcare provider, even if you start to feel 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. If you mix the medication with one of these substances, be sure to swallow it right away. Do not store the mixture for later use.
Storing and Disposing of Your Medication
Different brands of this medication may have specific storage instructions. Some brands should be stored in the refrigerator, but do not freeze. If you need to store the medication at room temperature, it can be kept at a temperature up to 77°F (25°C) for up to 45 days. If the medication is not used within 45 days, it should be discarded. Other brands can be stored at room temperature in a dry place, but should not be kept in the bathroom. Make sure you understand the storage instructions for your specific brand. If you have any questions, ask your pharmacist.
What to Do If You Miss 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 return to your regular schedule. Do not take two doses at the same time or take extra doses to make up for a missed dose.
To get the most benefit from your medication, follow your doctor's instructions carefully. Read all the information provided with your prescription and follow the instructions closely. Take your medication on an empty stomach, either 1 hour before or 2 hours after meals. Continue taking your medication as directed by your doctor or healthcare provider, even if you start to feel 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. If you mix the medication with one of these substances, be sure to swallow it right away. Do not store the mixture for later use.
Storing and Disposing of Your Medication
Different brands of this medication may have specific storage instructions. Some brands should be stored in the refrigerator, but do not freeze. If you need to store the medication at room temperature, it can be kept at a temperature up to 77°F (25°C) for up to 45 days. If the medication is not used within 45 days, it should be discarded. Other brands can be stored at room temperature in a dry place, but should not be kept in the bathroom. Make sure you understand the storage instructions for your specific brand. If you have any questions, ask your pharmacist.
What to Do If You Miss 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 return to your regular schedule. Do not take two doses at the same time or take extra doses to make up for a missed dose.
Lifestyle & Tips
- Adhere strictly to a low-tyrosine, low-phenylalanine diet as prescribed by your doctor or dietitian. This diet is crucial for preventing high tyrosine levels and associated side effects.
- Take nitisinone regularly as prescribed, usually once daily, at the same time each day.
- Do not stop taking nitisinone or change your dose without consulting your doctor.
- Attend all scheduled appointments for blood tests and medical examinations.
Available Forms & Alternatives
Available Strengths:
Dosing & Administration
Adult Dosing
Standard Dose:
Initial 0.5 mg/kg/day orally, adjusted based on plasma tyrosine levels
Dose Range:
0.5 - 2 mg
Condition-Specific Dosing:
Hereditary Tyrosinemia Type 1 (HT-1):
Initial 0.5 mg/kg/day, adjusted to maintain plasma tyrosine levels between 200-600 micromol/L. Maximum dose 2 mg/kg/day.
Pediatric Dosing
Neonatal:
Initial 0.5 mg/kg/day, adjusted based on plasma tyrosine levels. Maximum dose 2 mg/kg/day.
Infant:
Initial 0.5 mg/kg/day, adjusted based on plasma tyrosine levels. Maximum dose 2 mg/kg/day.
Child:
Initial 0.5 mg/kg/day, adjusted based on plasma tyrosine levels. Maximum dose 2 mg/kg/day.
Adolescent:
Initial 0.5 mg/kg/day, adjusted based on plasma tyrosine levels. Maximum dose 2 mg/kg/day.
Dose Adjustments
Renal Impairment:
Mild:
No dose adjustment necessary
Moderate:
No dose adjustment necessary
Severe:
No dose adjustment necessary
Dialysis:
Not established, caution advised. Nitisinone is highly protein-bound and not expected to be dialyzable.
Hepatic Impairment:
Mild:
No dose adjustment necessary
Moderate:
No dose adjustment necessary
Severe:
No dose adjustment necessary
Pharmacology
Mechanism of Action
Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme upstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting HPPD, nitisinone prevents the accumulation of toxic metabolites (maleylacetoacetate and fumarylacetoacetate) that cause liver and kidney damage in patients with hereditary tyrosinemia type 1 (HT-1). This inhibition leads to an accumulation of tyrosine, which is managed by a strict low-tyrosine, low-phenylalanine diet.
Pharmacokinetics
Absorption:
Bioavailability:
Not explicitly quantified, but well absorbed orally.
Tmax:
3-8 hours
FoodEffect:
Food does not significantly affect absorption.
Distribution:
Vd:
Approximately 0.2 L/kg
ProteinBinding:
>95% (primarily albumin)
CnssPenetration:
Limited
Elimination:
HalfLife:
Approximately 54 hours (range 36-90 hours)
Clearance:
Not available
ExcretionRoute:
Primarily renal (as metabolites)
Unchanged:
<1% in urine
Pharmacodynamics
OnsetOfAction:
Within days to weeks (biochemical effect on tyrosine levels)
PeakEffect:
Not applicable (chronic enzyme inhibition)
DurationOfAction:
Due to long half-life, effects persist for several days after discontinuation.
Safety & Warnings
Side Effects
Urgent Side Effects: Seek Medical Help Right Away
While rare, some people may experience severe and potentially life-threatening side effects when taking this medication. If you notice any of the following symptoms, contact your doctor or seek immediate medical attention:
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 infection, such as:
+ Fever
+ Chills
+ Sore throat (due to low white blood cell counts, which may increase the risk of infection)
Unexplained bruising or bleeding (due to low platelet counts, which may increase the risk of bleeding)
Other Possible Side Effects
Like all medications, this drug can cause side effects. Many people experience no side effects or only 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, discuss them with your doctor.
Reporting Side Effects
To report side effects, you can:
Call your doctor for medical advice
Contact the FDA at 1-800-332-1088
* Visit the FDA's MedWatch website at https://www.fda.gov/medwatch
While rare, some people may experience severe and potentially life-threatening side effects when taking this medication. If you notice any of the following symptoms, contact your doctor or seek immediate medical attention:
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 infection, such as:
+ Fever
+ Chills
+ Sore throat (due to low white blood cell counts, which may increase the risk of infection)
Unexplained bruising or bleeding (due to low platelet counts, which may increase the risk of bleeding)
Other Possible Side Effects
Like all medications, this drug can cause side effects. Many people experience no side effects or only 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, discuss them with your doctor.
Reporting Side Effects
To report side effects, you can:
Call your doctor for medical advice
Contact the FDA at 1-800-332-1088
* Visit the FDA's MedWatch website at https://www.fda.gov/medwatch
Seek Immediate Medical Attention If You Experience:
- Eye pain or redness
- Sensitivity to light (photophobia)
- Blurred vision or vision changes
- Skin thickening or lesions (especially on palms and soles)
- Numbness, tingling, or weakness in hands or feet
- Unexplained bleeding or bruising
- Yellowing of skin or eyes (jaundice)
- Swelling in abdomen or legs
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 health problems you have, as this medication may interact with other drugs or health conditions.
To ensure your safety, it is crucial to verify that it is safe to take this medication with all your other 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 health problems you have, as this medication may interact with other drugs or health conditions.
To ensure your safety, it is crucial to verify that it is safe to take this medication with all your other 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 recommend regular urine tests to check for any potential issues.
To monitor for any potential eye problems, follow your doctor's recommendations for scheduling an eye exam.
Adhere to the personalized diet plan that your doctor has outlined for you.
If you are pregnant, planning to become pregnant, or are breastfeeding, notify your doctor immediately. You and your doctor will need to discuss the potential benefits and risks of this medication to both you and your baby.
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 recommend regular urine tests to check for any potential issues.
To monitor for any potential eye problems, follow your doctor's recommendations for scheduling an eye exam.
Adhere to the personalized diet plan that your doctor has outlined for you.
If you are pregnant, planning to become pregnant, or are breastfeeding, notify your doctor immediately. You and your doctor will need to discuss the potential benefits and risks of this medication to both you and your baby.
Overdose Information
Overdose Symptoms:
- Exaggerated side effects, particularly those related to high tyrosine levels (e.g., severe eye pain, photophobia, skin lesions, neurological symptoms).
What to Do:
Seek immediate medical attention. Contact a poison control center (1-800-222-1222). Management is supportive and may involve reducing nitisinone dose and strict dietary control to lower tyrosine levels.
Drug Interactions
Monitoring
Baseline Monitoring
Plasma tyrosine levels
Rationale: To establish baseline and guide initial dosing.
Timing: Prior to initiation of therapy
Liver function tests (ALT, AST, bilirubin, albumin, INR)
Rationale: To assess baseline hepatic status, as HT-1 affects the liver.
Timing: Prior to initiation of therapy
Renal function tests (BUN, creatinine)
Rationale: To assess baseline renal status, as HT-1 affects the kidneys.
Timing: Prior to initiation of therapy
Platelet count
Rationale: To establish baseline, as thrombocytopenia can be an adverse effect.
Timing: Prior to initiation of therapy
Alpha-fetoprotein (AFP)
Rationale: Tumor marker for hepatocellular carcinoma, a complication of HT-1.
Timing: Prior to initiation of therapy
Routine Monitoring
Plasma tyrosine levels
Frequency: Weekly for the first month, then monthly or as clinically indicated
Target: 200-600 micromol/L
Action Threshold: If >600 micromol/L, consider dose reduction or dietary adjustment. If <200 micromol/L, consider dose increase or dietary adjustment.
Liver function tests (ALT, AST, bilirubin)
Frequency: Monthly for the first few months, then every 3-6 months or as clinically indicated
Target: Within normal limits
Action Threshold: Significant elevations may require investigation or dose adjustment.
Platelet count
Frequency: Monthly for the first few months, then every 3-6 months or as clinically indicated
Target: Within normal limits
Action Threshold: Significant decrease may require investigation or dose adjustment.
Alpha-fetoprotein (AFP)
Frequency: Every 3-6 months
Target: Decreasing or stable within normal limits
Action Threshold: Persistent elevation or increase may indicate hepatocellular carcinoma and require further imaging.
Ophthalmologic examination (slit lamp)
Frequency: Annually or if visual symptoms occur
Target: Normal
Action Threshold: Corneal opacities or other ocular findings may indicate high tyrosine levels.
Symptom Monitoring
- Eye pain
- Photophobia
- Corneal opacities
- Skin lesions (hyperkeratosis)
- Neurological symptoms (e.g., peripheral neuropathy)
- Unexplained bleeding or bruising (due to thrombocytopenia)
- Signs of liver dysfunction (e.g., jaundice, ascites)
Special Patient Groups
Pregnancy
Based on animal data, nitisinone may cause fetal harm. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. The underlying condition (HT-1) also poses risks to pregnancy.
Trimester-Specific Risks:
First Trimester:
Potential for teratogenicity based on animal studies.
Second Trimester:
Potential for fetal harm.
Third Trimester:
Potential for fetal harm.
Lactation
There are no data on the presence of nitisinone in human milk, the effects on the breastfed infant, or the effects on milk production. Due to the potential for serious adverse reactions in a breastfed infant, breastfeeding is not recommended during nitisinone treatment.
Infant Risk:
Unknown, but potential for serious adverse effects due to drug's mechanism of action and long half-life. Consider risk vs. benefit.
Pediatric Use
Nitisinone is indicated for pediatric patients with HT-1. Dosing is weight-based and adjusted according to plasma tyrosine levels. Long-term safety and efficacy have been established in this population.
Geriatric Use
Hereditary tyrosinemia type 1 is rarely diagnosed in geriatric patients. Clinical studies 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Clinical Information
Clinical Pearls
- Strict adherence to a low-tyrosine, low-phenylalanine diet is paramount for the efficacy and safety of nitisinone therapy. Nitisinone alone is insufficient to manage HT-1.
- Regular monitoring of plasma tyrosine levels is critical to ensure therapeutic efficacy and prevent tyrosine-related adverse effects (e.g., ocular and dermatological lesions).
- Patients should be monitored for signs of hepatocellular carcinoma (HCC) with regular AFP measurements and imaging, as nitisinone does not eliminate the risk of HCC in HT-1 patients.
- Nitisinone has a long half-life, allowing for once-daily dosing, but also meaning that steady-state is reached slowly and drug levels persist for an extended period after discontinuation.
- Educate patients and caregivers about the importance of reporting any new or worsening eye symptoms (e.g., photophobia, eye pain) or skin changes.
Alternative Therapies
- Liver transplantation (curative for HT-1, but associated with significant risks and lifelong immunosuppression)
Cost & Coverage
Average Cost:
Extremely high (orphan drug) per 30 capsules
Generic Available:
Yes
Insurance Coverage:
Specialty Tier (requires prior authorization and often case management)
General Drug Facts
If your symptoms or health condition do not improve or worsen over time, it is essential to contact your doctor for further evaluation and guidance. To ensure safe and effective treatment, never share your medication with others or take someone else's medication. Some medications may have additional patient information leaflets, so it is a good idea to consult with your pharmacist for more information. If you have any questions or concerns about your medication, do not hesitate to discuss them with 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 reporting the overdose, be prepared to provide detailed information, including the name of the medication taken, the amount consumed, and the time it occurred.