Orfadin 5mg 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
Category C
FDA Approved
Jan 2002
DEA Schedule
Not Controlled
Overview
What is this medicine?
Orfadin is a medication used to treat a rare genetic liver disease called hereditary tyrosinemia type 1 (HT-1). It works by blocking a specific enzyme in the body, which helps prevent the buildup of harmful substances that can damage the liver, kidneys, and nervous system. It must be taken along with a special low-tyrosine and low-phenylalanine 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 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 you store the medication at room temperature and do not use it within 45 days, discard it. Other brands can be stored at room temperature in a dry place, but not 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 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 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 you store the medication at room temperature and do not use it within 45 days, discard it. Other brands can be stored at room temperature in a dry place, but not 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.
Lifestyle & Tips
- Adhere strictly to a low-tyrosine and low-phenylalanine diet as prescribed by your doctor or dietitian. This is critical for preventing high tyrosine levels and associated side effects.
- Take the medication consistently every day as directed, usually once daily.
- Attend all scheduled doctor appointments and laboratory tests to monitor drug levels, tyrosine levels, and overall health.
- Report any new or worsening symptoms, especially eye pain, sensitivity to light, skin rashes, or changes in behavior, immediately to your healthcare provider.
Available Forms & Alternatives
Available Strengths:
Generic Alternatives:
Dosing & Administration
Adult Dosing
Standard Dose:
1 mg/kg/day orally, adjusted based on succinylacetone levels
Dose Range:
0.5 - 2 mg
Condition-Specific Dosing:
initialDose:
0.5 mg/kg/day, adjusted to 1 mg/kg/day if succinylacetone levels remain detectable
maximumDose:
2 mg/kg/day
Pediatric Dosing
Neonatal:
0.5 mg/kg/day orally, adjusted based on succinylacetone levels (same as adult)
Infant:
0.5 mg/kg/day orally, adjusted based on succinylacetone levels (same as adult)
Child:
0.5 mg/kg/day orally, adjusted based on succinylacetone levels (same as adult)
Adolescent:
0.5 mg/kg/day orally, adjusted based on succinylacetone levels (same as adult)
Dose Adjustments
Renal Impairment:
Mild:
No specific dose adjustment recommended, monitor closely
Moderate:
No specific dose adjustment recommended, monitor closely
Severe:
No specific dose adjustment recommended, monitor closely
Dialysis:
Not established, monitor closely
Hepatic Impairment:
Mild:
No specific dose adjustment recommended, monitor closely
Moderate:
No specific dose adjustment recommended, monitor closely
Severe:
No specific dose adjustment recommended, monitor closely
Pharmacology
Mechanism of Action
Nitisinone is a reversible 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 maleylacetoacetate and fumarylacetoacetate, which are converted to the toxic metabolites succinylacetoacetate and succinylacetone in patients with hereditary tyrosinemia type 1 (HT-1). This reduces the production of these toxic metabolites, thereby preventing liver and kidney damage, and neurological crises.
Pharmacokinetics
Absorption:
Bioavailability:
High (not precisely quantified, but well absorbed)
Tmax:
3 to 8 hours
FoodEffect:
Minimal effect on absorption, can be taken with or without food
Distribution:
Vd:
Approximately 0.2 L/kg
ProteinBinding:
>99% (primarily to albumin)
CnssPenetration:
Limited
Elimination:
HalfLife:
Approximately 54 hours (range 36 to 90 hours)
Clearance:
Not precisely quantified, but slow due to high protein binding and reabsorption
ExcretionRoute:
Primarily renal (as unchanged drug and metabolites)
Unchanged:
Approximately 60% of the dose is excreted unchanged in urine
Pharmacodynamics
OnsetOfAction:
Biochemical effect (reduction in succinylacetone) within days to weeks
PeakEffect:
Sustained reduction in succinylacetone levels with continued dosing
DurationOfAction:
Long, due to long half-life and tight binding to HPPD
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
Feeling confused, disoriented, or experiencing 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 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 an exhaustive 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.
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
Feeling confused, disoriented, or experiencing 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 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 an exhaustive 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)
- Skin lesions or rashes, especially on hands and feet
- Changes in behavior or development (in children)
- Unusual fatigue or weakness
- Yellowing of skin or eyes (jaundice)
- Easy bruising or bleeding
- Swelling in legs or abdomen
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 as a result of the allergy.
All medications you are currently taking, including prescription and over-the-counter (OTC) drugs, natural products, and vitamins. This information will help your doctor and pharmacist identify potential interactions between this medication and other substances you are taking.
* Any health problems you have, as this medication may interact with certain 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. Never start, stop, or change the dose of any medication without first consulting 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 as a result of the allergy.
All medications you are currently taking, including prescription and over-the-counter (OTC) drugs, natural products, and vitamins. This information will help your doctor and pharmacist identify potential interactions between this medication and other substances you are taking.
* Any health problems you have, as this medication may interact with certain 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. Never start, stop, or change the dose of any medication without first consulting your doctor.
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, 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.
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, 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.
Overdose Information
Overdose Symptoms:
- Symptoms of severe hypertyrosinemia (e.g., severe eye pain, photophobia, neurological symptoms, skin lesions)
- Increased liver enzyme levels
What to Do:
In case of suspected overdose, seek immediate medical attention or call a poison control center (e.g., 1-800-222-1222). Management is supportive and may involve reducing nitisinone dose and strict dietary control.
Drug Interactions
Moderate Interactions
- Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, phenobarbital): May decrease nitisinone levels, requiring dose adjustment.
- Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir): May increase nitisinone levels, though clinical significance is low due to high protein binding.
Monitoring
Baseline Monitoring
Liver function tests (ALT, AST, bilirubin)
Rationale: To assess baseline liver health and monitor for potential hepatotoxicity or progression of HT-1.
Timing: Prior to initiation of therapy
Kidney function tests (BUN, creatinine)
Rationale: To assess baseline kidney health, as HT-1 can affect renal tubules.
Timing: Prior to initiation of therapy
Plasma succinylacetone levels
Rationale: Primary biomarker for HT-1 disease activity and treatment efficacy. Levels should become undetectable.
Timing: Prior to initiation of therapy
Plasma tyrosine levels
Rationale: Nitisinone increases tyrosine levels; monitoring is crucial to prevent hypertyrosinemia-related adverse effects.
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
Ophthalmologic examination
Rationale: To assess for corneal opacities or other eye abnormalities associated with hypertyrosinemia.
Timing: Prior to initiation of therapy
Routine Monitoring
Plasma succinylacetone levels
Frequency: Weekly for the first month, then monthly until stable and undetectable, then every 3 months
Target: Undetectable
Action Threshold: If detectable, consider dose adjustment or adherence issues
Plasma tyrosine levels
Frequency: Weekly for the first month, then monthly until stable, then every 3 months
Target: <500-600 micromol/L (or <10 mg/dL)
Action Threshold: If >600 micromol/L, consider dietary adjustment or nitisinone dose reduction
Liver function tests (ALT, AST, bilirubin)
Frequency: Monthly for the first 3 months, then every 3-6 months
Target: Within normal limits
Action Threshold: Significant elevation may indicate disease progression or other liver issues
Alpha-fetoprotein (AFP)
Frequency: Every 3-6 months
Target: Within normal limits
Action Threshold: Persistent elevation may warrant further investigation for hepatocellular carcinoma
Ophthalmologic examination
Frequency: Annually, or more frequently if symptoms of hypertyrosinemia (e.g., photophobia, eye pain) occur
Target: Normal
Action Threshold: Presence of corneal opacities or other findings may require tyrosine level reduction
Symptom Monitoring
- Signs of hypertyrosinemia (e.g., eye pain, photophobia, corneal opacities, painful hyperkeratotic skin lesions, developmental delay, intellectual disability)
- Signs of liver dysfunction (e.g., jaundice, ascites, easy bruising/bleeding, fatigue)
- Signs of kidney dysfunction (e.g., edema, changes in urination)
- Neurological symptoms (e.g., peripheral neuropathy, seizures, weakness)
Special Patient Groups
Pregnancy
Category C. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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
It is not known whether nitisinone is excreted in human milk. Nitisinone is excreted in the milk of lactating rats. Because of the potential for serious adverse reactions in breastfed infants, 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.
Infant Risk:
Potential for serious adverse reactions; caution advised.
Pediatric Use
Approved for use in pediatric patients of all ages with HT-1. Dosing is weight-based and adjusted according to succinylacetone levels. Long-term safety and efficacy have been established.
Geriatric Use
Clinical studies of nitisinone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. No specific dose adjustments are recommended based on age, but monitor closely for adverse effects.
Clinical Information
Clinical Pearls
- Nitisinone is a life-saving medication for patients with hereditary tyrosinemia type 1 (HT-1) and must be used in conjunction with a strict low-tyrosine, low-phenylalanine diet.
- Regular monitoring of plasma succinylacetone (should be undetectable) and tyrosine levels (should be maintained below 500-600 micromol/L) is crucial for effective management and prevention of side effects.
- Hypertyrosinemia, if not controlled by diet, can lead to serious adverse effects including corneal opacities, painful skin lesions, and neurological symptoms.
- Lifelong treatment is typically required. Adherence to both medication and diet is paramount for preventing disease progression and complications.
- Patients should be educated on the importance of reporting any new visual or skin symptoms immediately.
Alternative Therapies
- Liver transplantation (curative, but associated with significant risks and complications, typically reserved for patients who fail medical therapy or present with advanced liver disease/hepatocellular carcinoma)
Cost & Coverage
Average Cost:
Extremely high (e.g., tens of thousands of USD) per 30 capsules
Generic Available:
Yes
Insurance Coverage:
Specialty Tier (requires prior authorization, often subject to high co-pays or co-insurance)
General Drug Facts
If your symptoms or health issues persist or worsen, it's essential to contact your doctor for further guidance. To ensure your safety, never share your medication with others or take someone else's medication. Some medications may come with an additional patient information leaflet, so be sure to check with your pharmacist for more information. If you have any questions or concerns about your 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 medical attention. When seeking help, be prepared to provide details about the medication taken, including the amount and time of ingestion.