2.1 Dosage

Starting Dosage

The recommended starting dosage of NITYR is 0.5 mg/kg orally twice daily. Round up to the nearest dosage that can be administered using the available tablet strengths [see Dosage Forms and Strengths (3)]. Titrate the dosage for individual patients, as needed based on biochemical and/or clinical response.

Dosage Titration

• Monitor plasma and/or urine succinylacetone concentrations, liver function parameters and alpha-fetoprotein levels.
• If succinylacetone is still detectable one month after the start of nitisinone treatment, increase the nitisinone dosage to 0.75 mg/kg twice daily. A maximum dosage of 1 mg/kg orally twice daily may be needed based on the evaluation of all biochemical parameters. Round up to the nearest dosage that can be administered using the available tablet strengths.
• If the biochemical response is satisfactory, the dosage should be adjusted only according to body weight gain.
• During the initiation of therapy or if there is a deterioration in the patient’s condition, it may be necessary to follow all available biochemical parameters more closely (i.e., plasma succinylacetone, urine 5-aminolevulinate (ALA) and erythrocyte porphobilinogen (PBG)-synthase activity).

2.2 Preparation and Administration Instructions

• Maintain dietary restriction of tyrosine and phenylalanine when taking NITYR.
• NITYR can be taken with or without food.
• For patients, including pediatric patients, who have difficulty swallowing intact tablets, NITYR can be disintegrated in water and administered using an oral syringe. If patients can swallow semi-solid foods, NITYR tablets can be crushed and mixed with applesauce. Administration of NITYR with other liquids or foods has not been studied and is not recommended.

Preparation and Administration of NITYR with Water in an Oral Syringe:

• A 5-mL oral syringe with a cap will be provided by a pharmacist.
• Follow the instructions below for one or two intact tablets, depending on the number of tablets needed to achieve the patient’s individual dosage.
• Do not prepare more than two tablets at once within the same oral syringe.
• If patient’s dosage requires more than two tablets, follow the steps below using multiple oral syringes to achieve the required dose.

One Tablet

1. Remove the plunger from the 5-mL oral syringe and insert a single, intact tablet.
2. Replace the plunger and draw up 2.6 mL of room temperature water. 
3. Cap the oral syringe and leave the oral syringe for at least 60 minutes.
4. After 60 minutes, turn the oral syringe up and down for at least 30 seconds to suspend the material.
5. Inspect the syringe to ensure the tablet has disintegrated prior to administration to the patient. Administer immediately. However, do not administer unless the tablet has fully disintegrated.
6. If the tablet is not fully disintegrated, leave the oral syringe for an additional 10 minutes. Before administration of the suspension to the patient, turn the oral syringe up and down for 30 seconds to re-suspend the particles.  Inspect the syringe again to ensure the tablet has disintegrated prior to administration to the patient. Do not administer unless the tablet has fully disintegrated.
7. Administer immediately. However, if this is not possible, the suspension can be stored at room temperature in the capped oral syringe, protected from direct sunlight for up to 24 hours after adding water to the tablets. Discard after 24 hours.
8. Uncap the oral syringe and administer the suspension into the patient's mouth. To facilitate full administration, avoid depressing the plunger to the end of the oral syringe and leave a gap between the plunger and the oral syringe.
9. Rinse the oral syringe by drawing up 2 mL of water. Cap the oral syringe and shake well for 10 seconds to suspend any remaining particles.
10. Uncap the oral syringe and administer the suspension into the patient’s mouth, this time fully depressing the plunger. If particles are still present in the syringe, repeat steps 9-10.

Two Tablets

1. Remove the plunger from the 5-mL oral syringe and insert two intact tablets.
2. Replace the plunger and draw up 5 mL of room temperature water. 
3. Cap the oral syringe and leave it for at least 60 minutes.
4. After 60 minutes, turn the oral syringe up and down for at least 30 seconds to suspend the material.
5. Inspect the syringe to ensure the tablets have disintegrated prior to administration to the patient. Administer immediately. However, do not administer unless the tablet has fully disintegrated.
6. If the tablet is not fully disintegrated, leave the oral syringe for an additional 10 minutes. Before administration of the suspension to the patient, turn the oral syringe up and down for 30 seconds to re-suspend the particles. Inspect the syringe again to ensure the tablet has disintegrated prior to administration to the patient. Do not administer unless the tablet has fully disintegrated.
7. Administer immediately. However, if this is not possible, the suspension can be stored at room temperature in the capped oral syringe, protected from direct sunlight for up to 24 hours after adding water to the tablets. Discard after 24 hours.
8. Uncap the oral syringe and administer the suspension into the patient's mouth. To facilitate full administration, avoid depressing the plunger to the end of the oral syringe and leave a gap between the plunger and the oral syringe.
9. Rinse the oral syringe by drawing up 2 mL of water. Cap the oral syringe and shake well for 10 seconds to suspend any remaining particles.
10. Uncap the oral syringe and administer the suspension into the patient’s mouth, this time fully depressing the plunger and ensuring the syringe is empty. If particles are still present in the syringe, repeat steps 9-10.

Preparation and Administration of NITYR Mixed in Applesauce

For patients who can swallow semi-solid food, NITYR can be crushed and mixed with applesauce:

1. Measure around one teaspoon of applesauce and transfer it into a clean container (e.g., clean glass).
2. Always crush one tablet at a time. Position the tablet between two metal teaspoons and apply light pressure on the top spoon. The two teaspoons should overlap each other to form a fine powder.
3. Press and rotate the two teaspoons against each other repeatedly until all of the tablet is in a fine powder.
4. Carefully transfer the resulting powder to the applesauce container ensuring all the powder is transferred, and no powder residue remains on the teaspoons.
5. If more than one tablet is needed, repeat the procedure starting from Step 2 and collect all the resulting powder together in the applesauce container.
6. Mix the powder into the applesauce until the powder is well dispersed.
7. Administer the entire NITYR-applesauce mixture to the patient’s mouth using a teaspoon. Administer immediately. However, if this is not possible, the mixture can be stored at room temperature, out of direct sunlight, for up to 2 hours after adding the crushed tablets to the applesauce. Discard any mixture that has not been given within 2 hours.
8. To assure that any leftover applesauce mixture from the container is recovered, add around one teaspoon of applesauce to the same container and mix the fresh applesauce with the remaining mixture.
9. Administer the additional NITYR-applesauce mixture immediately to the patient’s mouth using a teaspoon.  

5.1 Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques

Nitisinone is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway [see Clinical Pharmacology (12.1)]. Therefore, treatment with NITYR may cause an increase in plasma tyrosine levels in patients with HT-1. Maintain concomitant reduction in dietary tyrosine and phenylalanine while on NITYR. Do not adjust the dosage of NITYR in order to lower the plasma tyrosine concentration. Maintain plasma tyrosine levels below 500 micromol/L. Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine levels and levels greater than 500 micromol/L may lead to the following:

• Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia have been reported in patients treated with nitisinone [see Adverse Reactions (6.1)]. Therefore, a baseline ophthalmologic examination including slit-lamp examination should be considered prior to initiating NITYR treatment. Patients who develop photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning of the eyes during treatment with NITYR should undergo slit-lamp re-examination and immediate measurement of the plasma tyrosine concentration.
• Variable degrees of intellectual disability and developmental delay. In patients treated with NITYR who exhibit an abrupt change in neurologic status, perform a clinical laboratory assessment including plasma tyrosine levels.
• Painful hyperkeratotic plaques on the soles and palms.

In patients with HT-1 treated with dietary restrictions and NITYR who develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake.

5.2 Leukopenia and Severe Thrombocytopenia

In clinical trials, patients treated with another oral formulation of nitisinone and dietary restriction developed transient leukopenia (3%), thrombocytopenia (3%), or both (1.5%) [see Adverse Reactions (6.1)]. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Monitor platelet and white blood cell counts during therapy with NITYR.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of NITYR has been established based on studies of another oral formulation of nitisinone in patients with HT-1 [see Clinical Studies (14)]. Below is a display of the adverse reactions of nitisinone in these studies.

Nitisinone was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of nitisinone was 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, biochemical, and enzyme markers. The recommended starting dosage of NITYR is 0.5 mg/kg twice daily [see Dosage and Administration (2.1)]. Median duration of treatment was 22 months (range 0.1 to 80 months).

The most serious adverse reactions reported during nitisinone treatment were thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels [see Warnings and Precautions (5.1, 5.2)]. Fourteen patients experienced ocular/visual events. The duration of the symptoms varied from 5 days to 2 years. Six patients had thrombocytopenia, three of which had platelet counts 30,000/microL or lower. In 4 patients with thrombocytopenia, platelet counts gradually returned to normal (duration up to 47 days) without change in the nitisinone dose. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia.

Patients with HT-1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure requiring liver transplantation. These complications of HT-1 were observed in patients treated with nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 1%).

The most common adverse reactions reported in the clinical trial are summarized in Table 1.

Adverse reactions reported in less than 1% of the patients, included death, seizure, brain tumor, encephalopathy, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastrointestinal hemorrhage, melena, elevated hepatic enzymes, liver enlargement, hypoglycemia, septicemia, and bronchitis.

7.1 Interaction with CYP2C9 Substrates

If NITYR is co-administered with drugs that are metabolized by CYP2C9, additional monitoring may be warranted because of a potential for increased systemic exposure of these drugs [see Clinical Pharmacology (12.3)]. The risk is dependent upon the particular 2C9 substrate and its adverse reaction profile.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Pediatric patients with HT-1, ages birth to 17 years have been treated with nitisinone in an open-label, uncontrolled clinical study [see Clinical Studies (14)]. Monitoring of plasma and urine succinylacetone levels are recommended in the pediatric patients to ensure adequate control [see Dosage and Administration (2)]. A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine.

8.5 Geriatric Use

Clinical studies of nitisinone did not include any subjects aged 65 and over. No pharmacokinetic studies of nitisinone have been performed in geriatric patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy in this patient population.

12.1 Mechanism of Action

Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1.Nitisinone inhibits catabolism of the amino acid tyrosine and can result in elevated plasma levels of tyrosine. Therefore, treatment with nitisinone requires restriction of the dietary intake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasma levels of tyrosine [see Warnings and Precautions (5.1)].

12.3 Pharmacokinetics

The single-dose pharmacokinetics of nitisinone have been studied for NITYR tablets in healthy adult subjects.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of nitisinone was assessed in a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice. There were no drug-related neoplastic findings in male or female Tg.rasH2 mice at doses up to 100 mg/kg/ day nitisinone (approximately 8.1 times the recommended initial dose of 1 mg/kg/day on a body surface area basis).

Nitisinone was not genotoxic in the Ames test and the in vivo mouse liver unscheduled DNA synthesis (UDS) test. Nitisinone was mutagenic in the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test and in an in vivo mouse bone marrow micronucleus test.

In a single dose-group study in rats given 100 mg/kg (16.2 times the recommended initial dose of 1 mg/kg/day on a body surface area basis), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.

Important information for taking NITYR using an oral syringe

• Prepare only 1 or 2 NITYR tablets in an oral syringe at one time.
• Each tablet is white to beige in color and can have yellow to brown tiny specks.
• Use a 5 mL oral syringe with a cap (see below) to prepare NITYR tablets in an oral syringe. Ask your pharmacist for your oral syringe. You may need more than one 5 mL oral syringe if you take more than 2 NITYR tablets for your prescribed dose.
• Use only room temperature water to prepare NITYR tablets in an oral syringe.
• Wash your hands well before preparing NITYR tablets using an oral syringe.
• Talk to your healthcare provider or pharmacist if you have questions about NITYR tablets or how to use the oral syringe. You can also contact the NITYR Patient Support Program by calling the United States (U.S.) toll free phone number, 1-800-847-8714.

How to prepare and take 1 NITYR tablet using a 5 mL oral syringe:

Step 1. Remove the cap from the 5 mL oral syringe. Step 2. Remove the plunger from the oral syringe and place 1 whole NITYR tablet inside the oral syringe (See Figure A).
Step 3. Replace the plunger (See Figure B).
Step 4. Draw up 2.6 mL of room temperature water into the oral syringe. Each line on the barrel of the syringe is 0.2 mL. There may be some air in the oral syringe. Leave the air in the oral syringe (See Figure C).
Step 5. Replace the cap on the oral syringe. Let the oral syringe sit for at least 60 minutes (See Figure D).
Step 6. Turn the oral syringe up and down for at least 30 seconds (See Figure E).
Step 7. Check the oral syringe to see if the NITYR tablet has broken apart into very small pieces and the pieces are evenly spread through the water (suspension) (See Figure F). Do not take the suspension if there are any large pieces of the NITYR tablet in the suspension or if there are any pieces of the tablet that are not evenly spread through the water. If there are any pieces of the tablet that are not evenly spread through the water, let the oral syringe sit for 10 minutes. Before giving the suspension, turn the oral syringe up and down for 30 seconds to continue to spread the pieces of NITYR tablet in the suspension.
Step 8. Remove the cap from the oral syringe (See Figure G).
Step 9. Place the tip of the oral syringe in the mouth right away. If giving to a child, place the tip of the oral syringe along the inner cheek of the child’s mouth (See Figure H).
Step 10. While keeping the oral syringe in the mouth, slowly push down on the plunger until a small amount of air is left in the oral syringe, between the plunger and the tip of the oral syringe (See Figure I). Do not press the plunger all the way down to the end of the syringe.
Step 11. Draw up an additional 2 mL of water into the oral syringe (See Figure J).
Step 12. Replace the cap on the oral syringe. Shake the oral syringe well for 10 seconds to spread the remaining tablet pieces evenly through the water in the oral syringe (See Figure K).
Step 13. Remove the cap from the oral syringe (See Figure L).
Step 14. Place the tip of the oral syringe in the mouth right away. If giving to a child, place the tip of the oral syringe along the inner cheek of the child’s mouth (See Figure M).
Step 15. While keeping the oral syringe in the mouth, slowly push down on the plunger until the oral syringe is empty (See Figure N). In case any pieces of the tablet are still present in the oral syringe, repeat steps 11 through 15.

Step 16. After use, remove the plunger from the syringe barrel. Rinse the syringe and the plunger with water after each use and let it dry. Do not replace the plunger into the barrel of the oral syringe until ready to use again to allow it to dry. Do not throw away the oral syringe or plunger.

If you are not taking the water and NITYR tablet suspension as soon as it is prepared, complete steps 1 through 5. When you are ready to take the suspension, complete steps 6 through 16.

After adding water to the tablet in the oral syringe you can keep NITYR tablet suspension at room temperature for 24 hours. Store NITYR tablet suspension in the oral syringe with the cap on and out of direct sunlight until ready for use. The suspension does not need to be refrigerated. Throw away any suspension that is not used within 24 hours after adding water to the tablet in the oral syringe. Empty the syringe in the drain and throw away (dispose of) the syringe by placing it in a trash can.

How to prepare and take 2 NITYR tablets using a 5 mL oral syringe:

Step 1. Remove the cap from the 5 mL oral syringe. Step 2. Remove the plunger from the oral syringe and place 2 whole NITYR tablets inside the oral syringe (See Figure A).
Step 3. Replace the plunger (See Figure B).
Step 4. Draw up 5 mL of room temperature water into the oral syringe. There may be some air in the oral syringe. Leave the air in the oral syringe (See Figure C).
Step 5. Replace the cap on the oral syringe. Let the oral syringe sit for at least 60 minutes (See Figure D).
Step 6. Turn the oral syringe up and down for at least 30 seconds (See Figure E).
Step 7. Check the oral syringe to see if the NITYR tablets have broken apart into very small pieces and the pieces are evenly spread through the water (suspension) (See Figure F). Do not take the suspension if there are any large pieces of the NITYR tablets in the suspension or if there are any pieces of the tablets that are not evenly spread through the water. If there are any pieces of the tablets that are not evenly spread through the water, let the oral syringe sit for 10 minutes. Before giving the suspension, turn the oral syringe up and down for 30 seconds to continue to spread the pieces of NITYR tablets in the suspension.
Step 8. Remove the cap from the oral syringe (See Figure G).
Step 9. Place the tip of the oral syringe in the mouth right away. If giving to a child, place the tip of the oral syringe along the inner cheek of the child’s mouth (See Figure H).
Step 10. While keeping the oral syringe in the mouth, slowly push down on the plunger until a small amount of air is left in the oral syringe, between the plunger and the tip of the oral syringe (See Figure I). Do not press all the way down on the plunger.
Step 11. Draw up 2 mL of water into the oral syringe (See Figure J).
Step 12. Replace the cap on the oral syringe. Shake the oral syringe well for 10 seconds to spread the remaining tablet pieces evenly through the water in the oral syringe (See Figure K).
Step 13. Remove the cap from the oral syringe (See Figure L).
Step 14. Place the tip of the oral syringe in the mouth right away. If giving to a child, place the tip of the oral syringe along the inner cheek of the child’s mouth (See Figure M).
Step 15. While keeping the oral syringe in the mouth, slowly push down on the plunger until the oral syringe is empty (See Figure N). In case any pieces of the tablets are still present in the oral syringe, repeat steps 11 through 15.

Step 16. After use, remove the plunger from the oral syringe barrel. Rinse the oral syringe with water after each use and let it dry. Do not replace the plunger into the barrel of the oral syringe until ready to use again to allow it to dry. Do not throw away the oral syringe.

If you are not taking the water and NITYR tablets suspension as soon as it is prepared, complete steps 1 through 5. When you are ready to take the suspension, complete steps 6 through 16.

After adding water to the tablet in the oral syringe you can keep NITYR tablet suspension at room temperature for 24 hours. Store the suspension in the oral syringe with the cap on and out of direct sunlight until use. The suspension does not need to be refrigerated. Throw away any suspension that is not used within 24 hours after adding water to the tablets in the oral syringe. Empty the syringe in the drain and throw away (dispose of) the syringe by placing it in a trash can.

If more than two NITYR tablets are needed for the prescribed dose follow the instructions for "How to prepare and take 1 NITYR tablet using an oral syringe" and "How to prepare and take 2 NITYR tablets using an oral syringe" until you get your prescribed dose. You should not add more than 2 tablets to one syringe at a time.

How to prepare and take NITYR tablets in applesauce:

• Wash your hands well before preparing NITYR tablets in applesauce.
• Crush only 1 NITYR tablet at a time.

Take the NITYR tablet and applesauce mixture within 2 hours after adding the NITYR tablet powder to the applesauce. Store the NITYR tablet and applesauce mixture at room temperature and out of direct sunlight until use. The mixture does not need to be refrigerated. Throw away any mixture that is not used within 2 hours after mixing in a trash can.

How should I store NITYR?

• NITYR tablets do not need to be refrigerated.
• Store NITYR tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Store NITYR tablets in the container that it comes in and keep the container tightly closed.
• Keep NITYR tablets and NITYR that has been prepared in an oral syringe with water or in applesauce out of direct sunlight.

Take NITYR within 24 hours of adding water to NITYR tablets in an oral syringe. Throw away any unused NITYR tablets and water stored in the oral syringe after 24 hours of being mixed together.

Take NITYR within 2 hours of adding crushed NITYR tablets to applesauce. Throw away any crushed NITRY tablets and applesauce mixture that has not been used within 2 hours.

Talk to your healthcare provider or pharmacist if you have questions about NITYR tablets or how to use the oral syringe. You can also contact the NITYR Patient Support Program on the U.S. toll free number, 1-800-847-8714. For more information visit: www.nityr.us

Keep NITYR and all medicines out of the reach of children.

Active ingredient: nitisinone

Inactive ingredients: glyceryl dibehenate and lactose monohydrate

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured by:
Rivopharm SA
Centro Insema
6928 Manno, Switzerland

Marketed by:
Cycle Pharmaceuticals Ltd.
Bailey Grundy Barrett Building
Little St. Mary’s Lane
CB2 1RR, Cambridge, United Kingdom

AW000050

Issued: November 2018