Get your patient on Nityr - Nitisinone tablet (Nitisinone)

The recommended starting dosage of NITYR is 0.5 mg/kg (actual body weight) administered orally twice daily. Titrate the dose in each individual patient based on biochemical and/or clinical response.

Administer NITYR with or without food [see Clinical Pharmacology (12.3 )] .

Maintain dietary restriction of tyrosine and phenylalanine when administering NITYR.

Maintenance Dosage

The recommended maintenance dosage of NITYR in patients 5 years of age and older who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone, is 1 to 2 mg/kg once daily [see Clinical Pharmacology (12.2 )] .

A maximum total daily dosage of 2 mg/kg may be needed based on the evaluation of all biochemical parameters.

Missed Dose

If a dose of NITYR is missed, do not administer two doses at once to make up for a missed dose. Take the next dose at the scheduled time.

Monitor plasma and/or urine succinylacetone concentrations, liver function parameters and alpha-fetoprotein levels.

Monitor all biochemical parameters more closely (i.e. plasma and/or urine succinylacetone, urine 5-aminolevulinate (ALA), and erythrocyte porphobilinogen (PBG)-synthase activity during initiation of therapy, when switching from twice daily to once daily dosing, or if there is a deterioration in the patient’s condition.

If succinylacetone is still detectable in blood or urine 4 weeks after the start of nitisinone treatment, increase the NITYR dosage to 0.75 mg/kg twice daily. If the biochemical response is satisfactory (undetectable blood and/or urine succinylacetone), the dosage should be adjusted only according to body weight gain and not according to plasma tyrosine levels.

Maintain plasma tyrosine levels below 500 micromol/L by dietary restriction of tyrosine and phenylalanine intake [see Warnings and Precautions (5.1 )] . In patients who develop plasma tyrosine levels above 500 micromol/L, assess dietary tyrosine and phenylalanine intake. Do not adjust the NITYR dosage in order to lower the plasma tyrosine concentration.

For patients who have difficulty swallowing intact tablets, disintegrate NITYR in water and administer using an oral syringe. For patients who 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:
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 and prescribed number of tablets 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 the length of time below:
• 15 minutes for a 2 mg tablet
• 60 minutes for a 5 mg or 10 mg tablet

4. 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 fully disintegrated. If the tablet is not fully disintegrated, leave the oral syringe for an additional 10 minutes. Do not administer unless the tablet has fully disintegrated. Before administration of the suspension, turn the oral syringe up and down for 30 seconds to ensure the particles are suspended.

6. Uncap the oral syringe and administer all 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.

7. Fill the oral syringe by drawing up 2 mL of water. Shake well and administer while this time fully depressing the plunger. If particles are still present in the syringe, repeat this step.

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 the length of time below:
• 15 minutes for 2 mg tablets
• 60 minutes for 5 mg or 10 mg tablets

4. 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 fully disintegrated. If the tablet is not fully disintegrated, leave the oral syringe for an additional 10 minutes. Do not administer unless the tablet has fully disintegrated. Before administration of the suspension, turn the oral syringe up and down for 30 seconds to ensure the particles are suspended.

6. Uncap the oral syringe and administer all 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.

7. Fill the oral syringe by drawing up 2 mL of water. Shake well and administer while this time fully depressing the plunger. If particles are still present in the syringe, repeat this step.

Storage Instructions for the NITYR with water in an Oral Syringe

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.

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 approximately one teaspoon of applesauce and transfer it into a clean container (e.g., clean glass).

2. Crush only 1 tablet at a time between two teaspoons forming a fine powder. Repeat this step if more than 1 tablet is needed.

3. Transfer the powder to the applesauce container ensuring all the powder is transferred and no powder residue remains on the teaspoon.

4. Mix the powder into the applesauce until the powder is well dispersed.

5. Administer the entire NITYR-applesauce mixture to the patient immediately or within 2 hours of mixing.

6. To ensure that there is not any remaining NITYR-applesauce mixture, add approximately one teaspoon of applesauce to the same container and administer to the patient.

Storage Instructions for NITYR Mixed in Apple Sauce

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 after 2 hours.

The safety and effectiveness of nitisinone have been established for the treatment of HT-1 in combination with dietary restriction of tyrosine and phenylalanine in pediatric patients. Use of NITYR for this indication is supported by evidence from one open-label, uncontrolled clinical study conducted with another oral formulation of nitisinone in 207 patients with HT-1 ages 0 to 22 years (median age 9 months) [see Clinical Studies (14 )] .

Clinical studies of nitisinone did not include any subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 of concomitant disease or other drug therapy in this patient population.

Treatment with NITYR may cause elevated plasma tyrosine levels in patients with HT-1. 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. All of which have been reported in patients treated with nitisinone [see Adverse Reactions (6.1 )] . In a clinical study in a non HT-1 population without dietary restriction and reported tyrosine levels > 500 micromol/L both symptomatic and asymptomatic keratopathies have been observed. Therefore, perform a baseline ophthalmologic examination including slit-lamp examination prior to initiating NITYR treatment and regularly thereafter. Patients who develop photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning of the eyes or tyrosine levels are > 500 micromol/L during treatment with NITYR should undergo slit-lamp reexamination 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.

Maintain concomitant reduction in dietary tyrosine and phenylalanine while on NITYR treatment. In patients with HT-1 who are treated with NITYR and dietary restriction and develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake. Do not adjust NITYR dosage in order to lower the plasma tyrosine concentration. Maintain plasma tyrosine levels below 500 micromol/L.

In clinical trials, patients treated with another oral formulation of nitisinone and dietary restriction developed reversible 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 NITYR therapy.

Serious and or clinically significant adverse reactions described elsewhere in labeling include:

• Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques Due To Elevated Plasma Tyrosine Levels [see Warnings and Precautions (5.1 )]
• Leukopenia and Severe Thrombocytopenia [see Warnings and Precautions (5.2 )]

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.

Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer and an inhibitor of OAT1/OAT3. TABLE 2 includes drugs with clinically significant drug interactions when administered concomitantly with NITYR and instructions for preventing or managing them.

TABLE 2. Clinically Significant Interactions Affecting Co-Administered Drugs

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.

In a clinical study, patients with HT-1 were diagnosed by the presence of succinylacetone in urine or plasma and treated with another oral formulation of nitisinone [see Clinical Studies (14 )]. In all 186 patients whose urine succinylacetone was measured, the urinary succinylacetone concentration decreased to less than 1 mmol/mol creatinine, the lower limit of quantitation. The median time to normalization of urine succinylacetone was 0.3 months. The probability of recurrence of abnormal values of urine succinylacetone was 1% at a nitisinone concentration of 37 micromol/L (95% confidence interval: 23, 51 micromol/L). In 87% (150/172) of patients whose plasma succinylacetone was measured, the plasma succinylacetone concentration decreased to less than 0.1 micromol/L, the lower limit of quantitation. The median time to normalization of plasma succinylacetone was 3.9 months.

In another study, comparing two dosing regimens of another oral formulation of nitisinone, succinylacetone was measured in urine and/or blood in 16 patients with HT-1 aged 5 years to 24 years. All study patients were on a stable nitisinone daily dosage (0.4 mg/kg/day to 1 mg/kg/day) during both study dosing regimens. After at least 4 weeks of twice daily dosing with nitisinone, both the urine and/or blood succinylacetone concentrations were below the limit of quantitation for the assay. Patients were then switched to once daily dosing with the same total daily dosage of nitisinone and blood and/or urine succinylacetone concentrations remained undetectable when measured following at least 4 weeks of treatment with once daily dosing.

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 )] .

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

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.