Nitisinone by Eton Pharmaceuticals, Inc. / Zenara Pharma Private Limited / Sionc Pharmaceuticals Pvt. Ltd / Teena Biolabs Private Limited / Energon Labs Private Limited / Choksi Laboratorties Limited NITISINONE capsule

Nitisinone by

Drug Labeling and Warnings

Nitisinone by is a Prescription medication manufactured, distributed, or labeled by Eton Pharmaceuticals, Inc., Zenara Pharma Private Limited , Sionc Pharmaceuticals Pvt. Ltd, Teena Biolabs Private Limited, Energon Labs Private Limited, Choksi Laboratorties Limited. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NITISINONE CAPSULES safely and effectively. See full prescribing information for NITISINONE CAPSULES. NITISINONE Capsules, for oral use Initial U.S. Approval: 2002 1. INDICATIONS AND USAGE

    Nitisinone Capsules is indicated for the treatment of adult and pediatric patients with

    hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and

    phenylalanine.

  • 2. DOSAGE AND ADMINISTRATION

    2.1 Dosage

    Starting Dosage

    The recommended starting dosage of Nitisinone Capsules is 0.5 mg/kg administered orally

    twice daily.

    Maintenance Regimen

    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, the total daily

    dose of Nitisinone Capsules may be given once daily (e.g., 1 to 2 mg/kg once daily) [see

    Clinical Pharmacology (12.2)].

    Dosage Titration

    Titrate the dosage in each individual patient based on biochemical and/or clinical response.

    • Monitor plasma and/or urine succinylacetone concentrations, liver function

    parameters and alpha-fetoprotein levels.

    • If succinylacetone is still detectable in blood or urine 4 weeks after the start of

    nitisinone treatment, increase the nitisinone dosage to 0.75 mg/kg twice daily. A

    maximum total daily dosage of 2 mg/kg may be needed based on the evaluation of

    all biochemical parameters.

    • 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.

    • During initiation of therapy, when switching from twice daily to once daily dosing,

    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 and/or urine

    succinylacetone, urine 5- aminolevulinate (ALA) and erythrocyte porphobilinogen

    (PBG)-synthase activity).

    • 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 Nitisinone Capsules dosage in order to

    lower the plasma tyrosine concentration.

    2.2 Administration Instructions

    Administration of Nitisinone Capsules

    • Maintain dietary restriction of tyrosine and phenylalanine when taking Nitisinone

    Capsules.

    • Capsules: Take at least one hour before, or two hours after a meal [see Clinical

    Pharmacology (12.3)]. For patients who have difficulty swallowing the capsules, the

    capsules may be opened and the contents suspended in a small amount of water,

    formula or apple sauce immediately before use.

  • 3. DOSAGE FORMS AND STRENGTHS

    Capsules:

    • 2 mg: Size “3” hard gelatin capsules with white opaque cap imprinted with “NIT2” in

    black, and white opaque body imprinted ‘ZN11’ in black, filled with white to off-white

    powder.

    • 5 mg: Size “3” hard gelatin capsules with white opaque cap imprinted with “NIT5” in

    black, and white opaque body imprinted ‘ZN12’ in black, filled with white to off-white

    powder.

    • 10 mg: Size “3” hard gelatin capsules with white opaque cap imprinted with “NIT10”

    in black, and white opaque body imprinted ‘ZN13’ in black, filled with white to

    off-white powder.

    • 20 mg: Size “3” hard gelatin capsules with white opaque cap imprinted with “NIT20”

    in black, and white opaque body imprinted ‘ZN14’ in black, filled with white to

    off-white powder.

  • 4. CONTRAINDICATION

    None.

  • 5. WARNINGS AND PRECAUTIONS

    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

    nitisinone may cause an increase in plasma tyrosine levels in patients with HT-1. Maintain

    concomitant reduction in dietary tyrosine and phenylalanine while on nitisinone treatment.

    Do not adjust nitisinone dosage 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)]. 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 nitisinone 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 Nitisinone

    Capsules 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 nitisinone 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 nitisinone who develop elevated

    plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake.

    5.2. Leukopenia and Severe Thrombocytopenia

    In clinical trials, patients treated with 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 nitisinone therapy.

  • 6. ADVERSE REACTIONS

    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 clinical practice.

    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

    nitisinone 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 daysto 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 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.

    Table 1: Most Common Adverse Reactions in Patients with HT-1 Treated with Nitisinone*

    Elevated tyrosine levels>10%
    Leukopenia3%
    Thrombocytopenia3%
    Conjunctivitis2%
    Corneal opacity2%
    Keratitis2%
    Photophobia2%
    Eye pain1%
    Blepharitis1%
    Cataracts1%
    Granulocytopenia1%
    Epistaxis1%
    Pruritus1%
    Exfoliate dermatitis1%
    Dry skin1%
    Maculopapular rash1%
    Alopecia1%

    *reported in at least 1% of patients

    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. DRUG INTERACTIONS

    Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer and an inhibitor of

    OAT1/OAT3. Table 2 includes drugs with clinically important drug interactions when

    administered concomitantly with nitisinone and instructions for preventing or managing

    them.

    Table 2: Clinically Relevant Interactions Affecting Co-Administered Drugs

    Sensitive CYP2C9 Substrates (e.g., celecoxib, tolbutamide) or CYP2C9 Substrates with a Narrow Therapeutic Index (e.g., phenytoin, warfarin)

    Clinical ImpactIncreased exposure of the co-administered drugs metabolized by CYP2C9 [see Clinical Pharmacology (12.3)].
    InterventionReduce the dosage of the co-administered drugs metabolized by CYP2C9 drug by half. Additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs. See prescribing information for those drugs.

    OAT1/OAT3 Substrates (e.g., adefovir, ganciclovir, methotrexate)

    Clinical ImpactIncreased exposure of the interacting drug [see Clinical Pharmacology (12.3)].
    InterventionMonitor for potential adverse reactions related to the co-administered drug.

  • 8. USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Limited available data with nitisinone use in pregnant women are not sufficient to determine

    a drug-associated risk of adverse developmental outcomes. Animal reproduction studies have

    been conducted for nitisinone. In these studies, nitisinone was administered to mice and

    rabbits during organogenesis with oral doses of nitisinone up to 20 and 8 times respectively,

    the recommended initial dose of 1 mg/kg/day. In mice, nitisinone caused incomplete skeletal

    ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended

    initial dose and increased gestational length at doses 4 times the recommended initial dose.

    In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal

    bones at doses 1.6 times the recommended initial dose [see Data].

    The background risk of major birth defects and miscarriage for the indicated population are

    unknown. In the U.S. general population, the estimated background risk of major birth defects

    and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

    Data

    Animal Data

    Reproduction studies have been performed in mice at oral doses of about 0.4, 4 and 20 times

    the recommended initial dose (1 mg/kg/day) and in rabbits at oral doses of about 1.6, 4 and 8

    times the recommended initial dose based on the body surface area. In mice, nitisinone has

    been shown to cause incomplete skeletal ossification of fetal bones at 0.4, 4 and 20 times the

    recommended initial dose, increased gestational length at 4 and 20 times the recommended

    initial dose, and decreased pup survival at 0.4 times the recommended initial dose based on

    the body surface area. In rabbits, nitisinone caused incomplete skeletal ossification of fetal

    bones at 1.6, 4 and 8 times the recommended initial dose based on the body surface area.

    8.2 Lactation

    Risk Summary

    There are no data on the presence of nitisinone in human milk, the effects on the breastfed

    infant, or the effects on milk production. Data suggest that nitisinone is present in rat milk

    due to findings of ocular toxicity and lower body weight seen in drug naive nursing rat pups.

    The development and health benefits of breastfeeding should be considered along with the

    mother’s clinical need for nitisinone and any potential adverse effects on the breastfed infant

    from nitisinone or from the underlying maternal condition.

    8.4 Pediatric Use

    The safety and effectiveness of nitisinone have been established in pediatric patients for the

    treatment of HT-1 in combination with dietary restriction of tyrosine and phenylalanine. Use

    of nitisinone in pediatric patients is supported by evidence from one open-label, uncontrolled

    clinical study conducted in 207 patients with HT-1 ages 0 to 22 years (median age 9 months)

    [ see Clinical Studies (14)].

    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.

  • 10. OVERDOSAGE

    Accidental ingestion of nitisinone by individuals eating normal diets not restricted in tyrosine

    and phenylalanine will result in elevated tyrosine levels. In healthy subjects given a single 1

    mg/kg dose of nitisinone, the plasma tyrosine level reached a maximum of 1200 micromol/L

    at 48 to 120 hours after dosing. After a washout period of 14 days, the mean value of plasma

    tyrosine was still 808 micromol/L. Fasted follow-up samples obtained from volunteers

    several weeks later showed tyrosine values back to normal. There were no reports of changes

    in vital signs or laboratory data of any clinical significance. One patient reported sensitivity

    to sunlight. Hyper- tyrosinemia has been reported with nitisinone treatment [ see Warnings

    and Precautions (5.1)].

  • 11. DESCRIPTION

    Nitisinone capsules contain nitisinone, which is a 4-hydroxyphenyl-pyruvate dioxygenase

    inhibitor indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the

    treatment of hereditary tyrosinemia type 1 (HT-1).

    Nitisinone occurs as white to yellowish-white, crystalline powder. It is Freely soluble in

    Acetone, Ethyl acetate and Methylene chloride. Sparingly soluble in absolute alcohol and

    practically insoluble in water Chemically, nitisinone is 2-(2-nitro-4-trifluoromethylbenzoyl)-

    1,3-cyclohexanedione, and the structural formula is:

    Structural Formula

    Figure 1. The molecular formula is C14H10F3NO5 with a relative mass of 329.23

    Capsules: Hard, white-opaque capsule, 2 mg, 5 mg, 10 mg, and 20 mg strengths of nitisinone,

    intended for oral administration. Each capsule contains 2 mg, 5 mg, 10 mg, or 20 mg

    nitisinone, anhydrous lactose and stearic acid. The capsule shell contains gelatin and titanium

    dioxide, and the imprinting ink contains black iron oxide, propylene glycol, potassium

    hydroxide, shellac, and strong ammonia solution.

  • 12. CLINICAL PHARMACOLOGY

    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.

    12.2 Pharmacodynamics

    In a clinical study, patients with HT-1 were diagnosed by the presence of succinylacetone in

    urine or plasma and treated with 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, 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)].

    12.3 Pharmacokinetics

    The single-dose pharmacokinetics of nitisinone have been studied for Nitisinone Capsules in

    healthy adult subjects and the multiple-dose pharmacokinetics have been studied for

    Nitisinone Capsules in healthy subjects.

    Absorption

    The pharmacokinetic characteristics following single oral administration of nitisinone 30 mg

    under fasting conditions are shown in Table 3. The multiple-dose characteristics of nitisinone

    80 mg once daily are shown in Table 4. Steady-state (SS) was reached within 14 days dosing

    in all subjects.

    Table 3: Nitisinone Arithmetic Mean (CV%) Pharmacokinetic Parameters in Healthy Subjects

    Following a Single Oral 30 mg Dose of Nitisinone Under Fasting Conditions

    TreatmentCmax (micromol/L) [range]tmax* (h) [range]AUC 0-72h (micromol·h/L) [range]
    Nitisinone Capsule (n=12)10.5 (26)

    3.5

    [0.8-8.0]

    		406 (13)

    *presented as median [range]

    Table 4: Nitisinone Arithmetic Mean (CV%) Pharmacokinetic Parameters in Healthy Subjects Following

    Repeated Once Daily Administration of 80 mg Nitisinone Under Fasting Conditions.

    Treatment

    Cmax,ss (micromol/L)

    [CV%]

    Cmin,ss (micromol/L)

    [range]

    tmax,ss* (h)

    [range]

    AUC 0-24h, ss

    (micromol·h/L)

    [range]

    Nitisinone Capsule

    (n=18)

    		120 (23)73 (24)

    4.0

    [0.0 to 16.0]

    		2204 (18)

    *presented as median [range]

    Food Effect: No food effect study was conducted with Nitisinone capsules.

    Distribution

    In vitro binding of nitisinone to human plasma proteins is greater than 95% at 50 micromolar

    concentration.

    Elimination

    The mean terminal plasma half-life of single dose nitisinone in healthy male subjects is 54

    hours. The mean (CV%) apparent plasma clearance in 18 healthy adults following multiple

    once daily doses of Nitisinone 80 mg is 113 (16) mL/hr.

    Metabolism:In vitro studies have shown that nitisinone is relatively stable in human liver microsomes

    with minor metabolism possibly mediated by CYP3A4 enzyme.

    Excretion: Renal elimination of nitisinone is of minor importance, since the mean of the fraction of

    dose excreted as unchanged nitisinone in the urine (fe(%)) was 3.0% (n=3) following

    multiple oral doses of 80 mg daily in healthy subjects. The estimated mean (CV%) renal

    clearance of nitisinone was 0.003 L/h (25%).

    Drug Interaction Studies

    Nitisinone does not inhibit CYP2D6. Nitisinone is a moderate inhibitor of CYP2C9, and a

    weak inducer of CYP2E1 (Table 5). Nitisinone is an inhibitor of OAT1/3 (Table 5).

    Table 5: Percent Change in AUC 0-∞ and Cmax for Co-administered Drugs in the

    Presence of Nitisinone in 18 Healthy Subjects

    Co-administered Drug (a)Dose of Co-administered Drug (Route of Administration)

    Effect of Nitisinone on the Pharmacokinetics of Co-administered Drug (b)

    AUC 0-∞Cmax
    CYP2C9 Substrate Tolbutamide c500 mg (oral)131% ↑16% ↑
    CYP2E1 Substrate Chlorzoxazone250 mg (oral)27% ↓18% ↓
    OAT1/3 Substrate Furosemide20 mg (intravenous)72% ↑12% ↑

    ↑ = Increased; ↓ = Decreased

    (a) The interacting drug was administered alone on Day 1 and together with nitisinone on Day 17.

    (b) Multiple doses of 80 mg nitisinone were administered daily alone from Day 3 to Day 16.

    (c) 16 subjects in Period 2 received nitisinone and tolbutamide while 18 subjects in Period 1 received

    nitisinone alone.

    In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

    In vitro studies showed that nitisinone does not inhibit CYP1A2, 2C19, or 3A4. Nitisinone

    does not induce CYP1A2, 2B6 or 3A4/5. Nitisinone does not inhibit P-gp, BCRP, OATP1B1,

    OATP1B3 and OCT2-mediated transports at therapeutically relevant concentrations.

  • 13. NONCLINICAL TOXICOLOGY

    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 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.

  • 14. CLINICAL STUDIES

    The efficacy and safety of nitisinone in patients with HT-1 was evaluated in one open-label,

    uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age

    9 months). Patients were diagnosed with HT-1 by the presence of succinylacetone in the urine

    or plasma. All patients were treated with nitisinone at a starting dose of 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,

    liver and kidney function tests, platelet count, serum amino acids, urinary phenolic acid,

    plasma and urine succinylacetone, erythrocyte PBG-synthase, and urine 5-ALA. The median

    duration of treatment was 22 months (range less than 1 month to 80 months). Efficacy was

    assessed by comparison of survival and incidence of liver transplant to historical controls.

    For patients presenting with HT-1 younger than 2 months of age who were treated with

    dietary restriction and nitisinone, 2- and 4-year survival probabilities were 88% and 88%,

    respectively. Data from historical controls showed that patients presenting with HT-1 at

    younger than 2 months of age and treated with dietary restriction alone had 2- and 4-year

    survival probabilities of 29% and 29%, respectively. For patients presenting with HT-1

    between 2 months and 6 months of age who were treated with dietary restriction and

    nitisinone, 2- and 4-year survival probabilities were 94% and 94%, respectively. Data for

    historical controls showed that patients presenting with HT-1 between 2 months and 6 months

    of age treated with dietary restriction alone had 2- and 4-year survival probabilities of 74%

    and 60%, respectively.

    The effects of nitisinone on urine and plasma succinylacetone, porphyrin metabolism, and

    urinary alpha-1-microglobulin were also assessed in this clinical study.

    Porphyria-like crisis were reported in 3 patients (0.3% of cases per year) during the clinical

    study. This compares to an incidence of 5 to 20% of cases per year expected as part of the

    natural history of the disorder. An assessment of porphyria-like crises was performed because

    these events are commonly reported in patients with HT-1 who are not treated with nitisinone.

    Urinary alpha-1-microglobulin, a proposed marker of proximal tubular dysfunction, was

    measured in 100 patients at baseline. The overall median pretreatment level was 4.3 grams/mol

    creatinine. After one year of treatment in a subgroup of patients (N=100), overall median alpha-

    1-microglobulin decreased by 1.5 grams/mol creatinine. In patients 24 months of age and

    younger in whom multiple values were available (N=65), median alpha-1-microglobulin levels

    decreased from 5.0 to 3.0 grams/mol creatinine (reference value for age less than or equal to

    12 grams/mol creatinine). In patients older than 24 months in whom multiple values

    were available (N=35), median alpha-1-microglobulin levels decreased from 2.8 to 2.0 grams/mol

    creatinine (reference for age less than or equal to 6 grams/mol creatinine).

    The long-term effect of nitisinone on hepatic function was not assessed.

  • 16. HOW SUPPLIED/STORAGE AND HANDLING

    The capsules are packed in a high density (HD) polyethylene container fitted with 33 mm

    Child-Resistant closure. Each bottle contains 60 capsules.

    • 2 mg: Size “3” hard gelatin capsules with white opaque cap imprinted with “NIT2” in

    black and white opaque body imprinted ‘ZN11’ in black, filled with white to off-white

    powder. (NDC: 71863-119-60)

    • 5 mg: Size “3” hard gelatin capsules with white opaque cap imprinted with “NIT5” in

    black and white opaque body imprinted ‘ZN12’ in black, filled with white to off-white

    powder. (NDC: 71863-120-60)

    • 10 mg: Size “3” hard gelatin capsules with white opaque cap imprinted with “NIT10” in

    black and white opaque body imprinted ‘ZN13’ in black, filled with white to off-white

    powder. (NDC: 71863-121-60)

    • 20 mg: Size “3” hard gelatin capsules with white opaque cap imprinted with “NIT20” in

    black and white opaque body imprinted ‘ZN14’ in black, filled with white to off-white

    powder. (NDC: 71863-122-60)

    Store refrigerated at 2° to 8°C (36° to 46°F) “protect from light”. Alternatively,

    patients/caregivers may store Nitisinone Capsules at room temperature up to 25°C (77°F) for

    up to 45 days. If not used within 45 days, discard Nitisinone Capsules.

  • 17. PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling.

    Administration of Nitisinone Capsules

    • Maintain dietary restriction of tyrosine and phenylalanine when taking nitisinone.

    • Capsules: Take at least one hour before, or two hours after a meal. For patients who have

    difficulty swallowing the capsules, the capsules may be opened and the contents

    suspended in a small amount of water, formula or apple sauce immediately before use.

    Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay

    and Hyperkeratotic Plaques

    • Inform patients that inadequate restriction may be associated with ocular signs and

    symptoms, intellectual disability and developmental delay, and painful hyperkeratotic

    plaques on the soles and palms. Advise patients and caregivers of the need to maintain

    dietary restriction of tyrosine and phenylalanine and to report any unexplained ocular,

    neurologic, or other symptoms promptly to their healthcare provider [ see Warnings and

    Precautions (5.1)].

    Manufactured by:

    M/s Zenara Pharma Private Limited

    Plot No. 83/B, 84, 87 to 96, Phase III, IDA Cherlapally,

    Hyderabad, Telangana State - 500051,

    India (IND)

    Manufactured for:

    Eton Pharmaceuticals, Inc. Deer Park, IL 60010

    Issued: 02/2024

  • PRINCIPAL DISPLAY PANEL

    Nitisinone Capsules - NDC-71863-119-60 - 60 Capsules - 2 mg Container Label

    2 mg Container

    Nitisinone Capsules - NDC-71863-119-60 - 60 Capsules - 2 mg Carton Label

    2 mg Carton

    Nitisinone Capsules - NDC-71863-120-60 - 60 Capsules - 5 mg Container Label

    5 mg Container

    Nitisinone Capsules - NDC-71863-120-60 - 60 Capsules - 5 mg Carton Label

    5 mg Carton

    Nitisinone Capsules - NDC-71863-121-60 - 60 Capsules - 10 mg Container Label

    10 mg Container

    Nitisinone Capsules - NDC-71863-121-60 - 60 Capsules - 10 mg Carton Label

    10 mg Carton

    Nitisinone Capsules - NDC-71863-122-60 - 60 Capsules - 20 mg Container Label

    20 mg Container

    Nitisinone Capsules - NDC-71863-122-60 - 60 Capsules - 20 mg Carton Label

    20 mg Carton

  • INGREDIENTS AND APPEARANCE
    NITISINONE 
    nitisinone capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 71863-119
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    NITISINONE (UNII: K5BN214699) (NITISINONE - UNII:K5BN214699) NITISINONE2 mg
    Inactive Ingredients
    Ingredient NameStrength
    STEARIC ACID (UNII: 4ELV7Z65AP)  
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    Product Characteristics
    Colorwhite (White opaque cap filled with white to off-white powder) Scoreno score
    ShapeCAPSULESize3mm
    FlavorImprint Code
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 71863-119-601 in 1 CARTON01/15/2024
    160 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21620101/15/2024
    NITISINONE 
    nitisinone capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 71863-120
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    NITISINONE (UNII: K5BN214699) (NITISINONE - UNII:K5BN214699) NITISINONE5 mg
    Inactive Ingredients
    Ingredient NameStrength
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    STEARIC ACID (UNII: 4ELV7Z65AP)  
    Product Characteristics
    Colorwhite (white opaque cap filled with white to off-white powder) Scoreno score
    ShapeCAPSULESize3mm
    FlavorImprint Code
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 71863-120-601 in 1 CARTON01/15/2024
    160 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21620101/15/2024
    NITISINONE 
    nitisinone capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 71863-122
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    NITISINONE (UNII: K5BN214699) (NITISINONE - UNII:K5BN214699) NITISINONE20 mg
    Inactive Ingredients
    Ingredient NameStrength
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    STEARIC ACID (UNII: 4ELV7Z65AP)  
    Product Characteristics
    Colorwhite (White opaque cap filled with white to off-white powder) Scoreno score
    ShapeCAPSULESize3mm
    FlavorImprint Code
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 71863-122-601 in 1 CARTON01/15/2024
    160 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21620101/15/2024
    NITISINONE 
    nitisinone capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 71863-121
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    NITISINONE (UNII: K5BN214699) (NITISINONE - UNII:K5BN214699) NITISINONE10 mg
    Inactive Ingredients
    Ingredient NameStrength
    STEARIC ACID (UNII: 4ELV7Z65AP)  
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    Product Characteristics
    Colorwhite (White opaque cap filled with white to off-white powder) Scoreno score
    ShapeCAPSULESize3mm
    FlavorImprint Code
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 71863-121-601 in 1 CARTON01/15/2024
    160 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21620101/15/2024
    Labeler - Eton Pharmaceuticals, Inc. (080870465)
    Registrant - Eton Pharmaceuticals, Inc. (080870465)
    • © 2025 FDA.report
    This site is not affiliated with or endorsed by the FDA.