ADVERSE REACTIONS SECTION.

6. ADVERSE REACTIONS. Most common adverse reactions (>1%) are elevated tyrosine levels,thrombocytopenia, leukopenia, conjunctivitis, corneal opacity,keratitis, photophobia, eye pain, blepharitis, cataracts,granulocytopenia, epistaxis, pruritus, exfoliative dermatitis, dryskin, maculopapular rash and alopecia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contactEton Pharmaceuticals, Inc., at 1-855-224-0233 or FDA at1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction ratesobserved in the clinical trials of drug cannot be directly compared to rates in the clinicaltrials 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, ages0 to 22 years at enrollment (median age months), who were diagnosed with HT-1 by thepresence of succinylacetone in the urine or plasma. The starting dose of nitisinone was 0.3 to0.5 mg/kg twice daily, and the dose was increased in some patients to mg/kg twice dailybased on weight, biochemical, and enzyme markers. The recommended starting dosage ofnitisinone 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 werethrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated withelevated tyrosine levels [see Warnings and Precautions (5.1, 5.2)]. Fourteen patients experienced ocular/visual events. The duration of the symptoms varied from daysto years.Six patients had thrombocytopenia, three of which had platelet counts 30,000/microL orlower. In patients with thrombocytopenia, platelet counts gradually returned to normal(duration up to 47 days) without change in nitisinone dose. No patients developed infectionsor bleeding as result of the episodes of leukopenia and thrombocytopenia.Patients with HT- are at increased risk of developing porphyric crises, hepatic neoplasms,and liver failure requiring liver transplantation. These complications of HT- were observedin patients treated with nitisinone for median of 22 months during the clinical trial (livertransplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepaticneoplasms 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 NitisinoneElevated 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 patientsAdverse reactions reported in less than 1% of the patients, included death, seizure, braintumor, encephalopathy, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema,gastrointestinal hemorrhage, melena, elevated hepatic enzymes, liver enlargement,hypoglycemia, septicemia, and bronchitis.

CLINICAL PHARMACOLOGY SECTION.

12. CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Nitisinone is competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzymeupstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. Byinhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents theaccumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. Inpatients with HT-1, these catabolic intermediates are converted to the toxic metabolitessuccinylacetone and succinylacetoacetate, which are responsible for the observed liver andkidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading tothe accumulation of 5- aminolevulinate, neurotoxin responsible for the porphyric crisescharacteristic of HT-1.. 12.2 Pharmacodynamics. In clinical study, patients with HT-1 were diagnosed by the presence of succinylacetone inurine or plasma and treated with nitisinone see Clinical Studies (14)]. In all 186 patients whose urine succinylacetone was measured, the urinary succinylacetone concentrationdecreased to less than mmol/mol creatinine, the lower limit of quantitation. The mediantime to normalization of urine succinylacetone was 0.3 months. The probability of recurrenceof abnormal values of urine succinylacetone was 1% at nitisinone concentration of 37micromol/L (95% confidence interval: 23, 51 micromol/L). In 87% (150/172) of patientswhose plasma succinylacetone was measured, the plasma succinylacetone concentrationdecreased to less than 0.1 micromol/L, the lower limit of quantitation. The median time tonormalization of plasma succinylacetone was 3.9 months.In another study, comparing two dosing regimens, succinylacetone was measured in urineand/or blood in 16 patients with HT-1 aged years to 24 years. All study patients were on astable nitisinone daily dosage (0.4 mg/kg/day to mg/kg/day) during both study dosingregimens. After at least weeks of twice daily dosing with nitisinone, both the urine and/orblood 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 nitisinoneand blood and/or urine succinylacetone concentrations remained undetectable whenmeasured following at least weeks of treatment with once daily dosing.Nitisinone inhibits catabolism of the amino acid tyrosine and can result in elevated plasmalevels of tyrosine. Therefore, treatment with nitisinone requires restriction of the dietaryintake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasmalevels of tyrosine see Warnings and Precautions (5.1)]. 12.3 Pharmacokinetics. The single-dose pharmacokinetics of nitisinone have been studied for Nitisinone Capsules inhealthy adult subjects and the multiple-dose pharmacokinetics have been studied forNitisinone Capsules in healthy subjects.AbsorptionThe pharmacokinetic characteristics following single oral administration of nitisinone 30 mgunder fasting conditions are shown in Table 3. The multiple-dose characteristics of nitisinone80 mg once daily are shown in Table 4. Steady-state (SS) was reached within 14 days dosingin all subjects.Table 3: Nitisinone Arithmetic Mean (CV%) Pharmacokinetic Parameters in Healthy SubjectsFollowing 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 FollowingRepeated Once Daily Administration of 80 mg Nitisinone Under Fasting Conditions.TreatmentCmax,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. DistributionIn vitro binding of nitisinone to human plasma proteins is greater than 95% at 50 micromolarconcentration.EliminationThe mean terminal plasma half-life of single dose nitisinone in healthy male subjects is 54hours. The mean (CV%) apparent plasma clearance in 18 healthy adults following multipleonce 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) followingmultiple oral doses of 80 mg daily in healthy subjects. The estimated mean (CV%) renalclearance of nitisinone was 0.003 L/h (25%).Drug Interaction StudiesNitisinone does not inhibit CYP2D6. Nitisinone is moderate inhibitor of CYP2C9, and aweak 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 SubjectsCo-administered Drug (a)Dose of Co-administered Drug (Route of Administration) Effect of Nitisinone on the Pharmacokinetics of Co-administered Drug (b) AUC 0-CmaxCYP2C9 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 and together with nitisinone on Day 17.(b) Multiple doses of 80 mg nitisinone were administered daily alone from Day to Day 16.(c) 16 subjects in Period received nitisinone and tolbutamide while 18 subjects in Period receivednitisinone alone.In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated ClinicallyIn vitro studies showed that nitisinone does not inhibit CYP1A2, 2C19, or 3A4. Nitisinonedoes not induce CYP1A2, 2B6 or 3A4/5. Nitisinone does not inhibit P-gp, BCRP, OATP1B1,OATP1B3 and OCT2-mediated transports at therapeutically relevant concentrations.

CLINICAL STUDIES SECTION.

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 to 22 years at enrollment (median age9 months). Patients were diagnosed with HT-1 by the presence of succinylacetone in the urineor plasma. All patients were treated with nitisinone at starting dose of 0.3 to 0.5 mg/kg twicedaily, and the dose was increased in some patients to 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 medianduration of treatment was 22 months (range less than month to 80 months). Efficacy wasassessed by comparison of survival and incidence of liver transplant to historical controls.For patients presenting with HT-1 younger than months of age who were treated withdietary 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 atyounger than months of age and treated with dietary restriction alone had 2- and 4-yearsurvival probabilities of 29% and 29%, respectively. For patients presenting with HT-1between months and months of age who were treated with dietary restriction andnitisinone, 2- and 4-year survival probabilities were 94% and 94%, respectively. Data forhistorical controls showed that patients presenting with HT-1 between months and monthsof 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, andurinary alpha-1-microglobulin were also assessed in this clinical study.Porphyria-like crisis were reported in patients (0.3% of cases per year) during the clinicalstudy. This compares to an incidence of to 20% of cases per year expected as part of thenatural history of the disorder. An assessment of porphyria-like crises was performed becausethese events are commonly reported in patients with HT-1 who are not treated with nitisinone.Urinary alpha-1-microglobulin, proposed marker of proximal tubular dysfunction, wasmeasured in 100 patients at baseline. The overall median pretreatment level was 4.3 grams/molcreatinine. After one year of treatment in subgroup of patients (N=100), overall median alpha-1-microglobulin decreased by 1.5 grams/mol creatinine. In patients 24 months of age andyounger in whom multiple values were available (N=65), median alpha-1-microglobulin levelsdecreased from 5.0 to 3.0 grams/mol creatinine (reference value for age less than or equal to12 grams/mol creatinine). In patients older than 24 months in whom multiple valueswere available (N=35), median alpha-1-microglobulin levels decreased from 2.8 to 2.0 grams/molcreatinine (reference for age less than or equal to grams/mol creatinine).The long-term effect of nitisinone on hepatic function was not assessed.

DOSAGE & ADMINISTRATION SECTION.

2. DOSAGE AND ADMINISTRATION. Recommended Dosage (2.1):The recommended starting dosage is 0.5 mg/kg orally twicedaily.In patients years of age and older who have undetectableserum and urine succinylacetone concentrations after aminimum of weeks on stable dosage of nitisinone, the totaldaily dose may be given once daily.Titrate the dosage based on biochemical and/or clinicalresponse, as described in the full prescribing information.The maximum total daily dosage is mg/kg orally.Administration Instructions (2.2):Maintain dietary restriction of tyrosine and phenylalanineTake Nitisinone Capsules at least one hour before, or twohours after mealFor patients who have difficulties swallowing capsules, thecapsules may be opened and the contents suspended in smallamount of water, formula, or apple sauce immediately beforeuse.. The recommended starting dosage is 0.5 mg/kg orally twice. In patients years of age and older who have undetectable. Titrate the dosage based on biochemical and/or clinical. The maximum total daily dosage is mg/kg orally.. Maintain dietary restriction of tyrosine and phenylalanine. Take Nitisinone Capsules at least one hour before, or two. For patients who have difficulties swallowing capsules, the. 2.1 Dosage. Starting DosageThe recommended starting dosage of Nitisinone Capsules is 0.5 mg/kg administered orallytwice daily.Maintenance RegimenIn patients years of age and older who have undetectable serum and urine succinylacetoneconcentrations after minimum of weeks on stable dosage of nitisinone, the total dailydose of Nitisinone Capsules may be given once daily (e.g., to mg/kg once daily) [see Clinical Pharmacology (12.2)]. Dosage TitrationTitrate the dosage in each individual patient based on biochemical and/or clinical response.Monitor plasma and/or urine succinylacetone concentrations, liver functionparameters and alpha-fetoprotein levels.If succinylacetone is still detectable in blood or urine weeks after the start ofnitisinone treatment, increase the nitisinone dosage to 0.75 mg/kg twice daily. Amaximum total daily dosage of mg/kg may be needed based on the evaluation ofall biochemical parameters.If the biochemical response is satisfactory (undetectable blood and/or urinesuccinylacetone), the dosage should be adjusted only according to body weight gainand not according to plasma tyrosine levels.During initiation of therapy, when switching from twice daily to once daily dosing,or if there is deterioration in the patients condition, it may be necessary to followall available biochemical parameters more closely (i.e. plasma and/or urinesuccinylacetone, urine 5- aminolevulinate (ALA) and erythrocyte porphobilinogen(PBG)-synthase activity).Maintain plasma tyrosine levels below 500 micromol/L by dietary restriction oftyrosine and phenylalanine intake [see Warnings and Precautions (5.1)]. In patients who develop plasma tyrosine levels above 500 micromol/L, assess dietary tyrosineand phenylalanine intake. Do not adjust the Nitisinone Capsules dosage in order tolower the plasma tyrosine concentration.. Monitor plasma and/or urine succinylacetone concentrations, liver function. If succinylacetone is still detectable in blood or urine weeks after the start of. If the biochemical response is satisfactory (undetectable blood and/or urine. During initiation of therapy, when switching from twice daily to once daily dosing,. Maintain plasma tyrosine levels below 500 micromol/L by dietary restriction of. 2.2 Administration Instructions. Administration of Nitisinone CapsulesMaintain dietary restriction of tyrosine and phenylalanine when taking NitisinoneCapsules.Capsules: Take at least one hour before, or two hours after meal [see Clinical Pharmacology (12.3)]. For patients who have difficulty swallowing the capsules, the capsules may be opened and the contents suspended in small amount of water,formula or apple sauce immediately before use.. Maintain dietary restriction of tyrosine and phenylalanine when taking Nitisinone. Capsules: Take at least one hour before, or two hours after meal [see Clinical.

DRUG INTERACTIONS SECTION.

7. DRUG INTERACTIONS. Nitisinone is moderate CYP2C9 inhibitor, weak CYP2E1 inducer and an inhibitor ofOAT1/OAT3. Table includes drugs with clinically important drug interactions whenadministered concomitantly with nitisinone and instructions for preventing or managingthem.Table 2: Clinically Relevant Interactions Affecting Co-Administered Drugs Sensitive CYP2C9 Substrates (e.g., celecoxib, tolbutamide) or CYP2C9 Substrates with 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.. CYP2C9 Substrates: Increased systemic exposure of these co-administered drugs; reduce the dosage. Additionaldosage adjustments may be needed to maintaintherapeutic drug concentrations for narrow therapeutic indexdrugs.OAT1/OAT3 Substrates: Increased systemic exposure of these co-administered drugs; monitor for potential adverse reactions.See 17 for PATIENT COUNSELING INFORMATION andFDA approved patient labeling.Revised 02/2024. CYP2C9 Substrates: Increased systemic exposure of these OAT1/OAT3 Substrates: Increased systemic exposure of these.

HOW SUPPLIED SECTION.

16. HOW SUPPLIED/STORAGE AND HANDLING. The capsules are packed in high density (HD) polyethylene container fitted with 33 mmChild-Resistant closure. Each bottle contains 60 capsules.2 mg: Size 3 hard gelatin capsules with white opaque cap imprinted with NIT2 inblack and white opaque body imprinted ZN11 in black, filled with white to off-whitepowder. (NDC 71863-119-60)5 mg: Size 3 hard gelatin capsules with white opaque cap imprinted with NIT5 inblack and white opaque body imprinted ZN12 in black, filled with white to off-whitepowder. (NDC 71863-120-60)10 mg: Size 3 hard gelatin capsules with white opaque cap imprinted with NIT10 inblack and white opaque body imprinted ZN13 in black, filled with white to off-whitepowder. (NDC 71863-121-60)20 mg: Size 3 hard gelatin capsules with white opaque cap imprinted with NIT20 inblack and white opaque body imprinted ZN14 in black, filled with white to off-whitepowder. (NDC 71863-122-60)Store refrigerated at to 8C (36 to 46F) protect from light. Alternatively,patients/caregivers may store Nitisinone Capsules at room temperature up to 25C (77F) forup to 45 days. If not used within 45 days, discard Nitisinone Capsules.. mg: Size 3 hard gelatin capsules with white opaque cap imprinted with NIT2 in. mg: Size 3 hard gelatin capsules with white opaque cap imprinted with NIT5 in. 10 mg: Size 3 hard gelatin capsules with white opaque cap imprinted with NIT10 in. 20 mg: Size 3 hard gelatin capsules with white opaque cap imprinted with NIT20 in.

PATIENT COUNSELING INFORMATION.

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 meal. For patients who have difficulty swallowing the capsules, the capsules may be opened and the contentssuspended in small amount of water, formula or apple sauce immediately before use.Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delayand Hyperkeratotic PlaquesInform patients that inadequate restriction may be associated with ocular signs andsymptoms, intellectual disability and developmental delay, and painful hyperkeratoticplaques on the soles and palms. Advise patients and caregivers of the need to maintaindietary 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 LimitedPlot 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 60010Issued: 02/2024. Maintain dietary restriction of tyrosine and phenylalanine when taking nitisinone.. Capsules: Take at least one hour before, or two hours after meal. For patients who have Inform patients that inadequate restriction may be associated with ocular signs and.

SPL UNCLASSIFIED SECTION.

2.1 Dosage. Starting DosageThe recommended starting dosage of Nitisinone Capsules is 0.5 mg/kg administered orallytwice daily.Maintenance RegimenIn patients years of age and older who have undetectable serum and urine succinylacetoneconcentrations after minimum of weeks on stable dosage of nitisinone, the total dailydose of Nitisinone Capsules may be given once daily (e.g., to mg/kg once daily) [see Clinical Pharmacology (12.2)]. Dosage TitrationTitrate the dosage in each individual patient based on biochemical and/or clinical response.Monitor plasma and/or urine succinylacetone concentrations, liver functionparameters and alpha-fetoprotein levels.If succinylacetone is still detectable in blood or urine weeks after the start ofnitisinone treatment, increase the nitisinone dosage to 0.75 mg/kg twice daily. Amaximum total daily dosage of mg/kg may be needed based on the evaluation ofall biochemical parameters.If the biochemical response is satisfactory (undetectable blood and/or urinesuccinylacetone), the dosage should be adjusted only according to body weight gainand not according to plasma tyrosine levels.During initiation of therapy, when switching from twice daily to once daily dosing,or if there is deterioration in the patients condition, it may be necessary to followall available biochemical parameters more closely (i.e. plasma and/or urinesuccinylacetone, urine 5- aminolevulinate (ALA) and erythrocyte porphobilinogen(PBG)-synthase activity).Maintain plasma tyrosine levels below 500 micromol/L by dietary restriction oftyrosine and phenylalanine intake [see Warnings and Precautions (5.1)]. In patients who develop plasma tyrosine levels above 500 micromol/L, assess dietary tyrosineand phenylalanine intake. Do not adjust the Nitisinone Capsules dosage in order tolower the plasma tyrosine concentration.. Monitor plasma and/or urine succinylacetone concentrations, liver function. If succinylacetone is still detectable in blood or urine weeks after the start of. If the biochemical response is satisfactory (undetectable blood and/or urine. During initiation of therapy, when switching from twice daily to once daily dosing,. Maintain plasma tyrosine levels below 500 micromol/L by dietary restriction of.

USE IN SPECIFIC POPULATIONS SECTION.

8. USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryLimited available data with nitisinone use in pregnant women are not sufficient to determinea drug-associated risk of adverse developmental outcomes. Animal reproduction studies havebeen conducted for nitisinone. In these studies, nitisinone was administered to mice andrabbits during organogenesis with oral doses of nitisinone up to 20 and times respectively,the recommended initial dose of mg/kg/day. In mice, nitisinone caused incomplete skeletalossification of fetal bones and decreased pup survival at doses 0.4 times the recommendedinitial dose and increased gestational length at doses times the recommended initial dose.In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetalbones at doses 1.6 times the recommended initial dose [see Data]. The background risk of major birth defects and miscarriage for the indicated population areunknown. In the U.S. general population, the estimated background risk of major birth defectsand miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.DataAnimal Data Reproduction studies have been performed in mice at oral doses of about 0.4, and 20 timesthe recommended initial dose (1 mg/kg/day) and in rabbits at oral doses of about 1.6, and 8times the recommended initial dose based on the body surface area. In mice, nitisinone hasbeen shown to cause incomplete skeletal ossification of fetal bones at 0.4, and 20 times therecommended initial dose, increased gestational length at and 20 times the recommendedinitial dose, and decreased pup survival at 0.4 times the recommended initial dose based onthe body surface area. In rabbits, nitisinone caused incomplete skeletal ossification of fetalbones at 1.6, and times the recommended initial dose based on the body surface area.. 8.2 Lactation. Risk SummaryThere are no data on the presence of nitisinone in human milk, the effects on the breastfedinfant, or the effects on milk production. Data suggest that nitisinone is present in rat milkdue 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 themothers clinical need for nitisinone and any potential adverse effects on the breastfed infantfrom nitisinone or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of nitisinone have been established in pediatric patients for thetreatment of HT-1 in combination with dietary restriction of tyrosine and phenylalanine. Useof nitisinone in pediatric patients is supported by evidence from one open-label, uncontrolledclinical study conducted in 207 patients with HT-1 ages to 22 years (median age months)[ see Clinical Studies (14)]. 8.5 Geriatric Use. Clinical studies of nitisinone did not include any subjects aged 65 and over. Nopharmacokinetic studies of nitisinone have been performed in geriatric patients. In general,dose selection for an elderly patient should be cautious reflecting the greater frequency ofdecreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapyin this patient population.

WARNINGS AND PRECAUTIONS SECTION.

5. WARNINGS AND PRECAUTIONS. Elevated Plasma Tyrosine Levels, Ocular Symptoms,Developmental Delay and Hyperkeratotic Plaques: Inadequate restriction of tyrosine and phenylalanine intake can lead toelevations in plasma tyrosine, which at levels above 500micromol/L can result in symptoms, intellectual disability anddevelopmental delay or painful hyperkeratotic plaques on the solesand palms; do not adjust Nitisinone Capsules dosage in order tolower the plasma tyrosine concentration. Obtain slit-lampexamination prior to treatment, regularly during treatment;Reexamine patients if symptoms develop or tyrosine levelsare 500 micromol/L. Assess plasma tyrosine levels inpatients with an abrupt change in neurologic status. (5.1)Leukopenia and Severe Thrombocytopenia: Monitor platelet and white blood cell counts. (5.2). Reexamine patients if symptoms develop or tyrosine levels. Leukopenia and Severe Thrombocytopenia: Monitor platelet 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 thetyrosine metabolic pathway [see Clinical Pharmacology (12.1)]. Therefore, treatment with nitisinone may cause an increase in plasma tyrosine levels in patients with HT-1. Maintainconcomitant reduction in dietary tyrosine and phenylalanine while on nitisinone treatment.Do not adjust nitisinone dosage in order to lower the plasma tyrosine concentration. Maintainplasma tyrosine levels below 500 micromol/L. Inadequate restriction of tyrosine andphenylalanine intake can lead to elevations in plasma tyrosine levels and levels greater than500 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 withnitisinone [see Adverse Reactions (6.1)]. In clinical study in non HT-1 population without dietary restriction and reported tyrosine levels >500 micromol/l bothsymptomatic and asymptomatic keratopathies have been observed. Therefore, performa baseline ophthalmologic examination including slit-lamp examination prior toinitiating nitisinone treatment and regularly thereafter. Patients who developphotophobia, eye pain, or signs of inflammation such as redness, swelling, or burningof the eyes or tyrosine levels are 500 micromol/L during treatment with NitisinoneCapsules should undergo slit- lamp reexamination and immediate measurement of theplasma tyrosine concentration.Variable degrees of intellectual disability and developmental delay. In patients treatedwith nitisinone who exhibit an abrupt change in neurologic status, perform clinicallaboratory assessment including plasma tyrosine levels.Painful hyperkeratotic plaques on the soles and palmsIn patients with HT-1 treated with dietary restrictions and nitisinone who develop elevatedplasma tyrosine levels, assess dietary tyrosine and phenylalanine intake.. Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis,. Variable degrees of intellectual disability and developmental delay. In patients treated. Painful hyperkeratotic plaques on the soles and palms. 5.2. Leukopenia and Severe Thrombocytopenia. In clinical trials, patients treated with nitisinone and dietary restriction developed transientleukopenia (3%), thrombocytopenia (3%), or both (1.5%) [see Adverse Reactions (6.1)]. No patients developed infections or bleeding as result of the episodes of leukopenia andthrombocytopenia. Monitor platelet and white blood cell counts during nitisinone therapy.