ng drug [see clinical pharmacology ( 12.3 )] intervention monitor for potential adverse reactions related to the co-administered drug. cyp2c9 substrates : increased systemic exposure of these co-administered drugs; reduce the dosage. additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs. ( 7 ) oat1/oat3 substrates : increased systemic exposure of these co-administered drugs; monitor for potential adverse reactions. ( 7 ) additional pediatric use information is approved for swedish orphan biovitrum ab publ's orfadin (nitisinone) capsules. however, due to swedish orphan biovitrum ab publ's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

nzyme 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 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.

e 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, 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 dosage in order to lower the plasma tyrosine concentration. additional pediatric use information is approved for swedish orphan biovitrum ab publ’s orfadin (nitisinone) capsules. however, due to swedish orphan biovitrum ab publ’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.2 administration 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 [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.

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 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 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% leukopenia 3% thrombocytopenia 3% conjunctivitis 2% corneal opacity 2% keratitis 2% photophobia 2% eye pain 1% blepharitis 1% cataracts 1% granulocytopenia 1% epistaxis 1% pruritus 1% exfoliative dermatitis 1% dry skin 1% maculopapular rash 1% alopecia 1% *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.

ng drug [see clinical pharmacology ( 12.3 )] intervention monitor for potential adverse reactions related to the co-administered drug. cyp2c9 substrates : increased systemic exposure of these co-administered drugs; reduce the dosage. additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs. ( 7 ) oat1/oat3 substrates : increased systemic exposure of these co-administered drugs; monitor for potential adverse reactions. ( 7 ) additional pediatric use information is approved for swedish orphan biovitrum ab publ's orfadin (nitisinone) capsules. however, due to swedish orphan biovitrum ab publ's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

imated 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.

r 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.

ents 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. 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 )] . additional pediatric use information is approved for swedish orphan biovitrum abpubl's orfadin (nitisinone) capsules. however, due to swedish orphan biovitrum abpubl's marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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 treatment c max (micromol/l) [range] t max * (h) [range] auc 0-72h (micromol·h/l) [range] nitisinone capsule (n=12) 10.5 (26) 3.5 [0.8 to 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 nitisisnone under fasting conditions. c max,ss (micromol/l) c min,ss (micromol/l) t max,ss * (h) auc0-24h,ss (micromol·h/l) treatment [cv%] [range] [range] [range] nitisisnone capsule (n=18) 120 (23) 73(24) 4.0 2204(18) [0.0 to 16.0] * 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 c max 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-∞ c max cyp2c9 substrate tolbutamide c 500 mg (oral) 131% ↑ 16% ↑ cyp2e1 substrate chlorzoxazone 250 mg (oral) 27% ↓ 18% ↓ oat1/3 substrate furosemide 20 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.

once daily administration of 80 mg nitisisnone under fasting conditions. c max,ss (micromol/l) c min,ss (micromol/l) t max,ss * (h) auc0-24h,ss (micromol·h/l) treatment [cv%] [range] [range] [range] nitisisnone capsule (n=18) 120 (23) 73(24) 4.0 2204(18) [0.0 to 16.0] * 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 c max 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-∞ c max cyp2c9 substrate tolbutamide c 500 mg (oral) 131% ↑ 16% ↑ cyp2e1 substrate chlorzoxazone 250 mg (oral) 27% ↓ 18% ↓ oat1/3 substrate furosemide 20 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.

ies 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.

itium 10 mg" on body, filled with white to off white powder blend. ndc 0254- 3022 -02 bottles of 60 capsules with child-resistant closure and tamper resistant induction sealing store at room temperature between 20°c to 25°c (68°f to 77°f), excursions permitted to 15°c and 30°c (59°f and 86°f) [see usp controlled room temperature].

utions ( 5.1 ) ]. manufactured by: novitium pharma llc 70 lake drive, east windsor new jersey 08520 distributed by: par pharmaceutical chestnut ridge, ny 10977 revised: august, 2019