Orfadin Nitisinone 10 mg Capsule, 60-count — NDC 66658-110-60 (Billing 66658-0110-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics In a clinical study, patients with HT-1 were diagnosed by the presence of succinylacetone in urine or plasma and treated with ORFADIN [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 ORFADIN 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 ORFADIN, 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 ORFADIN 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 )].

12.3Pharmacokinetics The single-dose pharmacokinetics of nitisinone have been studied for both ORFADIN capsules and ORFADIN oral suspension in healthy adult subjects and the multiple-dose pharmacokinetics have been studied for ORFADIN capsules in healthy subjects. Absorption The pharmacokinetic characteristics following single oral administration of ORFADIN 30 mg under fasting conditions are shown in Table 3 . Compared to ORFADIN capsule, the median T max occurred about 3 hours earlier with ORFADIN oral suspension.

The multiple-dose characteristics of ORFADIN 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 ORFADIN Under Fasting Conditions Treatment C max (micromol/L) [range] t max * (h) [range] AUC 0-72h (micromol·h/L) [range] * presented as median [range] ORFADIN capsule (n=12) 10.5 (26) 3.5 406 (13) [0.8 to 8.0] ORFADIN oral suspension (n=12) 10.1 (34) 0.4 350 (17) [0.2 to 4.0] TABLE 4 Nitisinone Arithmetic Mean (CV%) Pharmacokinetic Parameters in Healthy Subjects Following Repeated Once Daily Administration of 80 mg ORFADIN Under Fasting Conditions.

Treatment C max,ss (micromol/L) [CV%] C mi… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics The single-dose pharmacokinetics of nitisinone have been studied for both ORFADIN capsules and ORFADIN oral suspension in healthy adult subjects and the multiple-dose pharmacokinetics have been studied for ORFADIN capsules in healthy subjects. Absorption The pharmacokinetic characteristics following single oral administration of ORFADIN 30 mg under fasting conditions are shown in Table 3 . Compared to ORFADIN capsule, the median T max occurred about 3 hours earlier with ORFADIN oral suspension.

The multiple-dose characteristics of ORFADIN 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 ORFADIN Under Fasting Conditions Treatment C max (micromol/L) [range] t max * (h) [range] AUC 0-72h (micromol·h/L) [range] * presented as median [range] ORFADIN capsule (n=12) 10.5 (26) 3.5 406 (13) [0.8 to 8.0] ORFADIN oral suspension (n=12) 10.1 (34) 0.4 350 (17) [0.2 to 4.0] TABLE 4 Nitisinone Arithmetic Mean (CV%) Pharmacokinetic Parameters in Healthy Subjects Following Repeated Once Daily Administration of 80 mg ORFADIN Under Fasting Conditions.

Treatment C max,ss (micromol/L) [CV%] C min,ss (micromol/L) [range] t max,ss * (h) [range] AUC 0-24h,ss (micromol·h/L) [range] * presented as median [range] ORFADIN capsule (n=18) 120 (23) 73(24) 4.0 2204(18) [0.0 to 16.0] Food Effect: No food effect study was conducted with ORFADIN capsules. For ORFADIN oral suspension, a high calorie (800 to 1000 calories) and high fat meal (approximately 50% of total caloric content) did not affect nitisinone total exposure (AUC 72h ), but decreased the C max by approximately 20% [see Dosage and Administration ( 2.2 )] .

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 ORFADIN 80 mg is 113 (16) mL/h.

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 ORFADIN in 18 Healthy Subjects ↑ = Increased; ↓ = Decreased a The interacting drug was administered alone on Day 1 and together with ORFADIN on Day 17. b Multiple doses of 80 mg ORFADIN were administered daily alone from Day 3 to Day 16. c 16 subjects in Period 2 received ORFADIN and tolbutamide while 18 subjects in Period 1 received ORFADIN alone. 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% ↑ 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.

12.2Pharmacodynamics In a clinical study, patients with HT-1 were diagnosed by the presence of succinylacetone in urine or plasma and treated with ORFADIN [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 ORFADIN 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 ORFADIN, 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 ORFADIN 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 )].

14 CLINICAL STUDIES The efficacy and safety of ORFADIN 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 ORFADIN 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.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of nitisinone was assessed in a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice. There were no drug-related neoplastic findings in male or female Tg.rasH2 mice at doses up to 100 mg/kg/ day nitisinone (approximately 8.1 times the recommended initial dose of 1 mg/kg/day on a body surface area basis). Nitisinone was not genotoxic in the Ames test and the in vivo mouse liver unscheduled DNA synthesis (UDS) test.

Nitisinone was mutagenic in the mouse lymphoma cell (L5178Y/TK +/- ) forward mutation test and in an in vivo mouse bone marrow micronucleus test. In a single dose-group study in rats given 100 mg/kg (16.2 times the recommended initial dose of 1 mg/kg/day on a body surface area basis), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.