Zileuton

1 INDICATIONS AND USAGE Zileuton extended-release tablets are indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Zileuton extended-release tablets are not indicated for use in the reversal of bronchospasm in acute asthma attacks. Therapy with zileuton extended-release tablet can be continued during acute exacerbations of asthma. Zileuton extended-release tablets are a leukotriene synthesis inhibitor indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. ( 1 ) Do not use zileuton extended-release tablet to treat an acute asthma attack. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of zileuton extended-release tablets for the treatment of patients with asthma is two 600 mg extended-release tablets twice daily, within one hour after morning and evening meals, for a total daily dose of 2400 mg. Tablets should not be chewed, cut or crushed. If a dose is missed, the patient should take the next dose at the scheduled time and not double the dose. Assess hepatic function enzymes prior to initiation of zileuton extended-release tablets and periodically during treatment [see Contraindications ( 4 ), Warnings and Precautions ( 5 ), and Use in Specific Populations ( 8.7 ) ]. Adults and children 12 years of age and older: The recommended dose of zileuton extended-release tablets is two 600 mg extended-release tablets twice daily, within one hour after morning and evening meals, for a total daily dose of 2400 mg. ( 2 ) Monitoring: Assess hepatic function enzymes prior to initiation of zileuton extended-release tablet and monitor periodically during treatment. ( 2 , 5.1 )

6 ADVERSE REACTIONS Hepatotoxicity: Elevations of one or more hepatic function enzymes and bilirubin may occur during zileuton extended-release tablets therapy [see Warnings and Precautions ( 5 ) ]. The most commonly occurring adverse reactions (≥5%) with zileuton extended-release tablets are sinusitis, nausea, and pharyngolaryngeal pain. Most common adverse reactions (≥5%) included: sinusitis, nausea, and pharyngolaryngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Annora Pharma Private Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Short-Term Clinical Studies Experience The safety data described below reflect exposure to zileuton extended-release tablets in 199 patients for 12 weeks duration. In a 12-week, randomized, double-blind, placebo-controlled trial in adults and adolescents 12 years of age and older with asthma, patients received zileuton extended-release tablets two 600 mg tablets (n=199) or placebo (n=198) twice daily by mouth. Eighty-three percent of patients were white, 48% were male, and the mean age was 34 years. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The most commonly reported adverse reactions (occurring at a frequency of ≥5%) in zileuton extended-release tablets -treated patients and at a frequency greater than placebo-treated patients are reflected in Table 1. Table 1. Adverse Reactions with ≥5% Incidence in a 12-Week Placebo-Controlled Trial in Patients with Asthma. Adverse Reaction Zileuton Extended-Release Tablets 600 mg 2 Tablets Twice Daily N=199 n (%) Placebo 2 Tablets Twice Daily N=198 n (%) Sinusitis 13 (6.5) 8 (4.0) Nausea 10 (5.0) 3 (1.5) Pharyngolaryngeal pain 10 (5.0) 8 (4.0) Less common adverse reactions occurring at a frequency ≥1% and more often in the zileuton extended-release tablets group than in the placebo group included gastrointestinal disorders (upper abdominal pain, diarrhea, dyspepsia, vomiting), rash, hypersensitivity, and hepatotoxicity. There were no differences in the incidence of adverse reactions based upon gender. The clinical trials did not include sufficient numbers of patients <18 years of age or non-Caucasians to determine whether there is any difference in adverse reactions based upon age or race. Hepatotoxicity In the 12-week placebo-controlled trial, the incidence of ALT elevations (≥3xULN) was 2.5% (5 of 199) in the zileuton extended-release tablets group, compared to 0.5% (1 of 198) in the placebo group. In the zileuton extended-release tablets group, the majority of ALT elevations (60%) occurred in the first month of treatment, and in 2 of the 5 patients in the zileuton extended-release tablets group, ALT elevations were detected 14 days after completion of the 3- month study treatment. The levels returned to <2xULN or normal within 9 and 12 days, respectively. The ALT elevations in the other 3 patients were observed to return to <2xULN or normal within 15, 19, and 31 days after zileuton extended-release tablets discontinuation. There appeared to be no clinically relevant relationship between the time of onset and the magnitude of the first elevation or the magnitude of first elevation and time to resolution. The hepatic function enzyme elevations attributed to zileuton extended-release tablets did not result in any cases of jaundice, development of chronic liver disease, or death in this clinical trial. 6.2 Long-Term Clinical Studies Experience The safety of zileuton extended-release tablets was evaluated in one 6-month, randomized, double-blind, placebo-controlled clinical trial in adults and adolescents 12 years of age and older with asthma. Patients received two 600 mg zileuton extended-release tablets (n=619) or placebo (n=307) twice daily by mouth along with usual asthma care. Eighty-six percent of patients were white, 40% were male, and the overall mean age was 36. The rate and type of adverse reactions observed in this study were comparable to the adverse reactions observed in the 12-week study. Other commonly reported adverse reactions (occurring at a frequency of ≥5%) in zileuton extended-release tablets-treated patients and at a frequency greater than placebo-treated patients included the following: headache (23%), upper respiratory tract infection (9%), myalgia (7%), and diarrhea (5%) compared to 21%, 7%, 5% and 2%, respectively, in the placebo-treated group. ALT elevations (≥3xULN) were observed in 1.8% of patients treated with zileuton extended-release tablets compared to 0.7% in patients treated with placebo. The majority of elevations (82%) were reported within the first 3 months of treatment and resolved within 21 days for most of these patients after discontinuation of the drug. The hepatic function enzyme elevations attributed to zileuton extended-release tablets did not result in any cases of jaundice, development of chronic liver disease, or death in this clinical trial. Occurrences of low white blood cell (WBC) count (<3.0 x 109/L) were observed in 2.6% (15 of 619) of the zileuton extended-release tablets-treated patients and in 1.7% (5 of 307) of the placebo-treated patients. The WBC counts returned to normal or baseline following discontinuation of zileuton extended-release tablets. The clinical significance of these findings is not known. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of zileuton immediate-release tablets and may be applicable to zileuton extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship. Cases of severe hepatic injury have been reported in patients taking zileuton immediate-release tablets. These cases included death, life-threatening liver injury with recovery, symptomatic jaundice, hyperbilirubinemia, and elevations of ALT >8xULN. Cases of sleep disorders and behavior changes have also been reported [see Warnings and Precautions ( 5.2 .) ].

12.3 Pharmacokinetics Information on the pharmacokinetics of zileuton following the administration of zileuton immediate-release tablets is available in healthy subjects. The results of two clinical pharmacology studies using zileuton extended-release tablets are described below. Absorption A three-way crossover study was conducted in healthy male and female subjects (n=23) with a mean age of 33 (range 20 to 55) following single dose of 1200 mg (2 x 600 mg) zileuton extended-release tablets under fasted and fed conditions, and two doses of 600 mg zileuton immediate-release tablets every 6 hours under fasted conditions. Food increased the peak mean plasma concentrations (C max ) and the mean extent of absorption (AUC) of zileuton extended-release tablets by 18 and 34%, respectively, and prolonged T max from 2.1 hours to 4.3 hours. The relative bioavailability of zileuton extended-release tablets to zileuton immediate-release tablets with respect to C max and AUC under fasted conditions were 0.39 (90% CI: 0.36, 0.43) and 0.57 (90% CI: 0.52, 0.62), respectively. Similarly, relative bioavailability of zileuton extended-release tablets to zileuton immediate-release tablets with respect to C max and AUC under fed conditions were 0.45 (90% CI: 0.41, 0.49) and 0.76 (90% CI: 0.70, 0.83), respectively. A three-way crossover study was conducted in healthy male and female subjects (n=24) with a mean age of 35 (range 19 to 56) following multiple doses of 1200 mg (2 x 600 mg) zileuton extended-release tablets administered every 12 hours under fasted and fed conditions, and 600 mg zileuton immediate-release tablets every 6 hours under fed conditions until steady state zileuton levels were achieved. Food increased AUC and C min of zileuton extended-release tablets by 43% and 170%, respectively, but had no effect on C max . Therefore, zileuton extended-release tablets are recommended to be administered with food [see Dosage and Administration ( 2 )] . At steady state, relative bioavailability of zileuton extended-release tablets to zileuton immediate-release tablets with respect to C max , C min , and AUC were 0.65 (90% CI: 0.60, 0.71), 1.05 (90% CI: 0.88, 1.25) and 0.85 (90% CI: 0.78, 0.92) respectively. These data indicate that at steady state under fed conditions the C max of zileuton extended-release tablets is about 35% lower than that of zileuton immediate-release tablets but the C min and AUC are similar for both formulations. Distribution The apparent volume of distribution (V/F) of zileuton is approximately 1.2 L/kg. Zileuton is 93% bound to plasma proteins, primarily to albumin, with minor binding to α1-acid glycoprotein. Elimination Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 3.2 hours. Apparent oral clearance (CL/F) of zileuton is 669 mL/min. Zileuton activity is primarily due to the parent drug. Studies with radiolabeled drug have demonstrated that orally administered zileuton is well absorbed into the systemic circulation with 94.5% and 2.2% of the radiolabeled dose recovered in urine and feces, respectively. Metabolism In vitro studies utilizing human liver microsomes have shown that zileuton and its N-dehydroxylated metabolite can be oxidatively metabolized by CYP1A2, CYP2C9 and CYP3A4. Several zileuton metabolites have been identified in human plasma and urine. These include two diastereomeric O-glucuronide conjugates (major metabolites) and an N-dehydroxylated metabolite (A-66193) of zileuton. The urinary excretion of the inactive A-66193 metabolite and unchanged zileuton each accounted for less than 0.5% of the single radiolabeled dose. Multiple doses of 1200 mg zileuton extended-release tablets twice daily resulted in peak plasma levels of 4.9 mcg/mL of the inactive metabolite A-66193 with an AUC of 93 mcg·hr/mL, showing large inter-subject variability. This inactive metabolite has been shown to be formed by the gastrointestinal microflora prior to the absorption of zileuton and its formation increases with delayed absorption of zileuton. Renal Impairment The pharmacokinetics of zileuton immediate-release tablets were similar in healthy subjects and in subjects with mild, moderate, and severe renal insufficiency. In subjects with renal failure requiring hemodialysis, zileuton pharmacokinetics were not altered by hemodialysis and a very small percentage of the administered zileuton dose (<0.5%) was removed by hemodialysis. Hence, dosing adjustment in patients with renal dysfunction or undergoing hemodialysis is not necessary. Hepatic Impairment The pharmacokinetics of zileuton immediate-release tablets were compared between subjects with mild and moderate chronic hepatic insufficiency. The mean apparent plasma clearance of total zileuton in subjects with hepatic impairment was approximately half the value of the healthy subjects. The percent binding of zileuton to plasma proteins after multiple dosing was significantly reduced in patients with moderate hepatic impairment. Zileuton extended-release tablets are contraindicated in patients with active liver disease or persistent ALT elevations ≥3xULN [see Warnings and Precautions ( 5 ) ]. Geriatric Use The pharmacokinetics of zileuton immediate-release tablets were investigated in healthy elderly subjects (ages 65 to 81 years, 9 males, 9 females) and healthy young subjects (ages 20 to 40 years, 5 males, 4 females) after single and multiple oral doses of 600 mg zileuton every 6 hours. Zileuton pharmacokinetics were similar in healthy elderly subjects (≥65 years) compared to healthy younger adults (20 to 40 years).