Zileuton

1 INDICATIONS AND USAGE Zileuton Extended-Release Tablets is 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 Tablets can be continued during acute exacerbations of asthma. Zileuton Extended-Release Tablets is 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 Tablets 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 Tablets and monitor periodically during treatment. ( 2 , 5.1 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Elevations of one or more hepatic function enzymes and bilirubin may occur with Zileuton Extended-Release Tablets. Assess hepatic function enzymes prior to initiation of Zileuton Extended-Release Tablets, monthly for the first 3 months, every 2-3 months for the remainder of the first year, and periodically thereafter. Use Zileuton Extended-Release Tablets with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. ( 5.1 ) Neuropsychiatric Events: Neuropsychiatric events, including sleep disorders and behavior changes, may occur with Zileuton Extended-Release Tablets. Instruct patients to be alert for neuropsychiatric events. Evaluate the risks and benefits of continuing treatment with Zileuton Extended-Release Tablets if such events occur. ( 5.2 ) 5.1 Hepatotoxicity Elevations of one or more hepatic function enzymes and bilirubin may occur during Zileuton Extended-Release Tablets therapy. These laboratory abnormalities may progress to clinically significant liver injury, remain unchanged, or resolve with continued treatment, usually within three weeks. The ALT (SGPT) test is considered the most sensitive indicator of liver injury for Zileuton Extended-Release Tablets. Assess hepatic function enzymes prior to initiation of, and during therapy with, Zileuton Extended-Release Tablets. Assess serum ALT before treatment begins, once a month for the first 3 months, every 2-3 months for the remainder of the first year, and periodically thereafter for patients receiving long-term Zileuton Extended-Release Tablets therapy. If clinical signs and/or symptoms of liver dysfunction develop (e.g., right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, or “flu-like” symptoms) or transaminase elevations ≥5×ULN occur, discontinue Zileuton Extended-Release Tablets and follow hepatic function enzymes until normal. In controlled and open-label clinical studies involving more than 5000 patients treated with zileuton immediate-release tablets, the overall rate of ALT elevation ≥3×ULN was 3.2%. In these trials, one patient developed symptomatic hepatitis with jaundice, which resolved upon discontinuation of therapy. An additional 3 patients with transaminase elevations developed mild hyperbilirubinemia that was less than 3×ULN. There was no evidence of hypersensitivity or other alternative etiologies for these findings. Since treatment with Zileuton Extended-Release Tablets may result in increased hepatic function enzymes and liver injury, Zileuton Extended-Release Tablets should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. 5.2 Neuropsychiatric Events Neuropsychiatric events have been reported in adult and adolescent patients taking zileuton, the active ingredient in Zileuton Extended-Release Tablets and zileuton immediate-release tablets. Post-marketing reports with zileuton include sleep disorders and behavior changes. The clinical details of some post-marketing reports involving zileuton appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Zileuton Extended-Release Tablets if such events occur [see Adverse Reactions (6.3) ]. 5.1 Hepatotoxicity Elevations of one or more hepatic function enzymes and bilirubin may occur during Zileuton Extended-Release Tablets therapy. These laboratory abnormalities may progress to clinically significant liver injury, remain unchanged, or resolve with continued treatment, usually within three weeks. The ALT (SGPT) test is considered the most sensitive indicator of liver injury for Zileuton Extended-Release Tablets. Assess hepatic function enzymes prior to initiation of, and during therapy with, Zile…

4 CONTRAINDICATIONS The use of Zileuton Extended-Release Tablets is contraindicated in patients with: Active liver disease or persistent hepatic function enzyme elevations greater than or equal to 3 times the upper limit of normal (≥3×ULN) [see Warnings and Precautions (5) , and Use in Specific Populations (8.7) ]. A history of allergic reaction to zileuton or any of the ingredients of Zileuton Extended Release Tablets (e.g., rash, eosinophilia, etc.). Active liver disease or persistent hepatic function enzyme elevations ≥3 times the upper limit of normal. ( 4 , 5.1 ) History of allergic reaction to Zileuton or any of the ingredients of Zileuton Extended-Release Tablets. ( 4 )

7 DRUG INTERACTIONS The following study results were obtained using zileuton immediate-release tablets but the conclusions also apply to Zileuton Extended-Release Tablets. Zileuton increases theophylline levels. Reduce theophylline dose and monitor levels. ( 7.1 ) Zileuton increases warfarin levels. Monitor prothrombin time and adjust warfarin dose accordingly. ( 7.2 ) Zileuton increases propranolol levels and beta-blocker activity. Monitor appropriately. ( 7.3 ) 7.1 Theophylline In a drug-interaction study in 16 healthy subjects, co-administration of multiple doses of zileuton immediate-release tablets (800 mg every 12 hours) and theophylline (200 mg every 6 hours) for 5 days resulted in a significant decrease (approximately 50%) in steady-state clearance of theophylline, an approximate doubling of theophylline AUC, and an increase in theophylline C max (by 73%). The elimination half-life of theophylline was increased by 24%. Also, during co-administration, theophylline-related adverse reactions were observed more frequently than after theophylline alone. Upon initiation of Zileuton Extended-Release Tablets in patients receiving theophylline, the theophylline dosage should be reduced by approximately one-half and plasma theophylline concentrations monitored. Similarly, when initiating therapy with theophylline in a patient receiving Zileuton Extended-Release Tablets, the maintenance dose and/or dosing interval of theophylline should be adjusted accordingly and guided by serum theophylline determinations. 7.2 Warfarin Concomitant administration of multiple doses of zileuton immediate-release tablets (600 mg every 6 hours) and warfarin (fixed daily dose obtained by titration in each subject) to 30 healthy male subjects resulted in a 15% decrease in R-warfarin clearance and an increase in AUC of 22%. The pharmacokinetics of S-warfarin were not affected. These pharmacokinetic changes were accompanied by a clinically significant increase in prothrombin times. Monitoring of prothrombin time, or other suitable coagulation tests, with the appropriate dose titration of warfarin is recommended in patients receiving concomitant Zileuton Extended-Release Tablets and warfarin therapy. 7.3 Propranolol Co-administration of zileuton immediate-release tablets and propranolol results in a significant increase in propranolol concentrations. Administration of a single 80 mg dose of propranolol in 16 healthy male subjects who received zileuton immediate-release tablets 600 mg every 6 hours for 5 days resulted in a 42% decrease in propranolol clearance. This resulted in an increase in propranolol C max , AUC, and elimination half-life by 52%, 104%, and 25%, respectively. There was an increase in β-blockade as shown by a decrease in heart rate associated with the co-administration of these drugs. Patients concomitantly on Zileuton Extended-Release Tablets and propranolol should be closely monitored and the dose of propranolol reduced as necessary. No formal drug-drug interaction studies between zileuton and other beta-adrenergic blocking agents (i.e., β-blockers) have been conducted. It is reasonable to employ appropriate clinical monitoring when these drugs are co-administered with Zileuton Extended-Release Tablets. 7.4 Other Concomitant Drug Therapy Drug-drug interaction studies conducted in healthy subjects between zileuton immediate-release tablets and prednisone and ethinyl estradiol (oral contraceptive), drugs known to be metabolized by the CYP3A4 isoenzyme, have shown no significant interaction. However, no formal drug-drug interaction studies between zileuton and CYP3A4 inhibitors, such as ketaconazole, have been conducted. It is reasonable to employ appropriate clinical monitoring when these drugs are co-administered with Zileuton Extended-Release Tablets. Drug-drug interaction studies in healthy subjects have been conducted with zileuton immediate-release tablets and digoxin, phenytoin, sulfasalazine, and naproxen. There was no significan…

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 Rising Pharma Holdings, Inc. at 1-844-874-7464 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 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 (≥3×ULN) 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 <2×ULN or normal within 9 and 12 days, respectively. The ALT elevations in the other 3 patients were observed to return to <2×ULN 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…