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 tablets 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 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)

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)

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 to 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 to 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)].

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, coadministration 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 coadministration, 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 Coadministration 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 coadministration 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 coadministered 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 coadministered 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 significant interaction between zileuton and any of these drugs.

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 Strides Pharma Inc at 1-877-244-9825 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 (≥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 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 (≥3×ULN) 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 × 10 9 /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 >8×ULN. Cases of sleep disorders and behavior changes have also been reported [see Warnings and Precautions (5.2)].

8 USE IN SPECIFIC POPULATIONS Information on specific populations is based on studies conducted with zileuton immediate-release tablets and is applicable to zileuton extended-release tablets. Hepatic Impairment: Zileuton extended-release tablets are contraindicated in patients with active liver disease and in patients with elevated hepatic function enzymes ≥3 times the upper limit of normal. (4, 5, 8.7) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labelling. 8.1 Pregnancy Risk Summary There are no adequate human data on zileuton extended-release tablets use in pregnant women to inform a drug associated risk. In animal studies, oral administration of zileuton to pregnant rats and rabbits during organogenesis produced adverse developmental outcomes. Structural abnormalities (cleft palate) were observed in rabbits at a dose similar to the maximum recommended human daily oral dose (MRHD), and alterations to growth (reduced fetal body weight and increased skeletal variations) were observed in rats at maternal plasma exposures 20 times greater than at the MRHD [see Data ]. In a pre- and post-natal development study, oral administration of zileuton to pregnant rats from organogenesis through weaning at maternal plasma exposures 20 times greater than the MRHD resulted in reduced pup survival and body weights. Zileuton and/or its metabolites cross the placental barrier of rats; therefore, zileuton extended-release tablets may be transmitted from the mother to the developing fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications during pregnancy. For more information, contact the MothersToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists at 1-877- 311-8972 or visit http://mothertobaby.org/pregnancy-studies/. Data Animal Data In a fertility and general reproductive performance study in rats, 0, 15, 75, 150 or 300 mg/kg/day zileuton was administered orally to male and female rats. The treated males were dosed daily for 100 days prior to mating with the treated females and 80 days prior to mating with untreated females, and throughout the mating periods. The treated females were dosed for 14 days before mating with untreated males and dosing continued throughout gestation, and in 1/3 of the females through parturition and lactation period. Maternal body weight gain was reduced at 150 and 300 mg/kg/day groups (9 to12% differences in body weight relative to controls). During fetal evaluation, zileuton produced lower litter size (7.1 pup/dams at 300 mg/kg/day vs. 9.6 pup/dams at 150 mg/kg/day vs. 13.5 pup/dams in control group), lower fetal weights (-9%), decreased viable fetuses, and increased in unossification of fetal skeletal structure at 300 mg/kg at exposures greater than 20 times the MRHD (on an AUC basis with data obtained from the comparable doses of 3-month general toxicity study). There were no embryofetal effects at 150 mg/kg/day. During post-natal development evaluation, zileuton produced decrease in pup viability (-16% at 150 mg/kg/day and -43.5% at 300 mg/kg/day on lactation Day 4) as well as depression of body weight gain in pups at ≥ 150 mg/kg/day at exposures close to 20 times the MRHD (on an AUC basis with data obtained from the comparable doses of 1-year general toxicity study). Observations of lower pup weight and survival rate at 300 mg/kg/day group were confirmed in a peri- & post-natal study administered with the same dose levels in pregnant rats. In a teratology study in pregnant rabbits, 0, 15, 50 or 150 mg/kg/day zileuton was administered orally to pregnant animals during organogenesis. Cleft palate was noted in three of 118 (2.5%) rabbit fetuses (or 2 of 17 litters) at 150 mg/kg/day. Additionally, two fetuses (1.7%) had domed head and two fetuses (1.7%) had hydrocephalus also at 150 mg/kg/day which was equivalent to the MRHD on a mg/m 2 basis. There were no adverse developmental outcomes at 50 mg/kg/day (approximately one-third the MRHD on a mg/m 2 basis). Oral dose of 5 mg radiolabeled zileuton indicated that zileuton crosses the placental barrier of rats. 8.2 Lactation Risk Summary Zileuton and/or its metabolites are excreted in rat milk. It is not known if zileuton is excreted in human milk, nor are there data on the effects of the drug on the breastfed infant or effects on maternal milk production. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity of zileuton shown in animal studies, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for zileuton extended-release tablets and any potential adverse effects on the breastfed child from zileuton extended-release tablets or from the underlying maternal condition. Data Animal Data Following an oral 70 mg/kg dose of radiolabeled 14 C-zileuton to lactating rats, total radioactivity was distributed into the milk of dams, but the mean concentrations did not exceed those in plasma. 8.4 Pediatric Use The safety and effectiveness of zileuton extended-release tablets in pediatric patients under 12 years of age have not been established. FDA has not required pediatric studies in patients under the age of 12 years due to risk of hepatotoxicity. Zileuton extended-release tablets are not appropriate for children less than 12 years of age. 8.5 Geriatric Use Subgroup analysis of controlled and open-label clinical studies with zileuton immediate-release tablets suggests that females ≥65 years of age appear to be at increased risk of ALT elevations. In zileuton extended-release tablets placebo-controlled studies there were no discernable trends in ALT elevations noted in subset analyses for patients ≥65 years of age, although the database may not have been sufficiently large to detect a trend [see Pharmacokinetics (12.3)]. 8.6 Renal Impairment Dosing adjustment in patients with renal dysfunction or patients undergoing hemodialysis is not necessary [see Pharmacokinetics (12.3)]. 8.7 Hepatic Impairment Zileuton extended-release tablets are contraindicated in patients with active liver disease or persistent ALT elevations ≥3×ULN [see Warnings and Precautions (5) and Pharmacokinetics (12.3)].