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 )

3 DOSAGE FORMS AND STRENGTHS • Extended-release tablets, 600 mg. Extended-release tablets: 600 mg. ( 3 )

4 CONTRAINDICATIONS The use of zileuton extended-release tablets are 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 (≥3xULN) [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 )

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 8xULN. Cases of sleep disorders and behavior changes have also been reported [see Warnings and Precautions ( 5.2 .) ].

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 sign …

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 ) 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 to 12% 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 hyd …

12.1 Mechanism of Action Zileuton is an inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB 4 , LTC 4 , LTD 4 and LTE 4 ) formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro and in vivo systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. LTB 4 , a chemoattractant for neutrophils and eosinophils, and cysteinyl leukotrienes (LTC 4 , LTD 4 , LTE 4 ) can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF), blood, urine and sputum from asthmatic patients. Zileuton is an orally active inhibitor of ex vivo LTB 4 formation in several species, including mice, rats, rabbits, dogs, sheep, and monkeys. Zileuton inhibits arachidonic acid-induced ear edema in mice, neutrophil migration in mice in response to polyacrylamide gel, and eosinophil migration into the lungs of antigen-challenged sheep. In a mouse model of allergic inflammation, zileuton inhibited neutrophil and eosinophil influx, reduced the levels of multiple cytokines in the BALF, and reduced serum IgE levels. Zileuton inhibits leukotriene-dependent smooth muscle contractions in vitro in guinea pig and human airways. The compound inhibits leukotriene-dependent bronchospasm in antigen and arachidonic acid-challenged guinea pigs. In antigen-challenged sheep, zileuton inhibits late-phase bronchoconstriction and airway hyperreactivity. The clinical relevance of these findings is unknown.

11 DESCRIPTION Zileuton is an orally active inhibitor of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Zileuton has the chemical name (±)-1-(1-Benzo[b]thien-2-ylethyl)-1-hydroxyurea and the following chemical structure: Zileuton has the molecular formula C 11 H 12 N 2 O 2 S and a molecular weight of 236.29. It is a racemic mixture (50:50) of R(+) and S(-) enantiomers. Zileuton USP is a white to off-white powder that is freely soluble in methanol and sparingly soluble in acetonitrile. The melting point ranges from 144.2oC to 145.2oC. Zileuton extended-release tablets for oral administration are bi-layer film-coated tablets comprised of an immediate-release layer, and an extended-release layer. Zileuton extended-release tablets are oblong biconvex, bilayer film-coated tablets with pink to red IR layer debossed with '66' on one side and white to off white ER layer debossed with 'V' on the other side. Each tablet contains 600 mg of zileuton USP and the following inactive ingredients: colloidal silicon dioxide, crospovidone, ferric oxide, hydroxypropyl cellulose, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, sodium starch glycolate. The film coating contains hypromellose and polyethylene glycol. zileutonertabstructure

10 OVERDOSAGE Human experience of acute overdose with zileuton is limited. A patient in a clinical study took between 6.6 and 9.0 grams of zileuton immediate-release tablets in a single dose. Vomiting was induced and the patient recovered without sequelae. Zileuton is not removed by dialysis. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted as required. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. A Certified Poison Control Center should be consulted for up-to-date information on management of overdose with zileuton extended-release tablets.

16 HOW SUPPLIED/STORAGE AND HANDLING Zileuton extended-release tablets are oblong biconvex, bilayer film-coated tablets with pink to red IR layer debossed with '66' on one side and white to off white ER layer debossed with 'V' on the other side; they are available in bottles of 120 tablets (NDC 31722- 044-12). Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light.