zileuton 600 MG Oral Tablet

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 )

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 )

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 ≥5xULN 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 ≥3xULN 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 3xULN. 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. Patient 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 ) ].

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 )

CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Zileuton is an orally active inhibitor of ex vivo LTB 4 formation in humans. The inhibition of LTB 4 formation in whole blood is directly related to zileuton plasma levels. In patients with asthma, the IC 50 is estimated to be 0.46 μg/mL, and maximum inhibition ≥80% is reached at a zileuton concentration of 2 μg/mL. In patients with asthma receiving zileuton immediate-release tablets 600 mg four times daily, peak plasma levels averaging 5.9 μg/mL were associated with a mean LTB 4 inhibition of 98%. Zileuton inhibits the synthesis of cysteinyl leukotrienes as demonstrated by reduced urinary LTE 4 levels. 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 × 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 μg/mL of the inactive metabolite A-66193 with an AUC of 93 μg . 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 ≥3×ULN [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 subjec