Zileuton (Page 3 of 5)

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 is 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 is contraindicated in patients with active liver disease or persistent ALT elevations ≥3xULN [see Warnings and Precautions (5) and Pharmacokinetics (12.3) ].

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.

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

zileuton

Zileuton has the molecular formula C11 H12 N2 O2 S and a molecular weight of 236.29. It is a racemic mixture (50:50) of R(+) and S(-) enantiomers. Zileuton is a practically odorless, white, crystalline powder that is soluble in methanol and ethanol, slightly soluble in acetonitrile, and practically insoluble in water and hexane. The melting point ranges from 144.2ºC to 145.2ºC.

Zileuton Extended-Release Tablets for oral administration are triple-layer tablets comprised of an immediate-release layer, a middle (barrier) layer, and an extended-release layer. Zileuton Extended-Release Tablets are oblong, film-coated tablets with one red layer between two white layers, debossed on one side with “CT2”. Each tablet contains 600 mg of zileuton and the following inactive ingredients: crospovidone, ferric oxide, glyceryl behenate, hydroxypropyl cellulose, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, pregelatinized starch, propylene glycol, sodium starch glycolate, and talc.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Zileuton is an inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4 , LTC4 , LTD4 and LTE4 ) 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. LTB4 , a chemoattractant for neutrophils and eosinophils, and cysteinyl leukotrienes (LTC4 , LTD4 , LTE4 ) 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 LTB4 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 LTB4 formation in humans. The inhibition of LTB4 formation in whole blood is directly related to zileuton plasma levels. In patients with asthma, the IC50 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 LTB4 inhibition of 98%. Zileuton inhibits the synthesis of cysteinyl leukotrienes as demonstrated by reduced urinary LTE4 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 20-55) 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 (Cmax ) and the mean extent of absorption (AUC) of Zileuton Extended-Release Tablets by 18 and 34%, respectively, and prolonged Tmax from 2.1 hours to 4.3 hours. The relative bioavailability of Zileuton Extended-Release Tablets to zileuton immediate-release tablets with respect to Cmax 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 Cmax 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 19-56) 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 Cmin of Zileuton Extended-Release Tablets by 43% and 170%, respectively, but had no effect on Cmax . Therefore, Zileuton Extended-Release Tablets is 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 Cmax , Cmin , 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 Cmax of Zileuton Extended-Release Tablets is about 35% lower than that of zileuton immediate-release tablets but the Cmin 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 intersubject 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 is 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).

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