Zileuton (Page 2 of 5)

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 (≥3xULN) 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 x 109 /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 >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.

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 Cmax (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 Cmax , 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 significant interaction between zileuton and any of these drugs.

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.

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 2-4% and 15-20%, 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 (9-12% 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 hydrocephalus also at 150 mg/kg/day which was equivalent to the MRHD on a mg/m2 basis. There were no adverse developmental outcomes at 50 mg/kg/day (approximately one-third the MRHD on a mg/m2 basis).

Oral dose of 5 mg radiolabeled zileuton indicated that zileuton crosses the placental barrier of rats.

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