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)

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)].