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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Elevations of one or more hepatic function enzymes and bilirubin may occur with ZYFLO CR. Assess hepatic function enzymes prior to initiation of ZYFLO CR, monthly for the first 3 months, every 2-3 months for the remainder of the first year, and periodically thereafter. Use ZYFLO CR 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 ZYFLO CR. Instruct patients to be alert for neuropsychiatric events. Evaluate the risks and benefits of continuing treatment with ZYFLO CR if such events occur. ( 5.2 ) 5.1 Hepatotoxicity Elevations of one or more hepatic function enzymes and bilirubin may occur during ZYFLO CR 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 ZYFLO CR. Assess hepatic function enzymes prior to initiation of, and during therapy with, ZYFLO CR. Assess serum ALT before treatment begins, once a month for the first 3 months, every 2-3 months for the remainder of the first year, and periodically thereafter for patients receiving long-term ZYFLO CR 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 ≥5×ULN occur, discontinue ZYFLO CR 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 ≥3×ULN 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 3×ULN. There was no evidence of hypersensitivity or other alternative etiologies for these findings. Since treatment with ZYFLO CR may result in increased hepatic function enzymes and liver injury, ZYFLO CR 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 ZYFLO CR 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. Patients 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 ZYFLO CR if such events occur [see Adverse Reactions (6.3) ].
6 ADVERSE REACTIONS Hepatotoxicity: Elevations of one or more hepatic function enzymes and bilirubin may occur during ZYFLO CR therapy [see Warnings and Precautions (5) ]. The most commonly occurring adverse reactions (≥5%) with ZYFLO CR 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 Chiesi USA, Inc. at 1-888-661-9260 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 ZYFLO CR 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 ZYFLO CR 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 ZYFLO CR-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 ZYFLO CR 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 ZYFLO CR 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 ZYFLO CR group, compared to 0.5% (1 of 198) in the placebo group. In the ZYFLO CR group, the majority of ALT elevations (60%) occurred in the first month of treatment, and in 2 of the 5 patients in the ZYFLO CR 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 ZYFLO CR 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 ZYFLO CR 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 ZYFLO CR 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 ZYFLO CR 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 ZYFLO CR-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 ZYFLO CR 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 ZYFLO CR 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 ZYFLO CR-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 ZYFLO CR. 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 ZYFLO CR. 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) ].