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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
N=199 n (%)
2 Tablets Twice
|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.
In the 12-week placebo-controlled trial, the incidence of ALT elevations ( ≥ 3xULN) 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 < 2xULN or normal within 9 and 12 days, respectively. The ALT elevations in the other 3 patients were observed to return to < 2xULN 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.
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 ( ≥ 3xULN) 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 x 109/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.
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 > 8xULN.
Read the Zyflo CR (zileuton extended release tablets) Side Effects Center for a complete guide to possible side effects
The following study results were obtained using zileuton immediate-release tablets but the conclusions also apply to ZYFLO CR.
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 ZYFLO CR 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 ZYFLO CR, the maintenance dose and/or dosing interval of theophylline should be adjusted accordingly and guided by serum theophylline determinations.
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 ZYFLO CR and warfarin therapy.
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 p-blockade as shown by a decrease in heart rate associated with the co-administration of these drugs. Patients concomitantly on ZYFLO CR 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., p-blockers) have been conducted. It is reasonable to employ appropriate clinical monitoring when these drugs are co-administered with ZYFLO CR.
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 ZYFLO CR. 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.
Read the Zyflo CR Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 12/12/2011
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