Zileuton

ZYFLO is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.

ZYFLO tablets are contraindicated in patients with: Active liver disease or transaminase elevations greater than or equal to three times the upper limit of normal (≥3xULN) (see PRECAUTIONS, Hepatic ). Hypersensitivity to zileuton or any of its inactive ingredients.

ZYFLO is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Therapy with ZYFLO can be continued during acute exacerbations of asthma. Co-administration of ZYFLO and theophylline results in, on average, an approximate doubling of serum theophylline concentrations. Theophylline dosage in these patients should be reduced and serum theophylline concentrations monitored closely (see PRECAUTIONS, Drug Interactions ). Co-administration of ZYFLO and warfarin results in a clinically significant increase in prothrombin time (PT). Patients on oral warfarin therapy and ZYFLO should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see PRECAUTIONS, Drug Interactions ). Co-administration of ZYFLO and propranolol results in doubling of propranolol AUC and consequent increased beta-blocker activity. Patients on ZYFLO and propranolol should be closely monitored and the dose of the propranolol reduced as necessary (see PRECAUTIONS, Drug Interactions ).

Hepatic : Elevations of one or more liver function tests may occur during ZYFLO therapy. These laboratory abnormalities may progress, remain unchanged, or resolve with continued therapy. In a few cases, initial transaminase elevations were first noted after discontinuing treatment, usually within 2 weeks. The ALT (SGPT) test is considered the most sensitive indicator of liver injury. In placebo-controlled clinical trials, the frequency of ALT elevations greater than or equal to three times the upper limit of normal (3xULN) was 1.9% for ZYFLO-treated patients, compared with 0.2% for placebo-treated patients. In a long-term safety surveillance study, 2458 patients received ZYFLO in addition to their usual asthma care and 489 received their usual asthma care. In patients treated for up to 12 months with ZYFLO in addition to their usual asthma care, 4.6% developed an ALT of at least 3xULN, compared with 1.1% of patients receiving only their usual asthma care. Sixty-one percent of these elevations occurred during the first two months of ZYFLO therapy. After two months of treatment, the rate of new ALT elevations ≥3xULN stabilized at a mean of 0.30% per month for patients receiving ZYFLO-plus-usual-asthma care compared with 0.11% per month for patients receiving usual asthma care alone. Of the 61 ZYFLO plus-usual-asthma-care patients with ALT elevations between 3 to 5xULN, 32 patients (52%) had ALT values decrease to below 2xULN while continuing ZYFLO therapy. Twenty-one of the 61 patients (34%) had further increases in ALT levels to ≥5xULN and were withdrawn from the study in accordance with the study protocol. In patients who discontinued ZYFLO, elevated ALT levels returned to <2xULN in an average of 32 days (range 1-111 days). In controlled and uncontrolled clinical trials involving more than 5000 patients treated with ZYFLO, the overall rate of ALT elevation ≥3xULN 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 three times the upper limit of normal. There was no evidence of hypersensitivity or other alternative etiologies for these findings. In subset analyses, females over the age of 65 appeared to be at an increased risk for ALT elevations. Patients with pre-existing transaminase elevations may also be at an increased risk for ALT elevations (see CONTRAINDICATIONS ). It is recommended that hepatic transaminases be evaluated at initiation of, and during therapy with, ZYFLO. Serum ALT should be monitored before treatment begins, once-a-month for the first 3 months, every two to three months for the remainder of the first year, and periodically thereafter for patients receiving long-term ZYFLO therapy. If clinical signs and/or symptoms of liver dysfunction (e.g., right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, or “flu-like” symptoms) develop or transaminase elevations greater than 5 times the ULN occur, ZYFLO should be discontinued and transaminase levels followed until normal. Since treatment with ZYFLO may result in increased hepatic transaminases, ZYFLO should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Neuropsychiatric Events : Neuropsychiatric events have been reported in adult and adolescent patients taking zileuton, the active ingredient in ZYFLO and zileuton extended-release tablets. Post-marketing reports with zileuton include sleep disorders and behavior changes. The clinical details of some post-marketing reports involving ZYFLO 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 if such events occur (see ADVERSE REACTIONS, Post-marketing Experience ). Information for Patients: Patients should be told that: ZYFLO is indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods. ZYFLO is not a bronchodilator and should not be used to treat acute episodes of asthma. When taking ZYFLO, they should not decrease the dose or stop taking any other antiasthma medications unless instructed by a physician. While using ZYFLO, medical attention should be sought if short-acting bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed. The most serious side effect of ZYFLO is elevation of liver enzyme tests and that, while taking ZYFLO, they must return for liver enzyme test monitoring on a regular basis. If they experience signs and/or symptoms of liver dysfunction (e.g., right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, or “flu-like” symptoms), they should contact their physician immediately. Patients should be instructed to notify their healthcare provider if neuropsychiatric events occur while using ZYFLO. ZYFLO can interact with other drugs and that, while taking ZYFLO, they should consult their doctor before starting or stopping any prescription or non-prescription medicines. A patient leaflet is included with the tablets. Drug Interactions : In a drug-interaction study in 16 healthy volunteers, co-administration of multiple doses of zileuton (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 C max (by 73%). The elimination half-life of theophylline was increased by 24%. Also, during co-administration, theophylline-related adverse events were observed more frequently than after theophylline alone. Upon initiation of ZYFLO 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, the maintenance dose and/or dosing interval of theophylline should be adjusted accordingly and guided by serum theophylline determinations (see WARNINGS ). Concomitant administration of multiple doses of ZYFLO (600 mg every 6 hours) and warfarin (fixed daily dose obtained by titration in each subject) to 30 healthy male volunteers 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 and warfarin therapy (see WARNINGS ). Co-administration of ZYFLO and propranolol results in a significant increase in propranolol concentrations. Administration of a single 80-mg dose of propranolol in 16 healthy male volunteers who received ZYFLO 600 mg every 6 hours for 5 days resulted in a 42% decrease in propranolol clearance. This resulted in an increase in propranolol C max , AUC, and elimination half-life by 52%, 104%, and 25%, respectively. There was an increase in β-blockade and decrease in heart rate associated with the co-administration of these drugs. Patients on ZYFLO and propranolol should be closely monitored and the dose of propranolol reduced as necessary (see WARNINGS ). No formal drug-drug interaction studies between ZYFLO 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 ZYFLO. […]

Clinical Studies : A total of 5542 patients have been exposed to zileuton in clinical trials, 2252 of them for greater than 6 months and 742 for greater than 1 year. Adverse events most frequently occurring (frequency ≥3%) in ZYFLO-treated patients and at a frequency greater than placebo-treated patients are summarized in Table 2. Proportion of Patients Experiencing Adverse Events in Placebo-Controlled Studies in Asthma Less common adverse events occurring at a frequency of greater than 1% and more commonly in ZYFLO-treated patients included: arthralgia, chest pain, conjunctivitis, constipation, dizziness, fever, flatulence, hypertonia, insomnia, lymphadenopathy, malaise, neck pain/rigidity, nervousness, pruritus, somnolence, urinary tract infection, vaginitis, and vomiting. The frequency of discontinuation from the asthma clinical studies due to any adverse event was comparable between ZYFLO (9.7%) and placebo-treated (8.4%) groups. In placebo-controlled clinical trials, the frequency of ALT elevations ≥3xULN was 1.9% for ZYFLO-treated patients, compared with 0.2% for placebo-treated patients. In controlled and uncontrolled 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 three times the upper limit of normal. There was no evidence of hypersensitivity or other alternative etiologies for these findings. ZYFLO is contraindicated in patients with active liver disease or transaminase elevations greater than or equal to 3xULN (see CONTRAINDICATIONS ). It is recommended that hepatic transaminases be evaluated at initiation of and during therapy with ZYFLO (see P RECAUTIONS , Hepatic ). Occurrences of low white blood cell count (≤2.8 x 10 9 /L) were observed in 1.0% of 1,678 patients taking ZYFLO and 0.6% of 1,056 patients taking placebo in placebo-controlled studies. These findings were transient and the majority of cases returned toward normal or baseline with continued ZYFLO dosing. All remaining cases returned toward normal or baseline after discontinuation of ZYFLO. Similar findings were also noted in a long-term safety surveillance study of 2458 patients treated with ZYFLO plus usual asthma care versus 489 patients treated only with usual asthma care for up to one year. The clinical significance of these observations is not known. In the long-term safety surveillance trial of ZYFLO plus usual asthma care versus usual asthma care alone, a similar adverse event profile was seen as in other clinical trials. Post-Marketing Experience : Cases of sleep disorders and behavior changes have been reported ( see PRECAUTIONS, Neuropsychiatric Events ). Rash and urticaria have been also reported with ZYFLO. Proportion of Patients Experiencing Adverse Events in Placebo-Controlled Studies in Asthma