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warnings
WARNINGS 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 ).
ADVERSE REACTIONS 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. TABLE 2 Proportion of Patients Experiencing Adverse Events in Placebo-Controlled Studies in Asthma BODY SYSTEM/Event ZYFLO 600 mg 4 times daily % Occurrence (N = 475) Placebo % Occurrence (N = 491) BODY AS A WHOLE Headache 24.6 24.0 Pain (unspecified) 7.8 5.3 Abdominal Pain 4.6 2.4 Asthenia 3.8 2.4 Accidental Injury 3.4 2.0 DIGESTIVE SYSTEM Dyspepsia 8.2 p ≤0.05 vs placebo 2.9 Nausea 5.5 3.7 MUSCULOSKELETAL Myalgia 3.2 2.9 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 ≥3×ULN 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 3×ULN (see CONTRAINDICATIONS ). It is recommended that hepatic transaminases be evaluated at initiation of and during therapy with ZYFLO (see PRECAUTIONS, Hepatic ). Occurrences of low white blood cell count (≤2.8 × 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 Rash and urticaria have been reported with ZYFLO.