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).
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-amonth 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 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 nonprescription medicines. A patient leaflet is included with the tablets.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In 2-year carcinogenicity studies, increases in the incidence of liver, kidney, and vascular tumors in female mice and a trend towards an increase in the incidence of liver tumors in male mice were observed at 450 mg/kg/day (providing approximately 4 times [females] or 7 times [males] the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). No increase in the incidence of tumors was observed at 150 mg/kg/day (providing approximately 2 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). In rats, an increase in the incidence of kidney tumors was observed in both sexes at 170 mg/kg/day (providing approximately 6 times [males] or 14 times [females] the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). No increased incidence of kidney tumors was seen at 80 mg/kg/day (providing approximately 4 times [males] or 6 times [females] the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). Although a dose-related increased incidence of benign Leydig cell tumors was observed, Leydig cell tumorigenesis was prevented by supplementing male rats with testosterone.
Zileuton was negative in genotoxicity studies including bacterial reverse mutation (Ames) using S. typhimurium and E. coli, chromosome aberration in human lymphocytes, in vitro unscheduled DNA synthesis (UDS), in rat hepatocytes with or without zileuton pretreatment and in mouse and rat kidney cells with zileuton pretreatment, and mouse micronucleus assays. However, a dose-related increase in DNA adduct formation was reported in kidneys and livers of female mice treated with zileuton. Although some evidence of DNA damage was observed in a UDS assay in hepatocytes isolated from Aroclor-1254 treated rats, no such finding was noticed in hepatocytes isolated from monkeys, where the metabolic profile of zileuton is more similar to that of humans.
In reproductive performance/fertility studies, zileuton produced no effects on fertility in rats at oral doses up to 300 mg/kg/day (providing approximately 8 times [male rats] and 18 times [female rats] the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). Comparative systemic exposure (AUC) is based on measurements in male rats or nonpregnant female rats at similar dosages. However, reduction in fetal implants was observed at oral doses of 150 mg/kg/day and higher (providing approximately 9 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). Increases in gestation length, prolongation of estrous cycle, and increases in stillbirths were observed at oral doses of 70 mg/kg/day and higher (providing approximately 4 times the systemic exposure (AUC) achieved at the maximum recommended human daily oral dose). In a perinatal/postnatal study in rats, reduced pup survival and growth were noted at an oral dose of 300 mg/kg/day (providing approximately 18 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose).
Pregnancy Category C: Developmental studies indicated adverse effects (reduced body weight and increased skeletal variations) in rats at an oral dose of 300 mg/kg/day (providing approximately 18 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). Comparative systemic exposure[AUC] is based on measurements in nonpregnant female rats at a similar dosage. Zileuton and/or its metabolites cross the placental barrier of rats. Three of 118 (2.5%) rabbit fetuses had cleft palates at an oral dose of 150 mg/kg/day (equivalent to the maximum recommended human daily oral dose on a mg/m² basis). There are no adequate and well-controlled studies in pregnant women. ZYFLO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Zileuton and/or its metabolites are excreted in rat milk. It is not known if zileuton is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for ZYFLO in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of ZYFLO in pediatric patients under 12 years of age have not been established. Due to the risk of hepatotoxicity, use of ZYFLO in pediatric patients under 12 years is not recommended.
In subset analyses, females over the age of 65 appeared to be at an increased risk for ALT elevations. Zileuton pharmacokinetics were similar in healthy elderly subjects ( ≥ 65 years) compared to healthy younger adults (18 to 40 years) (see Pharmacokinetics -Special populations: Effect of age).
Last reviewed on RxList: 6/29/2012
This monograph has been modified to include the generic and brand name in many instances.
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