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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 > 5xULN 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 > 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 3xULN. 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.
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].
Patient Counseling Information
Information for Patients
Patients should be told that:
- ZYFLO CR is indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods.
- ZYFLO CR is a leukotriene synthesis inhibitor which works by inhibiting the formation of leukotrienes.
- ZYFLO CR should be taken within one hour after morning and evening meals.
- ZYFLO CR tablets should not be cut, chewed or crushed.
- ZYFLO CR is not a bronchodilator and should not be used to treat acute episodes of asthma.
- When taking ZYFLO CR, they should not decrease the dose or stop taking any other antiasthma medications unless instructed by a health care provider. If a dose is missed, they should take the next dose at the scheduled time and not double the dose.
- While using ZYFLO CR, 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 CR is potential elevation of liver enzymes (in 2% of patients) and that, while taking ZYFLO CR, 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 health care provider immediately. . Patients should be instructed to notify their healthcare provider if neuropsychiatric events occur while using ZYFLO CR.
- ZYFLO CR can interact with other drugs and that, while taking ZYFLO CR, they should consult their health care provider before starting or stopping any prescription or non-prescription 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 toward an increase in the incidence of liver tumors in male mice were observed at 450 mg/kg/day (providing approximately 5 times [females] or 8 times [males] the systemic exposure [AUC=64 µg·hr/mL] 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 2-3 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 8 times [males] or 16 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 7 times [females] the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). Although a dose-related increased incidence of benign Ley dig 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 12 times [male rats] and greater than 10 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 10 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose). These effects were not seen at an estimated 4 times clinical exposure. Increases in gestation length, prolongation of estrus cycle, and increases in stillbirths were observed at oral doses of 70 mg/kg/day and higher (providing approximately 3 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 greater than 10 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose).
Use In Specific Populations
Information on specific populations is based on studies conducted with zileuton immediate-release tablets and is applicable to ZYFLO CR.
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 greater than 10 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 CR 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 zileuton 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 CR in pediatric patients under 12 years of age have not been established. FDA has not required pediatric studies in patients under the age of 12 years due to the risk of hepatotoxicity. ZYFLO CR is not appropriate for children less than 12 years of age.
Subgroup analysis of controlled and open-label clinical studies with zileuton immediate-release tablets suggests that females ≥ 65 years of age appear to be at increased risk of ALT elevations. In ZYFLO CR placebo-controlled studies there were no discernable trends in ALT elevations noted in subset analyses for patients ≥ 65 years of age, although the database may not have been sufficiently large to detect a trend [see Pharmacokinetics].
Last reviewed on RxList: 12/12/2011
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