Zyflo

Overdose

Human experience of acute overdose with zileuton is limited. A patient in a clinical study took between 6.6 and 9.0 grams of zileuton immediate-release tablets in a single dose. Vomiting was induced and the patient recovered without sequelae. Zileuton is not removed by dialysis. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted as required. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. A Certified Poison Control Center should be consulted for up-to-date information on management of overdose with Zyflo.

The oral minimum lethal doses in mice and rats were 500-4000 and 300-1000 mg/kg, respectively (providing greater than 3 and 9 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose, respectively). In dogs, at an oral dose of 1000 mg/kg (providing in excess of 12 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose) no deaths occurred but nephritis was reported.

Contraindications

The use of Zyflo is contraindicated in patients with:

• Active liver disease or persistent hepatic function enzyme elevations greater than or equal to 3 times the upper limit of normal ( > 3xULN).
• A history of allergic reaction to zileuton or any of the ingredients of Zyflo (e.g., rash, eosinophilia, etc.).

Undesirable effects

Hepatotoxicity: Elevations of one or more hepatic function enzymes and bilirubin may occur during Zyflo therapy.

The most commonly occurring adverse reactions ( ≥ 5%) with Zyflo are sinusitis, nausea, and pharyngolaryngeal pain.

The safety data described below reflect exposure to Zyflo 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 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-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.

Less common adverse reactions occurring at a frequency ≥ 1% and more often in the Zyflo 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 group, compared to 0.5% (1 of 198) in the placebo group. In the Zyflo group, the majority of ALT elevations (60%) occurred in the first month of treatment, and in 2 of the 5 patients in the Zyflo 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 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 did not result in any cases of jaundice, development of chronic liver disease, or death in this clinical trial.

The safety of Zyflo 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 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-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 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 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-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. 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. 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.

Cases of sleep disorders and behavior changes have also been reported.

Therapeutic indications

Zyflo is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Zyflo is not indicated for use in the reversal of bronchospasm in acute asthma attacks. Therapy with Zyflo can be continued during acute exacerbations of asthma.

Pharmacodynamic properties

Zileuton is an orally active inhibitor of ex vivo LTB4 formation in humans. The inhibition of LTB4 formation in whole blood is directly related to zileuton plasma levels. In patients with asthma, the IC50 is estimated to be 0.46 µg/mL, and maximum inhibition ≥ 80% is reached at a zileuton concentration of 2 µg/mL. In patients with asthma receiving zileuton immediate-release tablets 600 mg four times daily, peak plasma levels averaging 5.9 µg/mL were associated with a mean LTB4 inhibition of 98%. Zileuton inhibits the synthesis of cysteinyl leukotrienes as demonstrated by reduced urinary LTE4 levels.

Pharmacokinetic properties

Information on the pharmacokinetics of zileuton following the administration of zileuton immediate-release tablets is available in healthy subjects. The results of two clinical pharmacology studies using Zyflo are described below.

A three-way crossover study was conducted in healthy male and female subjects (n=23) with a mean age of 33 (range 20-55) following single dose of 1200 mg (2 x 600 mg) Zyflo tablets under fasted and fed conditions, and two doses of 600 mg zileuton immediate-release tablets every 6 hours under fasted conditions. Food increased the peak mean plasma concentrations (Cmax) and the mean extent of absorption (AUC) of Zyflo by 18 and 34%, respectively, and prolonged Tmax from 2.1 hours to 4.3 hours. The relative bioavailability of Zyflo to zileuton immediate-release tablets with respect to Cmax and AUC under fasted conditions were 0.39 (90% CI: 0.36, 0.43) and 0.57 (90% CI: 0.52, 0.62), respectively. Similarly, relative bioavailability of Zyflo to zileuton immediate-release tablets with respect to Cmax and AUC under fed conditions were 0.45 (90% CI: 0.41, 0.49) and 0.76 (90% CI: 0.70, 0.83), respectively.

A three-way crossover study was conducted in healthy male and female subjects (n=24) with a mean age of 35 (range 19-56) following multiple doses of 1200 mg (2 x 600 mg) Zyflo tablets administered every 12 hours under fasted and fed conditions, and 600 mg zileuton immediate-release tablets every 6 hours under fed conditions until steady state zileuton levels were achieved. Food increased AUC and Cmin of Zyflo by 43% and 170%, respectively, but had no effect on Cmax. Therefore, Zyflo is recommended to be administered with food. At steady state, relative bioavailability of Zyflo to zileuton immediate-release tablets with respect to Cmax, Cmin, and AUC were 0.65 (90% CI: 0.60, 0.71), 1.05 (90% CI: 0.88, 1.25) and 0.85 (90% CI: 0.78, 0.92) respectively. These data indicate that at steady state under fed conditions the Cmax of Zyflo is about 35% lower than that of zileuton immediate-release tablets but the Cmin and AUC are similar for both formulations.

The apparent volume of distribution (V/F) of zileuton is approximately 1.2 L/kg. Zileuton is 93% bound to plasma proteins, primarily to albumin, with minor binding to al-acid glycoprotein.

Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 3.2 hours. Apparent oral clearance (CL/F) of zileuton is 669 mL/min. Zileuton activity is primarily due to the parent drug. Studies with radiolabeled drug have demonstrated that orally administered zileuton is well absorbed into the systemic circulation with 94.5% and 2.2% of the radiolabeled dose recovered in urine and feces, respectively.

In vitro studies utilizing human liver microsomes have shown that zileuton and its N-dehydroxylated metabolite can be oxidatively metabolized by CYP1A2, CYP2C9 and CYP3A4.

Several zileuton metabolites have been identified in human plasma and urine. These include two diastereomeric 0-glucuronide conjugates (major metabolites) and an N-dehydroxylated metabolite (A-66193) of zileuton. The urinary excretion of the inactive A-66193 metabolite and unchanged zileuton each accounted for less than 0.5% of the single radiolabeled dose. Multiple doses of 1200 mg ZYFLO CR twice daily resulted in peak plasma levels of 4.9 µg/mL of the inactive metabolite A-66193 with an AUC of 93 µg-hr/mL, showing large inter-subject variability. This inactive metabolite has been shown to be formed by the gastrointestinal microflora prior to the absorption of zileuton and its formation increases with delayed absorption of zileuton.

The pharmacokinetics of zileuton immediate-release tablets were similar in healthy subjects and in subjects with mild, moderate, and severe renal insufficiency. In subjects with renal failure requiring hemodialysis, zileuton pharmacokinetics were not altered by hemodialysis and a very small percentage of the administered zileuton dose ( < 0.5%) was removed by hemodialysis. Hence, dosing adjustment in patients with renal dysfunction or undergoing hemodialysis is not necessary.

The pharmacokinetics of zileuton immediate-release tablets were compared between subjects with mild and moderate chronic hepatic insufficiency. The mean apparent plasma clearance of total zileuton in subjects with hepatic impairment was approximately half the value of the healthy subjects. The percent binding of zileuton to plasma proteins after multiple dosing was significantly reduced in patients with moderate hepatic impairment. Zyflo is contraindicated in patients with active liver disease or persistent ALT elevations ≥ 3xULN.

The pharmacokinetics of zileuton immediate-release tablets were investigated in healthy elderly subjects (ages 65 to 81 years, 9 males, 9 females) and healthy young subjects (ages 20 to 40 years, 5 males, 4 females) after single and multiple oral doses of 600 mg zileuton every 6 hours. Zileuton pharmacokinetics were similar in healthy elderly subjects ( > 65 years) compared to healthy younger adults (20 to 40 years).

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Elevations of one or more hepatic function enzymes and bilirubin may occur during Zyflo 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.

Assess hepatic function enzymes prior to initiation of, and during therapy with, Zyflo. 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 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 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 may result in increased hepatic function enzymes and liver injury, 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 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 if such events occur.

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 a leukotriene synthesis inhibitor which works by inhibiting the formation of leukotrienes.
• Zyflo should be taken within one hour after morning and evening meals.
• Zyflo tablets should not be cut, chewed or crushed.
• 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 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, 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 potential elevation of liver enzymes (in 2% of patients) 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 health care provider 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 health care provider before starting or stopping any prescription or non-prescription medicines.
• A patient leaflet is included with the tablets.

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).

Information on specific populations is based on studies conducted with zileuton immediate-release tablets and is applicable to Zyflo.

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 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 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 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.

Dosing adjustment in patients with renal dysfunction or patients undergoing hemodialysis is not necessary.

Zyflo is contraindicated in patients with active liver disease or persistent ALT elevations ≥ 3xULN.

Dosage (Posology) and method of administration

The recommended dosage of Zyflo for the treatment of patients with asthma is two 600 mg extended-release tablets twice daily, within one hour after morning and evening meals, for a total daily dose of 2400 mg. Tablets should not be chewed, cut or crushed. If a dose is missed, the patient should take the next dose at the scheduled time and not double the dose. Assess hepatic function enzymes prior to initiation of Zyflo and periodically during treatment.