No

5-Lipoxygenase Inhibitor

Prophylaxis and chronic treatment of asthma in adults and children greater than or equal to 12 years of age

C

Clinical effects on the fetus: Developmental studies indicated adverse effects (reduced body weight and increased skeletal variations ) in rats at an oral dose of 300 mg/kg/day. There are no adequate and well controlled studies in pregnant women.

Breast-feeding/lactation: Zileuton and its metabolites are excreted in rat milk; it is not known if zileuton is excreted in breast milk

Active liver disease or transaminase elevations greater than or equal to three times the upper limit of normal ( greater than or equal to 3 x ULN), hypersensitivity to zileuton or any of its active ingredients

Elevations of one or more liver function tests may occur during therapy. These laboratory abnormalities may progress, remain unchanged or resolve with continued therapy. Use with caution in patients who consume substantial quantities of alcohol or have a past history of liver disease. Zileuton is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Zileuton can be continued during acute exacerbations of asthma.

>10%:

Central nervous system: Headache (24.6%)

Hepatic: Increased ALT (12%)

1% to 10%:

Cardiovascular: Chest pain

Central nervous system: Pain, dizziness, fever, insomnia, malaise, nervousness, somnolence

Gastrointestinal: Dyspepsia, nausea, abdominal pain, constipation, flatulence

Hematologic: Low white blood cell count

Neuromuscular & skeletal: Myalgia, arthralgia, weakness

Ocular: Conjunctivitis

Symptoms of overdose: Human experience is limited. Oral minimum lethal doses in mice and rats were 500-1000 and 300-1000 mg/kg, respectively (providing >3 and 9 times the systemic exposure achieved at the maximum recommended human daily oral dose, respectively). No deaths occurred, but nephritis was reported in dogs at an oral dose of 1000 mg/kg.

Treat symptomatically; institute supportive measures as required. If indicated, achieve elimination of unabsorbed drug by emesis or gastric lavage; observe usual precautions to maintain the airway. Zileuton is NOT removed by dialysis.

CYP1A2, 2C9, and 3A3/4 enzyme substrate; CYP1A2 and 3A3/4 inhibitor

Propranolol: Doubling of propranolol AUC and consequent increased beta-blocker activity

Terfenadine: Decrease in clearance of terfenadine leading to increase in AUC

Theophylline: Doubling of serum theophylline concentrations - reduce theophylline dose and monitor serum theophylline concentrations closely.

Warfarin: Clinically significant increases in prothrombin time (PT) - monitor PT closely

Specific inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB1, LTC1, LTD1 and LTE1) formation. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability and smooth muscle contraction.

Peak concentrations: 1-2 hours

Absorption: Oral: Rapidly absorbed

Distribution: 1.2 L/kg

Protein binding: 93%

Metabolism: Several metabolites in plasma and urine; metabolized by the cytochrome P-450 isoenzymes 1A2, 2C9 and 3A4

Bioavailability: Absolute bioavailability is unknown

Half-life: 2.5 hours

Time to peak serum concentration: 1.7 hours

Elimination: Predominantly via metabolism

Dialyzable: Not removed (>0.5%)

Oral:

Elderly: Zileuton pharmacokinetics were similar in healthy elderly subjects (>65 years) compared with healthy younger adults (18-40 years)

Dosing adjustment in renal impairment: Dosing adjustment is not necessary in renal impairment or renal failure (even during dialysis)

Dosing adjustment in hepatic impairment: Contraindicated in patients with active liver disease

Evaluate hepatic transaminases at initiation of and during therapy with zileuton. Monitor 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 zileuton therapy. If symptoms of liver dysfunction (right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice or "flu-like" symptoms) develop or transaminase elevations >5 times the ULN occur, discontinue therapy and follow transaminase levels until normal.

May cause dizziness, drowsiness, insomnia, or nervousness

Concurrent use with propranolol may enhance beta-blocker activity

No information available to require special precautions

No effects or complications reported

This medication is not for an acute asthmatic attack; in acute attack, follow instructions of prescriber. Do not stop other asthma medication unless advised by prescriber. Take with meals and at bedtime on a continuous bases; do not discontinue even if feeling better (this medication may help reduce incidence of acute attacks). Avoid alcohol and other medications unless approved by your prescriber. You may experience mild headache (mild analgesic may help); fatigue or dizziness (use caution when driving); or nausea or heartburn (small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Report persistent headache, chest pain, rapid heartbeat, or palpitations; skin rash or itching; unusual bleeding (eg, tarry stools, easy bruising, or blood in stool, urine, or mouth); skin rash or irritation; muscle weakness or tremors; redness, irritation, or infections of the eye; or worsening of asthmatic condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Consult prescriber if breast-feeding.

Tablet: 600 mg