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Zileuton (Systemic)


VA CLASSIFICATION
Primary: RE180

Commonly used brand name(s): Zyflo.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antiasthmatic (leukotriene inhibitor)—

Indications

Accepted

Asthma, chronic (prophylaxis and treatment)—Zileuton is indicated in patients with chronic asthma to improve asthma symptoms, improve pulmonary function (forced expiratory volume in 1 second [FEV 1], morning and evening peak expiratory flow rates), and to decrease the use of an inhaled beta 2-agonist {01}. In clinical trials, zileuton was used to treat patients with mild to moderate persistent asthma {03} {04}.

Unaccepted
Zileuton is not indicated for the treatment of bronchospasm in acute asthma attacks, including status asthmaticus; however, zileuton does not need to be discontinued during an acute exacerbation {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    236.29 {01}

Mechanism of action/Effect:

Zileuton is a selective inhibitor of 5-lipoxygenase, which is the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Specifically, it inhibits the formation of leukotrienes LTC 4, LTD 4, and LTE 4, which are the active constituents of slow-reacting substances of anaphylaxis, and LTB 4, a substance that attracts neutrophils and eosinophils. Leukotrienes produce numerous biological effects, including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. {01}

Absorption:

Rapidly and almost completely absorbed {01}.

Protein binding:

High (93%). Bound primarily to albumin {01}.

Biotransformation:

Hepatic. In vitro studies using human liver microsomes have shown that zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9, and 3A4. {01}

Half-life:

Mean terminal half-life is 2.5 hours {01}.

Onset of action:

Significant improvement from baseline in FEV 1 occurred 2 hours after initial administration in clinical trials {01}.

Time to peak plasma concentration

1.7 hours {01}.


Precautions to Consider

Carcinogenicity/Tumorigenicity

A 2-year study in female mice given zileuton in doses of approximately four times the systemic exposure achieved at the maximum recommended human daily oral dose showed an increased incidence of liver, kidney, and vascular tumors. The same study in male mice given zileuton in doses of approximately seven times the systemic exposure achieved at the maximum recommended human daily oral dose showed a trend toward an increase in the incidence of liver tumors. Zileuton was not tumorigenic in mice given zileuton in doses of approximately two times the systemic exposure achieved at the maximum recommended human daily oral dose. {01}

In rats, an increased incidence of kidney tumors was shown in females and males given zileuton in doses of approximately 14 and 6 times, respectively, the systemic exposure achieved at the maximum recommended human daily oral dose. Zileuton was not tumorigenic in male and female rats given doses of approximately four and six times, respectively, the systemic exposure achieved at the maximum recommended human daily oral dose. {01}

Mutagenicity

Zileuton was not mutagenic in multiple in vivo and in vitro assays; however, the livers and kidneys of female mice treated with zileuton showed a dose-related increase in DNA adduct formation. Although some evidence of DNA damage was shown in the hepatocytes of Aroclor 1254–treated rats in an unscheduled DNA synthesis assay, the results of a similar study in monkeys were negative. {01}

Pregnancy/Reproduction
Fertility—
Zileuton produced no effects on fertility in male and female rats given oral doses of up to approximately 8 and 18 times, respectively, the systemic exposure achieved at the maximum recommended human daily oral dose. However, a reduction in rat fetal implantations was seen with oral doses of approximately nine times the systemic exposure achieved at the maximum recommended human daily oral dose. In addition, reduced rat pup survival and growth were noted following maternal oral doses of approximately 18 times the systemic exposure achieved at the maximum recommended human daily oral dose. {01}



Pregnancy—
Adequate and well-controlled studies have not been done in humans {01}.

Zileuton and its metabolites cross the placenta in rats. When zileuton was administered orally to pregnant rats in doses of approximately 18 times the systemic exposure achieved at the maximum recommended human daily oral dose, the fetuses showed reduced body weight and increased skeletal variations. {01}

Administration of zileuton to pregnant rabbits in doses equivalent to the maximum recommended human daily oral dose produced cleft palate in 2.5% of the fetuses {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether zileuton is distributed into the breast milk of humans; however, the drug and its metabolites are distributed into the milk of lactating rats. Because of the potential for tumorigenicity shown in animal studies {01}, use of zileuton during breast-feeding is not recommended.

Pediatrics

Appropriate studies on the relationship of age to the effects of zileuton have not been performed in the pediatric population. Safety and efficacy in children up to 12 years of age have not been established. {01}


Geriatrics


In clinical studies, the pharmacokinetics of zileuton in healthy adults 65 years of age and older were similar to those of adults 18 to 40 years of age {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Drug interaction studies have been conducted with zileuton and prednisone and with zileuton and ethinyl estradiol, an oral contraceptive; no significant interactions were shown {01}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Astemizole or
Cisapride or
Cyclosporine or
Dihydropyridine calcium channel blocking agents, such as:
Felodipine
Isradipine
Nicardipine
Nifedipine
Nimodipine    (these medications are metabolized by the cytochrome P450 isoenzyme 3A4; although studies have not been done with zileuton and these medications, concurrent use should be monitored carefully, since zileuton is known to inhibit CYP3A4 in vitro {01})


» Beta-adrenergic blocking agents (systemic and ophthalmic)    (concurrent administration of zileuton and propranolol doubles the area under the plasma concentration–time curve and increases the pharmacologic effects of propranolol; although studies have not been done with other beta-adrenergic blocking agents, patients using beta-adrenergic blocking agents and zileuton should be monitored carefully {01})


» Terfenadine    (concurrent administration of recommended doses of terfenadine and zileuton for 7 days increased the mean area under the plasma concentration–time curve and peak serum concentration of terfenadine by approximately 35%; although no cardiac effects were noted, concurrent administration of these medications is not recommended {01})


» Theophylline    (concurrent administration of zileuton and theophylline approximately doubles the serum theophylline concentration; theophylline dosage should be reduced approximately by half and serum theophylline concentrations monitored closely in patients using these medications concurrently {01} {05})


» Warfarin    (concurrent administration of zileuton and warfarin results in a clinically significant increase in the prothrombin time; prothrombin times should be monitored closely and warfarin dose adjusted accordingly in patients using these medications concurrently {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Transaminases, hepatic    (elevations of one or more liver function tests may occur during therapy with zileuton; the values may continue to rise, remain unchanged, or return to normal during continued therapy {01})

    (if clinical signs or symptoms of hepatic function impairment or ALT values ³ five times the upper limit of normal develop, therapy with zileuton should be stopped and ALT monitored until values return to normal {01})

    (in clinical trials involving more than 5000 patients treated with zileuton, there was a 3.2% incidence of serum ALT values at least three times the upper limit of normal. One patient developed symptomatic hepatitis with jaundice that resolved following discontinuation of zileuton. Three patients with transaminase elevations developed hyperbilirubinemia that was less than three times the upper limit of normal. In subset analyses, females older than 65 years of age and patients with pre-existing transaminase elevations appeared to be at increased risk for ALT elevations {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Hepatic disease, active
» Hepatic function impairment    (zileuton is not recommended in patients with active hepatic disease or transaminase elevations three times the upper limit of normal or greater {01})


Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active    (caution is recommended in patients taking zileuton who consume substantial quantities of alcohol, because of possible hepatic function impairment {01})


Hypersensitivity to zileuton{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Alanine aminotransferase, serum (ALT [SGPT])    (serum ALT determinations are recommended before treatment starts, once a month for the first 3 months, every 2 to 3 months for the remainder of the first year, and periodically thereafter during zileuton therapy {01})

    (if clinical signs or symptoms of hepatic function impairment or ALT values ³ five times the upper limit of normal develop, therapy with zileuton should be stopped and ALT monitored until values return to normal {01})




Side/Adverse Effects

Note: In clinical trials involving more than 5000 patients treated with zileuton, there was a 3.2% incidence of serum ALT values at least three times the upper limit of normal. One patient developed symptomatic hepatitis with jaundice that resolved following discontinuation of zileuton. Three patients with transaminase elevations developed hyperbilirubinemia that was less than three times the upper limit of normal. In subset analyses, females older than 65 years of age and patients with pre-existing transaminase elevations appeared to be at increased risk for ALT elevations. {01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Hepatic function impairment {01}(flu-like symptoms; itching; nausea; right upper abdominal pain; unusual tiredness or weakness; yellow eyes or skin)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Dyspepsia {01}(upset stomach)
    
nausea {01}

Incidence less frequent
    
Abdominal pain {01}
    
asthenia {01}(weakness)





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Zileuton (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to zileuton

Pregnancy—Risk-benefit should be considered because of the potential for fetal abnormalities shown in animal studies





Breast-feeding—Use is not recommended
Other medications, especially beta-adrenergic blocking agents, terfenadine, theophylline, or warfarin
Other medical problems, especially active alcoholism, hepatic function impairment, or hepatic disease

Proper use of this medication
» Importance of not using this medication to treat acute asthma symptoms

» Proper dosing
Missed dose: Taking as soon as possible; if almost time for next dose, skipping missed dose; not doubling doses

» Proper storage

Precautions while using this medication
» Compliance with therapy by using every day in regularly spaced doses, even during symptom-free periods

» Importance of regular visits to physician to check progress and to test liver enzymes

» Checking with health care professional if more inhalations than usual of an inhaled, short-acting bronchodilator are needed to relieve an acute attack or if more than the maximum number of inhalations of the bronchodilator prescribed for a 24-hour period are needed

» Checking with health care professional before stopping or reducing therapy with any other asthma medications


Side/adverse effects
Signs of potential side effects, especially hepatic function impairment


Oral Dosage Forms

ZILEUTON TABLETS

Usual adult and adolescent dose
Antiasthmatic
Oral, 600 mg four times a day {01}.


Usual adult and adolescent prescribing limits
2400 mg a day {01}.

Usual pediatric dose
Children up to 12 years of age—Safety and efficacy have not been established {01}.

Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


600 mg (Rx) [Zyflo]

Canada—
Not commercially available.

Packaging and storage:
Store at controlled room temperature, between 20 and 25 °C (68 and 77 °F). Protect from light. {01}



Revised: 03/22/1999



References
  1. Zyflo package insert (Abbott—US), Rev 12/96.
  1. Sorkness CA. The use of 5-lipoxygenase inhibitors and leukotriene receptor antagonists in the treatment of chronic asthma. Pharmacotherapy 1997; 17(1 Pt 2): 50S-54S.
  1. Israel E, Rubin P, Kemp JP, et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med 1993; 119: 1059-66.
  1. Israel E, Cohn J, Dube L, et al. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. JAMA 1996; 275: 931.
  1. Granneman GR, Braeckman RA, Locke CS, et al. Effect of zileuton on theophylline pharmacokinetics. Clin Pharmacokinet 1995; 29 Suppl 2: 77-83.
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