VA Class:RE109

AHFS Class:

• Leukotriene Modifiers 48:10.24

Generic Name(s):

• Zileuton

Molecular Formula:

• C₁₁H₁₂N₂O₂S

Zileuton, a leukotriene synthesis inhibitor, is an antiasthmatic agent.1,2

Asthma

Zileuton is used for the prevention and long-term symptomatic management of asthma.1,8,46

Zileuton is not a bronchodilator and should not be used to relieve symptoms of acute asthma, including status asthmaticus; however, therapy with the drug generally should be continued during acute asthmatic attacks.1,46 All patients receiving zileuton should be provided with a short-acting, orally inhaled sympathomimetic agent (e.g., albuterol) to use as supplemental therapy for acute symptoms that may occur despite zileuton therapy.21,27 Patients receiving zileuton should be cautioned not to decrease the dosage of, or discontinue therapy with, other antiasthmatic medications unless instructed to do so by a clinician.1,21,46 In addition, patients should be advised to seek medical attention for reevaluation of asthma therapy if they require supplemental β₂-agonist bronchodilator therapy more frequently than usual (i.e., if there is a need to increase the dose or frequency of administration of the short-acting, inhaled bronchodilator) while receiving zileuton.1,46

Mild Persistent Asthma

Drugs for asthma may be categorized as relievers (e.g., bronchodilators taken as needed for acute symptoms) or controllers (principally inhaled corticosteroids or other anti-inflammatory agents taken regularly to achieve long-term control of asthma).39,45 When control of symptoms deteriorates in patients with intermittent asthma and symptoms become persistent (e.g., daytime symptoms of asthma more than twice weekly but less than once daily, and nocturnal symptoms of asthma 3-4 times per month), current asthma management guidelines and most clinicians recommend initiation of an anti-inflammatory agent, preferably with a low-dose orally inhaled corticosteroid (e.g., 88-264, 88-176, or 176 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adolescents and adults, children 5-11 years of age, or children 4 years of age or younger, respectively) as first-line therapy for persistent asthma, supplemented by as-needed use of a short-acting, inhaled β₂-agonist.21,28,29,39,45 Alternatives to low-dose inhaled corticosteroids for mild persistent asthma include certain leukotriene modifiers (i.e., montelukast, zafirlukast), extended-release theophylline, or mast-cell stabilizers (i.e., cromolyn, nedocromil [preparation for oral inhalation no longer commercially available in the US]), but these therapies are less effective and generally not preferred as initial therapy.39,45,47 The National Asthma Education and Prevention Program (NAEPP) does not recommend zileuton in patients with mild persistent asthma because of limited efficacy data and the need for liver function test monitoring during therapy.45

Moderate Persistent Asthma

According to current asthma management guidelines, therapy with a long-acting inhaled β₂-agonist such as salmeterol or formoterol generally is recommended in adults and adolescents who have moderate persistent asthma and daily asthmatic symptoms that are inadequately controlled following addition of low-dose inhaled corticosteroids to as-needed inhaled β₂-agonist treatment.39,45 However, the NAEPP recommends that the beneficial effects of long-acting inhaled β₂-agonists should be weighed carefully against the increased risk (although uncommon) of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents.45 (See Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects, in Salmeterol 12:12.08.12.)

Current asthma management guidelines also state that an alternative, but equally preferred option for management of moderate persistent asthma that is not adequately controlled with a low dosage of inhaled corticosteroid is to increase the maintenance dosage to a medium dosage (e.g., exceeding 264 but not more than 440 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adults and adolescents).39,45 Alternative, less effective therapies that may be added to a low dosage of an inhaled corticosteroid include certain leukotriene modifiers (i.e., montelukast, zafirlukast) or oral extended-release theophylline.39,45 Limited data are available in infants and children 11 years of age or younger with moderate persistent asthma, and recommendations of care are based on expert opinion and extrapolation from studies in adults.39,45 According to current asthma management guidelines, a long-acting inhaled β₂-agonist (e.g., salmeterol, formoterol), a leukotriene modifier (i.e., montelukast, zafirlukast), or extended-release theophylline (with appropriate monitoring) may be added to low-dose inhaled corticosteroid therapy in children 5-11 years of age.39,45 Because comparative data establishing relative efficacy of these agents in this age group are lacking, there is no clearly preferred agent for use as adjunctive therapy with a low-dose inhaled corticosteroid for treatment of asthma in these children.45

Severe Persistent Asthma

Maintenance therapy with an inhaled corticosteroid at medium dosages (e.g., exceeding 264 but not more than 440 mcg of fluticasone propionate in adults and adolescents or 176 but not more than 352 mcg of the drug [or its equivalent] in children 5-11 years of age daily via a metered-dose inhaler) or high dosages (e.g., exceeding 440 mcg of fluticasone propionate in adults and adolescents or 352 mcg of the drug [or its equivalent] in children 5-11 years of age daily via a metered-dose inhaler) and adjunctive therapy with a long-acting inhaled β₂-agonist is the preferred treatment according to current asthma management guidelines in adults and children 5 years of age or older with severe persistent asthma (i.e., continuous daytime asthma symptoms, nighttime symptoms 7 times per week).39,45 Such recommendations in children 5-11 years of age are based on expert opinion and extrapolation from studies in older children and adults.45 Alternatives to a long-acting inhaled β₂-agonist for severe persistent asthma in adults and children 5 years of age or older receiving medium-dose inhaled corticosteroids include certain leukotriene modifiers (i.e., montelukast, zafirlukast) or extended-release theophylline, but these therapies are generally not preferred.39,45 Omalizumab may be considered in adults and adolescents with severe persistent asthma with an allergic component.45 In infants and children 4 years of age or younger with severe asthma, maintenance therapy with an inhaled corticosteroid at medium dosages (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler) or high dosages (e.g., exceeding 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with either a long-acting inhaled β₂-agonist or montelukast is the only preferred treatment according to current asthma management guidelines.45 Recommendations for care of infants and children with severe asthma are based on expert opinion and extrapolation from studies in adolescents and adults.45 For additional details on the stepped-care approach to drug therapy in asthma, see Asthma under Uses: Bronchospasm, in Albuterol 12:12.08.12 and see Bronchospasm, under Uses: Asthma, in Montelukast Sodium 48:10.24.

Clinical Efficacy of Zileuton

Current data indicate that leukotriene modifiers such as zileuton generally produce modest improvements in lung function, diminish asthma symptoms, and may decrease the need for supplemental, short-acting β₂-adrenergic agonist therapy in patients with mild to moderate asthma.5,6,7,8,10,21 Efficacy of extended-release zileuton has been established in a placebo-controlled trial in adolescents and adults with severe asthma (i.e., mean baseline forced expiratory volume in 1 second [FEV₁] averaging 58.5% of the predicted normal value) who received zileuton 1.2 g twice daily for 12 weeks.45,46 Zileuton was more effective than placebo in improving pulmonary function (as measured by peak expiratory flow rate [PEFR] and mean change from baseline trough FEV₁) and reducing the need for supplemental therapy with short-acting β₂-adrenergic agonists.46 Efficacy of immediate-release zileuton has been established in a limited number of controlled studies in patients with mild to moderate persistent asthma (i.e., mean baseline FEV₁ averaging 40-80% of the predicted normal value) who received zileuton 400 or 600 mg 4 times daily for 1-6 months.1,5,6,8,20 In these trials, immediate-release zileuton was more effective than placebo in alleviating respiratory symptoms (i.e., daytime or nighttime asthma symptoms), improving pulmonary function (as measured by FEV₁ and morning PEFR), and reducing the need for supplemental therapy with orally inhaled sympathomimetic agents (e.g., albuterol)5,6,8 or systemic corticosteroids for acute exacerbations of asthma.5,6,8

In a randomized, placebo-controlled study in 373 patients who received immediate-release zileuton 400 or 600 mg 4 times daily for 6 months, patients receiving the higher dosage had a 37% improvement in daytime asthma symptom scores compared with baseline values (i.e., mean symptom score reduction of 0.49 with zileuton versus 0.28 with placebo, respectively, on a scale of 0 to 3) and approximately a 31% greater improvement in nighttime asthma symptoms (i.e., a mean symptom score reduction of 0.29 versus 0.04 with zileuton or placebo, respectively, on a scale of 0 to 3) compared with baseline.1,6 Immediate-release zileuton 600 mg 4 times daily produced modest improvements in trough FEV₁ compared with baseline (mean improvement of 0.27 L versus 0.14 L with placebo), morning PEFR (mean improvement of 30.6 versus 5.04 L/minute with placebo), and reduced supplemental therapy with a short-acting β₂-agonist (average decline: 1.77 puffs daily) usage.1,5,6,9,11 Patients treated with the lower dosage of zileuton (400 mg 4 times daily) did not have consistent improvements in lung function (i.e., as measured by FEV₁, forced vital capacity [FVC]) or asthma symptoms or reductions in supplemental use of short-acting β₂-adrenergic agonists.1,5,6,8 Analysis of pooled data from 2 large clinical trials5,6 indicates that immediate-release zileuton therapy reduced the need for treatment of asthma exacerbations with systemic corticosteroid therapy; in these trials, systemic corticosteroid therapy was required in 18.7% of placebo-treated patients versus 7% of zileuton-treated patients.1,5,6

Patients with mild to moderate asthma who respond to immediate-release zileuton therapy generally experience appreciable improvement in lung function (i.e., FEV₁) within 2-5 hours after administration of the drug; improvement in asthma control (e.g., as measured by increases in FEV₁ and PEFR, decrease in acute asthma exacerbations requiring corticosteroid therapy, decrease in the need for supplemental use of a short-acting β₂-agonist) has persisted during long-term therapy (e.g., up to 6 months) with zileuton.1,5,6,8,14,17,19 Post hoc analyses in these trials suggested that response to zileuton was greater in patients who had low FEV₁ values (e.g., less than 50% of predicted) at baseline.1,5,19

Clinical Safety Considerations

Zileuton should not be used in patients who have active liver disease or serum aminotransferase concentrations equal to or exceeding 3 times the upper limit of normal.1,27,46 Zileuton therapy may be associated with hepatic (e.g., hepatocellular) toxicity as evidenced by increases in serum aminotransferase values (e.g., serum ALT), and patients should be advised that they must return for liver enzyme test monitoring on a regular basis while taking the drug.1,27,46 ALT abnormalities generally occur within the first 3 months of therapy with zileuton; patients with pre-existing aminotransferase elevations and women aged 65 years of age or older may be at increased risk for ALT elevations with immediate-release zileuton.1,27,46 No discernable trends in ALT elevations were noted in geriatric patients 65 years of age or older receiving extended-release zileuton, but limited data available with extended-release zileuton in geriatric patients may preclude firm conclusions.46 The manufacturer recommends that serum ALT determinations be performed before initiation of zileuton therapy, then once a month for 3 months, every 2-3 months for the remainder of the first year, and periodically thereafter.1,27,46 If signs or symptoms of liver dysfunction (e.g., right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, “flu-like” symptoms) are present or elevations in serum aminotransferase concentrations equal or exceed 5 times the upper limit of normal, zileuton therapy should be discontinued and serum aminotransferase concentrations monitored until they return to normal.1,27,46 Zileuton should be used with caution in patients who are known to consume large quantities of alcohol, those with mild hepatic impairment (serum ALT less than 3 times the upper limit of normal), and those who have a past history of liver disease.1,27,46

Because of postmarketing reports of neuropsychiatric events (e.g., depression, anxiety, agitation, aggressive behavior, irritability, suicidal ideation and behavior [suicidality]) in adults, adolescents, and pediatric patients, the US Food and Drug Administration (FDA) reviewed the safety of zileuton and other leukotriene modifiers to evaluate a possible link between the use of these agents and such behavior or mood changes.48,52,53 Data from placebo-controlled trials with zileuton, zafirlukast, and montelukast submitted to FDA indicate that suicidal ideation occurred in 0.01% of 9929 patients treated with montelukast and in none of the patients treated with other leukotriene modifiers.52 In these studies, no completed suicide occurred during therapy with any leukotriene modifier.52 Following review of postmarketing reports and analysis of available clinical data, FDA has concluded that some of the neuropsychiatric events (e.g., sleep disorders, behavior changes) reported during postmarketing surveillance with zileuton appear consistent with a drug-induced effect.1,46,53 The manufacturer of zileuton states that patients receiving the drug and their clinicians should be alert to the potential for neuropsychiatric events.1,46,53 Patients should be instructed to contact their clinician if behavior or mood changes occur during therapy with zileuton.1,46,53 Clinicians should carefully evaluate the risks and benefits of continuing zileuton therapy in patients who develop neuropsychiatric symptoms.1,46,53

Drug Interaction Considerations

Concomitant administration of zileuton and warfarin may result in clinically important increases in prothrombin time.1,23,46 In healthy men receiving warfarin (with dosage titrated to achieve a prothrombin time of 14-18 seconds over 8 days), administration of zileuton (600 mg every 6 hours for 24 consecutive doses) decreased warfarin clearance by 15% and increased mean prothrombin time (PT) by 2-2.3 seconds; a small number of individuals were withdrawn from therapy as a result of excessive prothrombin times (i.e., greater than 23 seconds).1,23 Because warfarin has a narrow therapeutic margin, patients receiving concurrent therapy with zileuton should have close monitoring of prothrombin times and adjustment of their anticoagulant dosage if indicated.1,23,46

Zileuton appears to inhibit the cytochrome P-450 enzyme system (e.g., CYP1A, CYP3A) responsible for metabolism of theophylline, and concomitant administration of zileuton and theophylline results in a substantial (approximately 50%) reduction in theophylline clearance and an increase in plasma theophylline concentrations.1,27,30,46 Upon initiation of zileuton in patients receiving theophylline, the theophylline dosage should be reduced by approximately 50% and plasma theophylline concentrations monitored.1,46 In addition, patients receiving zileuton in whom theophylline therapy is initiated should have the dosage and/or dosing interval of theophylline adjusted appropriately as determined by monitoring of serum theophylline concentrations.1,30,46

Concomitant administration of propranolol and zileuton results in a doubling of propranolol area under the plasma concentration-time curve (AUC) and a resultant increase in β-adrenergic blocker activity.1,46 Patients receiving zileuton and propranolol should be closely monitored and the dosage of propranolol reduced as necessary.1,46

Administration

Zileuton is administered orally as conventional (immediate-release) and extended-release tablets.1,46 Immediate-release zileuton is usually given in 4 equally divided doses daily.1 Administration of immediate-release zileuton with food does not appreciably affect the rate or extent of absorption; therefore, for ease of administration, the drug may be taken with meals and at bedtime.1 Extended-release zileuton is usually given in 2 equally divided doses daily.46 Administration of extended-release zileuton with food increases the rate and extent of absorption; therefore, for ease of administration, the drug should be taken within 1 hour after morning and evening meals.46

Dosage

For the prevention and long-term symptomatic control of asthma, the usual dosage of immediate-release zileuton for adults and children 12 years of age or older is 600 mg 4 times daily.1 Limited evidence from clinical trials suggests that a smaller dosage of the drug (400 mg 4 times daily) does not produce consistent improvements in asthma control (i.e., as determined by changes in FEV₁, FVC, asthma symptoms, or reduction in supplemental use of β-agonist bronchodilators).1,5,6,8 For the prevention and long-term symptomatic control of asthma, the usual dosage of extended-release zileuton for adults and children 12 years of age or older is 1.2 g twice daily.46

Dosage in Renal and Hepatic Impairment

Limited data suggest that renal impairment does not affect the pharmacokinetics of zileuton, and the manufacturer states that dosage adjustment in patients with impaired renal function or in those undergoing hemodialysis is not necessary.1,46

Since hepatic metabolism is the principal means of elimination of zileuton, the drug is contraindicated in patients with active liver disease or serum aminotransferase concentrations of at least 3 times the upper limit of normal;1,46 zileuton should be used with caution in patients with mild hepatic impairment (serum ALT less than 3 times the upper limit of normal)27 or in those with a history of liver disease and/or excessive alcohol consumption.46 The manufacturer states that liver function tests should be performed prior to initiation of zileuton therapy and monitored periodically during therapy.46

Description

Zileuton, a leukotriene synthesis inhibitor, is an antiasthmatic agent.1,2,46 The drug differs chemically and pharmacologically from other antiasthmatic agents (e.g., corticosteroids, mast-cell stabilizers, β-adrenergic agonist bronchodilators, theophylline), including other currently available drugs that modify leukotriene activity (e.g., zafirlukast).3,8,10,12,13,15,18,19 Current evidence indicates that asthma is a chronic inflammatory disorder of the airways involving the production and activity of several endogenous inflammatory mediators, including leukotrienes.1,11,13,15,18,19,22 Leukotriene B₄ (LTB₄), a potent chemotactic mediator, and the cysteinyl leukotrienes C₄ (LTC₄), D₄ (LTD₄), and E₄ (LTE₄) are derived from the initial unstable product of arachidonic acid metabolism, leukotriene A₄ (LTA₄).1,13,15,18,19,22 Leukotrienes are associated with numerous biologic effects, including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability and edema, and smooth muscle contraction.1,4,10,13,14,15,17,18,26,46

The involvement of leukotrienes in asthma is supported by evidence of increased concentrations of leukotrienes in biologic fluids (e.g., urine, bronchoalveolar lavage fluid, nasal fluid, plasma) of some asthmatic patients following allergen challenge, episodes of asthma, and in patients with aspirin-induced asthma.10,13,15,18,19,46

Zileuton exerts beneficial effects in patients with asthma by inhibiting 5-lipoxygenase, the first dedicated enzyme active in the conversion of arachidonic acid to leukotrienes.3,4,12,19 Zileuton does not appreciably inhibit either the acute bronchoconstrictor response (immediate/early asthmatic response [IAR, EAR]) or the delayed inflammatory response (late asthmatic response [LAR]) to inhaled antigen and irritants, but the drug does inhibit bronchoconstriction occurring after administration of aspirin to aspirin-sensitive asthmatic patients.3,4,7,10,11,12,13,15,18,22 Commercially available zileuton is a racemic mixture (50:50) of the r+ and s- enantiomers, both of which have been shown in vitro to be pharmacologically active inhibitors of 5-lipoxygenase.1,25,46

Because of the role of leukotrienes in the pathogenesis of asthma, modulation of leukotriene formation by interruption of 5-lipoxygenase action may reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control.3,4,6,8,14,17 Leukotriene modifiers (e.g., zileuton, zafirlukast) have actions consistent with those of anti-inflammatory agents in that an expert panel of the National Asthma Education and Prevention Program has defined anti-inflammatory agents as those that reduce the markers of airway inflammation (e.g., eosinophils, mast cells, activated lymphocytes, macrophages, cytokines) in airway tissue or airway secretions and thereby reduce the intensity of airway hyperresponsiveness.21,31,32,33,39 However, the precise anti-inflammatory actions responsible for therapeutic effects of drugs in asthma (e.g., symptom reduction, improvement in expiratory flow, reduction in airway hyperresponsiveness, prevention of exacerbations, prevention of airway wall remodeling) remain to be fully elucidated.3,4,19,21,27 Zileuton does not appear to produce appreciable bronchodilation in healthy individuals.14

Additional Information

SumMon^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications.

1. Cornerstone Therapeutics Inc. Zyflo^® (zileuton) tablets prescribing information. Lexington, MA; 2009 Jul.

2. Kane GC, Pollice M, Kim CJ et al. A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental antigen challenge in human beings. J Allergy Clin Immunol . 1996; 97:646-54. [PubMed 8621850]

3. McGill KA, Busse WW. Zileuton. Lancet . 1996; 348:519-24. [PubMed 8757156]

4. Wenzel SE, Kamada AK. Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma: a randomized controlled trial. Ann Pharmacother . 1996; 30:858-64. [PubMed 8826571]

5. Israel E, Cohn J, Dubé L et al et al. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma: a randomized controlled trial. JAMA . 1996; 275:931-6. [PubMed 8598621]

6. Liu MC, Dubé LM, Lancaster J et al. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. J Allergy Clin Immunol . 1996; 98:859-71. [PubMed 8939149]

7. Hendeles L, Marshik PL. Zileuton: a new therapy for asthma or just the first of a new class of drugs? Ann Pharmacother . 1996; 30:873-5. (IDIS 369051)

8. 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. [PubMed 8239223]

9. Hendeles L. Introduction. Pharmacotherapy . 1997; 17:1-2S. [PubMed 9017761]

10. Busse WW. The role of leukotrienes in asthma and allergic rhinitis. Clin Exp Allergy . 1996; 26:868-79. [PubMed 9011329]

11. Hendeles L, Harman E. Use of allergen bronchoprovocation to screen drugs for anti-asthma activity. Pharmacotherapy . 1997; 17:39-49S.

12. Israel E, Fischer AR, Rosenberg MA et al. The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis . 1993; 148:1447-51. [PubMed 8256883]

13. Spector SL. Leukotriene inhibitors and antagonists in asthma. Ann Allergy Asthma Immunol . 1995; 75:463-70, 473. [PubMed 8603274]

14. Wenzel SE, Trudeau JB, Kaminsky DA et al. Effect of 5-lipoxygenase inhibition on bronchoconstriction and airway inflammation in nocturnal asthma. Am J Respir Crit Care Med . 1995; 152:897-905. [PubMed 7663802]

15. Smith LJ. Leukotrienes in asthma: the potential therapeutic role of antileukotriene agents. Arch Intern Med . 1996; 156:2181-9. [PubMed 8885816]

16. Fabbri LM, Piattella M, Caramori G et al. Oral vs inhaled asthma therapy: pros, cons and combinations. Drugs . 1996; 52(Suppl 6):20-8. [PubMed 8941500]

17. Fischer AR, McFadden CA, Frantz R et al. Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects. Am J Respir Crit Care Med . 1995; 152:1203-7. [PubMed 7551371]

18. Larsen JS, Jackson SK. Antileukotriene therapy for asthma. Am J Health-Syst Pharm . 1996; 53:2821-30. [PubMed 8957342]

19. Holgate ST, Bradding P, Sampson AP. Leukotriene antagonists and synthesis inhibitors: new directions in asthma therapy. J Allergy Clin Immunol . 1996; 98:1-13. [PubMed 8765812]

20. Drazen J, Israel E, Cohn J et al et al. The efficacy of zileuton in the treatment of asthma: results of combined double-blind, placebo-controlled trials. J Allergy Clin Immunol . 1995; 95:388.

21. National Asthma Education and Prevention Program. Expert Panel Report II: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health. 1997 Feb.

22. Harris RR, Carter GW, Bell RL et al. Clinical activity of leukotriene inhibitors. Intl J Immunopharmacol . 1995; 17:147-56.

23. Awni WM, Hussein Z, Granneman GR et al. Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans. Clin Pharmacokinet . 1995; 29(Suppl 2):67-76. [PubMed 8620673]

25. Awni WM, Cavanaugh JH, Braeckman RA et al. The effect of mild or moderate hepatic impairment (cirrhosis) on the pharmacokinetics of zileuton. Clin Pharmacokinet . 1995; 29(Suppl 2):49-61. [PubMed 8620671]

26. Wenzel SE. Arachidonic acid metabolites: mediators of inflammation in asthma. Pharmacotherapy . 1997; 17:3-12S.

27. Abbott, Abbott Park, IL: Personal communication.

28. Kelly HW. Issues and advances in the pharmacotherapy of asthma. J Clin Pharm Ther . 1992; 17:271-81. [PubMed 1361192]

29. North of England Asthma Guideline Development Group. North of England evidence based guidelines development project: summary version of evidence based guideline for the primary care management of asthma in adults. BMJ . 1996; 312:762-6. [PubMedCentral][PubMed 8605467]

30. Granneman GR, Braeckman RA, Locke CS et al. Effect of zileuton on theophylline pharmacokinetics. Clin Pharmacokinet . 1995; 29(Suppl 2):77-83. [PubMed 8620674]

31. Zeneca Pharmaceuticals. Accolate^® (zafirlukast) tablets prescribing information. Wilmington, DE; 1996 Sep.

32. Zeneca Pharmaceuticals, Wilmington, DE: Personal communication on zafirlukast 48:10.24.

33. Reviewers' comments (personal observations) on zafirlukast 48:10.24.

34. Hoechst Marion Roussel. Seldane^® (terfenadine) tables prescribing information. Kansas City, MO; 1997 Sep.

35. Hoechst Marion Roussel. Seldane-D^® (terfenadine and pseudoephedrine hydrochloride) extended-release tablets prescribing information. Kansas City, MO; 1997 Sep.

36. Janssen Pharmaceutica. Hismanal^® (astemizole tablets) prescribing information. Titusville, NJ. 1998 Feb.

37. Klausner MA. Dear doctor letter regarding important drug warning of Hismanal^® (astemizole). Titusville, NJ: Janssen Pharmaceutica; 1998 Feb.

39. National Institutes of Health, National Heart, Lung, and Blood Institute. Global initiative for asthma: global strategy for asthma management and prevention. Bethesda, MD: National Institutes of Health. 2009 Dec. Available from: [Web]. Accessed 2010 Sep 23. [Web]

45. National Asthma Education and Prevention Program. Expert panel report III: guidelines for the diagnosis and management of asthma. 2007 Jul. Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute. Available from NIH website. Accessed Jul 27, 2008. [Web]

46. Cornerstone Therapeutics Inc. Zyflo CR^® (zileuton) extended-release tablets prescribing information. Lexington, MA; 2009 Aug.

47. British Thoracic Society/Scottish Intercollegiate Guidelines Network. Guidelines on the management of asthma: a national clinical guideline. London, Eng; British Thoracic Society. 2007 Jul. Available from BTS website. Accessed Aug 20, 2007. [Web]

48. Food and Drug Administration, Center for Drug Evaluation and Research. Early communication about an ongoing safety review of montelukast (Singular). 2008 Mar 27. Available from FDA website. Accessed 2008 Oct 7. [Web]

52. Food and Drug Administration. Update of safety review. Follow-up to the March 27, 2008 communication about the ongoing safety review of montelukast (Singulair). 2009 Jan 13. Available at: [Web]. Accessed 2009 Oct 13.

53. Food and Drug Administration. Updated information on leukotriene inhibitors: montelukast (marketed as Singulair), zafirlukast (marketed as Accolate), and zileuton (marketed as Zyflo and Zyflo CR). 2009 Aug 28. Available at: [Web]. Accessed 2009 Oct 13.