Dr. Paul Answers Your Questions About Asthma. Watch The Video

Zileuton

Class: Leukotriene Modifiers
VA Class: RE109
Molecular Formula: C11H12N2O2S
CAS Number: 111406-87-2
Brands: Zyflo, Zyflo CR

Introduction

Antiasthmatic agent; a leukotriene synthesis inhibitor.1 2 46

Uses for Zileuton

Asthma

Prevention and long-term symptomatic management of asthma; used as an alternative, but not preferred adjunctive therapy.1 45 46

In patients with mild persistent asthma, low-dose orally inhaled corticosteroids considered first-line agents for long-term control.21 28 29 39 45 47 Alternative agents, including certain leukotriene modifiers (i.e., montelukast, zafirlukast), may be used but are less effective than inhaled corticosteroids and are not preferred as initial therapy.39 45 47

Slideshow: Asthma: 10 Things You Need To Do To Keep It In Check

In patients with moderate persistent asthma, low-dose inhaled corticosteroids with a long-acting inhaled β2-agonist bronchodilator (e.g., salmeterol, formoterol) or monotherapy with medium-dose inhaled corticosteroids preferred.39 45 However, the National Asthma Education and Prevention Program recommends that the beneficial effects of long-acting inhaled β2-agonists be weighed carefully against increased risk of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents.45

Alternative agents, including certain leukotriene modifiers (i.e., montelukast, zafirlukast), can be added to a low dosage of inhaled corticosteroid for treatment of moderate persistent asthma, but these options are less effective.39 45 Considerations favoring combination with orally inhaled corticosteroids include intolerance to long-acting β2-adrenergic agonists, marked preference for oral therapy, and demonstration of superior responsiveness to these leukotriene modifiers.45

Not recommended for relief of acute bronchospasm; however, may continue therapy during acute asthma exacerbations.1 46 (See Acute Asthma under Cautions.)

Zileuton Dosage and Administration

Administration

Oral Administration

Conventional (immediate-release) tablets: Administer orally in 4 equally divided doses daily without regard to meals.1 May be swallowed whole or cut in half.1

Extended-release tablets: Administer orally in 2 equally divided doses daily.46 Give within 1 hour after morning and evening meals.46 Swallow tablets whole; do not chew, cut, or crush.46 If a dose is missed, do not administer a double dose; take next dose at the regularly scheduled time.46

Dosage

Pediatric Patients

Asthma
Oral

Conventional (immediate-release) tablets: 600 mg 4 times daily in children ≥12 years of age.1

Extended-release tablets: 1.2 g twice daily in children ≥12 years of age.46

Adults

Asthma
Oral

Conventional (immediate-release) tablets: 600 mg 4 times daily.1

Extended-release tablets: 1.2 g twice daily.46

Prescribing Limits

Pediatric Patients

Asthma
Oral

Children ≥12 years of age: Maximum 2.4 g daily as conventional (immediate-release) or extended-release tablets.1 46

Adults

Asthma
Oral

Maximum 2.4 g daily as conventional (immediate-release) or extended-release tablets.1 46

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.46 a Do not use in patients with active liver disease or transaminases ≥3 times the ULN.1 27 46 (See Contraindications and also Hepatic Effects under Cautions.)

Renal Impairment

Dosage adjustment not required.1 46 a

Geriatric Patients

Dosage adjustment not required.1 46 a

Cautions for Zileuton

Contraindications

Active liver disease or serum aminotransferase concentrations ≥3 times the ULN.1 27 46 (See Hepatic Effects under Cautions.)

Known hypersensitivity to zileuton or any ingredient in the formulation.1 27 46

Warnings/Precautions

Warnings

Acute Asthma

Do not use for the relief of acute bronchospasm (including status asthmaticus); zileuton can be continued during acute exacerbations of asthma, but it will not provide immediate symptomatic relief.1 46

Interactions

Possible serious and/or life-threatening events associated with concomitant use with drugs dependent on CYP isoenzymes for metabolism (e.g., theophylline, propranolol, warfarin).1 23 27 30 46 (See Specific Drugs under Interactions.)

General Precautions

Hepatic Effects

Associated with increases in serum aminotransferase values (e.g., serum ALT);1 27 46 generally occurs within the first 3 months of therapy.1 27 46 Possible increased risk for ALT elevations in patients with preexisting aminotransferase elevations and women ≥65 years of age receiving immediate-release zileuton.1 27

Perform liver function tests (serum ALT) before initiating 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 Discontinue therapy if signs or symptoms of liver dysfunction (e.g., right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, “flu-like” symptoms) occur or serum ALT concentrations increase to ≥5 times the ULN; monitor serum ALT concentrations until they return to normal.1 27 46

Use contraindicated in patients with active liver disease or serum ALT concentrations ≥3 times the ULN.1 27 46 (See Contraindications under Cautions.) Use with caution in patients who consume large quantities of alcohol, those with mild hepatic impairment (serum ALT <3 times the ULN), and those with history of liver disease.1 27 46

Neuropsychiatric Effects

Neuropsychiatric events reported with zileuton during postmarketing experience.1 46 48 52 53 Data from placebo-controlled trials with leukotriene modifiers indicate that suicidal ideation occurred in 0.01% of 9929 patients treated with montelukast and in none of those receiving other leukotriene modifiers; no completed suicide occurred during therapy with any leukotriene modifier.52 FDA concluded that some neuropsychiatric events reported with zileuton (e.g., sleep disorders, behavior changes) appear consistent with a drug-induced effect.1 46 53

Be alert to the potential for neuropsychiatric events in patients receiving the drug.1 46 53 Instruct patients to contact their clinician if behavior or mood changes occur.1 46 53 Carefully evaluate the risks and benefits of continuing zileuton therapy in patients who develop neuropsychiatric symptoms.1 46 53

Specific Populations

Pregnancy

Conventional (immediate-release) and extended-release tablets: Category C.1 46

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 46 Discontinue nursing or the drug.1 46

Pediatric Use

Conventional (immediate-release) tablets: Safety and efficacy not established in children <12 years of age.1

Extended-release tablets: Safety and efficacy not established in children <12 years of age.46 FDA has not required studies in children <12 years of age because of risk of hepatotoxicity.46 Manufacturer states that therapy not appropriate for children <12 years of age.46

Geriatric Use

Conventional (immediate-release) tablets: Pharmacokinetics similar to those in younger adults.1 Possible increased risk for ALT elevations in women ≥65 years of age.1 27

Extended-release tablets: No substantial differences in ALT elevations observed in patients ≥65 years of age compared with younger adults, but increased sensitivity cannot be ruled out.46

Hepatic Impairment

Contraindicated in patients with active liver disease or serum ALT concentrations ≥3 times the ULN.1 27 46 Use with caution in patients with mild hepatic impairment (serum ALT <3 times the ULN), those with history of liver disease, and/or those who consume large quantities of alcohol.1 27 46 (See Hepatic Effects under Cautions.)

Renal Impairment

Pharmacokinetics not altered.1 46 Dosage adjustment not necessary.1 46

Common Adverse Effects

Conventional (immediate-release) tablets: Dyspepsia, nausea, abdominal pain, pain (unspecified), headache.1

Extended-release tablets: Sinusitis, nausea, pharyngolaryngeal pain.46

Interactions for Zileuton

Metabolized principally by CYP1A2, CYP2C9, and CYP3A4;1 46 may inhibit CYP1A and CYP3A.1 27 30

Specific Drugs

Drug

Interaction

Comments

Antihistamines (terfenadine and astemizole [no longer commercially available in US])

Increased plasma terfenadine concentrations; no substantial changes in QTc interval1 34 35

Possible increased plasma astemizole concentrations1 34 35

Terfenadine: Concomitant use not recommended1 34 35 36 37

Astemizole: Concomitant use not evaluated; appropriate monitoring recommended with concomitant use1

Calcium channel blockers, dihydropyridine

Possible increased plasma concentrations of dihydropyridine calcium-channel blocking agents1

Concomitant use not evaluated; appropriate monitoring recommended with concomitant use1

Cisapride (no longer commercially available in US)

Possible increased plasma cisapride concentrations1

Concomitant use not evaluated; appropriate monitoring recommended with concomitant use1

Contraceptives, oral (ethinyl estradiol)

Pharmacokinetic interactions unlikely1 46

Cyclosporine

Possible increased plasma cyclosporine concentrations1

Concomitant use not evaluated; appropriate monitoring recommended with concomitant use1

Digoxin

Pharmacokinetic interactions unlikely1 46

Naproxen

Pharmacokinetic interactions unlikely1 46

Phenytoin

Pharmacokinetic interactions unlikely1 46

Prednisone

Pharmacokinetic interactions unlikely1 46

Propranolol

Substantial increase in plasma propranolol concentrations resulting in increased β-adrenergic blockade 1 46

Close monitoring recommended; reduce propranolol dosage as necessary1 46

Sulfasalazine

Pharmacokinetic interactions unlikely1 46

Theophylline

Substantial increase in plasma theophylline concentrations1 27 30 46

Reduce theophylline dosage by approximately 50% and monitor plasma theophylline concentrations;1 46 adjust dosage and/or dosing interval if indicated1 30 46

Warfarin

Possible increased plasma warfarin concentrations and clinically important increases in PT1 23 46

Closely monitor PT; adjust anticoagulant dosage if indicated1 23 46

Zileuton Pharmacokinetics

Absorption

Bioavailability

Conventional (immediate-release) tablets: Rapidly absorbed following oral administration; however, absolute bioavailability is not known.1

Onset

Conventional (immediate-release) tablets: Following oral administration, improvement in asthma symptoms and/or lung function evident within 2–5 hours.1 5 6 8 14 17 19

Food

Conventional (immediate-release) tablets: Food increases peak plasma concentration but does not affect extent of absorption.1

Extended-release tablets: Food increases peak plasma concentration and extent of absorption.46

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1 46

Plasma Protein Binding

93% (mainly albumin).1 46

Elimination

Metabolism

Oxidatively metabolized to inactive metabolites principally via CYP1A2, CYP2C9, and CYP3A4.1 46

Elimination Route

Excreted in urine (94.5%) and in feces (2.2%) as metabolites and unchanged drug.1 46

Half-life

Conventional (immediate-release) tablets: Terminal half-life averages 2.5 hours.1

Extended-release tablets: Terminal half-life averages 3.2 hours.46

Stability

Storage

Oral

Tablets

Conventional (immediate-release) tablets: 20–25°C; protect from light.1

Extended-release tablets: 20–25°C (may be exposed to 15–30°C); protect from light.46

Actions

  • Inhibits 5-lipoxygenase, the first dedicated enzyme active in the conversion of arachidonic acid to leukotrienes;3 4 12 19 results in inhibition of leukotriene B4 (LTB4), and the cysteinyl leukotrienes C4 (LTC4), D4 (LTD4), and E4 (LTE4).1 13 15 18 19 22

  • May reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control.3 4 6 8 14 17 May also reduce markers of airway inflammation (e.g., eosinophils, mast cells, activated lymphocytes, macrophages, cytokines) in airway tissue or airway secretions and reduce the intensity of airway hyperresponsiveness.21 31 32 33

  • Does not 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.3 4 7 10 11 12 13 15 18 22

  • Does not appear to produce appreciable bronchodilation in healthy individuals.14

Advice to Patients

  • Importance of taking zileuton at regular intervals, when asymptomatic as well as during periods of worsening asthma.1 46

  • Importance of swallowing zileuton extended-release tablets whole and not chewing, cutting, or crushing the tablets.46

  • Importance of advising patient that if a dose of zileuton extended-release tablets is missed, not to double the dose, but to take the next dose at the regularly scheduled time.46

  • Importance of contacting clinician if asthma is not well controlled; seek medical attention if short-acting, inhaled β2-adrenergic bronchodilators are needed more often than usual or if more than the maximum number of inhalations for a 24-hour period are needed.1 46

  • Importance of not using zileuton for the relief of bronchospasm.1 46 Patients should be provided with and instructed in the use of a short-acting, inhaled β2-adrenergic bronchodilator as supplemental therapy for acute asthma symptoms.1 46

  • Importance of not discontinuing or reducing the dosage of other antiasthmatic agents unless instructed to do so by the clinician.1 46

  • Risk of liver toxicity; importance of immediately informing clinician if right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, or “flu-like” symptoms occur.1 46

  • Importance of informing clinicians if behavior or mood changes occur.1 46 53

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 46

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and alcohol consumption.1 46

  • Importance of informing patients of other important precautionary information.1 46 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Zileuton

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

600 mg

Zyflo (scored)

Cornerstone Therapeutics

Tablets, film-coated, extended-release

600 mg

Zyflo CR

Cornerstone Therapeutics

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Zyflo CR 600MG 12-hr Tablets (CORNERSTONE BIOPHARMA): 60/$493.99 or 120/$977.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions April 24, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Cornerstone Therapeutics. 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. [IDIS 360733] [PubMed 8621850]

3. McGill KA, Busse WW. Zileuton. Lancet. 1996; 348:519-24. [IDIS 371380] [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. [IDIS 369046] [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. [IDIS 362020] [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. [IDIS 377230] [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. [IDIS 322559] [PubMed 8239223]

9. Hendeles L. Introduction. Pharmacotherapy. 1997; 17:1-2S. [IDIS 378737] [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. [IDIS 323814] [PubMed 8256883]

13. Spector SL. Leukotriene inhibitors and antagonists in asthma. Ann Allergy Asthma Immunol. 1995; 75:463-70, 473. [IDIS 357677] [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. [IDIS 356177] [PubMed 7663802]

15. Smith LJ. Leukotrienes in asthma: the potential therapeutic role of antileukotriene agents. Arch Intern Med. 1996; 156:2181-9. [IDIS 374494] [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. [IDIS 355989] [PubMed 7551371]

18. Larsen JS, Jackson SK. Antileukotriene therapy for asthma. Am J Health-Syst Pharm. 1996; 53:2821-30. [IDIS 377124] [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. [IDIS 371811] [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. [IDIS 304352] [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. [IDIS 363124] [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: . Accessed 2010 Sep 23.

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 2008 Jul 27.

46. Cornerstone Therapeutics Inc. Zyflo CR (zileuton) extended-release tablets prescribing information. Lexington, MA; 2011 Nov.

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 2007 Aug 20.

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.

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: . 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: . Accessed 2009 Oct 13.

a. AHFS drug information 2006. McEvoy GK, ed. Zileuton. Bethesda, MD: American Society of Health-System Pharmacists. 2708-10.

Hide
(web4)