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Continuing Education Activity

Zileuton is a 5-lipoxygenase inhibitor mainly used for the prophylaxis and treatment of chronic asthma for those patients who are age 12 and older. Zileuton is used along with inhaled corticosteroids for treatment. It can also be used in patients with aspirin-induced asthma. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, toxicity, and monitoring, of zileuton so that providers can direct patient therapy in asthma relief as part of the interprofessional team.


  • Describe the therapeutic mechanism of action of zileuton.
  • Summarize the adverse event profile for zileuton.
  • Identify the contraindications for zileuton, including age restrictions.
  • Outline interprofessional team strategies for improving care coordination and communication to use zileuton properly to improve patient outcomes for asthma.


Zileuton is a 5-lipoxygenase inhibitor, primarily used for the prophylaxis and treatment of chronic asthma for those patients who are age 12 and older. Clinicians can use zileuton along with inhaled corticosteroids for treatment. It can also play a therapeutic role in patients with aspirin-induced asthma. It is not useful for patients in an acute asthma attack. Research has also shown zileuton to help treat patients with chronic obstructive pulmonary disease (COPD), upper airway inflammatory conditions, and dermatological conditions such as acne, pruritic in Sjogren-Larsson syndrome, and atopic dermatitis.

Studies have shown that those with exercise-induced asthma can also benefit from the drug if used one hour before exercise. Zileuton has also demonstrated to inhibit chronic myeloid leukemia when used in combination with imatinib or alone. However, further testing is necessary for this potential clinical use.

Mechanism of Action

There are two primary approaches to leukotriene inhibition. One approach is to antagonistically block cys-LT1 receptors from cysteinyl leukotrienes on bronchial smooth muscle cells, which is the mechanism of action for montelukast and zafirlukast.[1][2][3]

The second approach is that of zileuton. The enzyme 5-lipoxygenase is necessary for the biosynthesis of leukotrienes. Zileuton is a 5-lipoxygenase inhibitor, which in turn, inhibits the formation of leukotrienes B4, C4, D4, E4. Limiting these leukotrienes, in turn, helps to reduce inflammation, edema, mucus secretion, and bronchoconstriction in the airways. This action occurs by reducing leukocyte adhesion, smooth muscle contraction, capillary permeability, and the migration and aggregation of neutrophil and eosinophils. As a result, patients benefit from a reduction in asthma exacerbations and improvement in asthma symptoms.


Zileuton is only available in a tablet dosage form. The tablets are one dosage strength, 600 mg white, oval, film-coated tablets. Zileuton should be stored at room temperature 20 C to 25 C  (68 F to 77 F).

Administer two 600 mg extended-release tablets twice daily.  Use within one hour of morning and evening meals. It can be used in conjunction with inhaled corticosteroids. These tablets should not be crushed, split in half, or chewed. Patients should not use this drug for acute asthma attacks. Patients should not take a double dose if they missed a scheduled drug doe. 

Patients are advised not to change the dosage of any other anti-asthma medication unless told by a clinician. As liver enzyme elevation is the most serious complication, patients should get a regular check-up to check liver enzymes.

Adverse Effects

Serum alanine aminotransferase (ALT) concentrations must be obtained from the patient before treatment with the drug as hepatotoxicity can occur. ALT is the most sensitive liver enzyme for liver injury with zileuton treatments. Signs and symptoms include jaundice, right upper abdominal pain, edema, or pruritus. If ALT concentrations are normal, concentrations must be monitored once a month for the first three months, and then every three months for the year. After that, they require periodic monitoring when receiving long-term treatment. Discontinuation of the drug can cause a resolution of toxicity within 21 days. Patients with a history of liver disease or excessive alcohol use should use zileuton with caution.[4][5][6]

Patients taking zileuton may experience sleep disorders or changes in behavior. Patients undergoing long-term therapy (e.g., taking zileuton for more than six months) may experience frequent headaches, upper respiratory tract infections, diarrhea, or myalgia. However, the occurrence of these symptoms is similar to placebo treatment in many cases, e.g., headache: 25% for zileuton and 24% for placebo. In one study, dyspepsia was the most statistically significant side effect when compared to the placebo group.

Other reported adverse events include sinusitis, nausea, sleep disturbance, headache, abdominal pain, or pharyngolaryngeal pain. If neuropsychiatric events occur, patients should contact their healthcare provider.

Zileuton can also less commonly cause a decrease in white blood cell count. For the majority of the cases, the white count returned to normal or baseline without changing zileuton treatment.


Patients with active liver disease, serum ALT concentrations greater than or equal to three times the normal upper limit, or a history of hypersensitivity to zileuton or any of its dosage form ingredients should not take zileuton. Patients with ALT elevations more than three times the normal upper limit should avoid taking zileuton, and consider a different therapy course.[7][8]

There are no contraindications for use in pregnant patients. However, patients should not use zileuton unless the benefit to the mother justifies the risk to the fetus.

Children under the age of 12 should avoid the use of zileuton as its safety and effectiveness in the age group has not been established. Concerns in this group are primarily due to the risk of hepatoxicity.

Female patients over the age of 65 must use zileuton with caution as they are more susceptible to hepatotoxicity and liver injury.

Those with advanced stage renal disease on dialysis do not require dosage intervention or hemodialysis adjustment.


Monitor liver function tests (LFT), as well as plasma concentrations of theophylline, warfarin, and propranolol, as zileuton can increase serum concentrations of these medications when taken at the same time.

Studies have shown a 15% decrease in warfarin clearance leading to a significant increase in prothrombin times. Therefore, the recommendation is to monitor prothrombin times if the patient is taking warfarin with zileuton. 

Also, research has shown that patients taking zileuton immediate-release tablets and propranolol experienced an increase in serum propranolol concentrations within five days leading to bradycardia, as well as the risk for hypotension. Therefore, patients taking propranolol or other beta-blocking agents must be monitored or have their beta-blocker dose reduced to prevent complications.

In patients taking theophylline and zileuton concurrently, studies resulted in a decrease in theophylline clearance within five days. If patients are using theophylline and zileuton, clinicians should reduce the theophylline dosage by half and have the plasma concentrations of theophylline monitored daily. Be sure also to adjust the maintenance dose of theophylline if the patient is already on zileuton.


Overdose is treated based on symptoms with supportive care if a patient has signs of toxicity. Dialysis does not remove zileuton from the bloodstream. Treatment with gastric lavage may be necessary for the elimination of any unabsorbed drug. However, when an overdose occurs, there is only limited experience with zileuton. One case reported a patient that took between 6.6 gm to 9.0 gm of zileuton, and the patient was able to achieve full recovery without any complications.

Enhancing Healthcare Team Outcomes

The healthcare team, including the primary care provider and nurse practitioner who prescribes zileuton, should be familiar with the drug's indications and contraindications. Zileuton is only used for prophylaxis of asthma and not recommended to use alone. It also has several off label uses. Patients on zileuton should have their liver function monitored regularly. Also, the drug can interact with propranolol and induce bradycardia. Therefore, a thorough review of the patient's medication profile by a pharmacist will prevent drug interactions. [Level V]

Article Details

Article Author

Daniel Bouchette

Article Editor:

Charles Preuss


8/31/2021 10:29:28 AM

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