Zileuton


Article Author:
Daniel Bouchette


Article Editor:
Charles Preuss


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Lauren Camaione


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Phillip Hynes


Updated:
3/13/2019 6:57:10 PM

Indications

Zileuton is a 5-lipoxygenase inhibitor that is 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. It should not be used for patients with an acute asthma attack. Zileuton has also been shown to 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 was also found to inhibit chronic myeloid leukemia when used in combination with imatinib or alone. However, further testing is required 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. This is the mechanism of action for montelukast and zafirlukast.[1][2][3]

The second approach is that of zileuton. The enzyme 5-lipoxygenase is required 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 is done 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.

Administration

Zileuton is only available in tablet dosage form. The tablets are one dosage strength; 600 mg white, oval, film-coated tablets. Zileuton is recommended to 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. Do not take a double dose if scheduled drug dosage was missed. 

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 are advised to get a check up on a regular basis 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 levels 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 should be monitored every so often 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 6 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 change in zileuton treatment.

Contraindications

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 inactive products should not take zileuton. Patients with ALT elevations less than three times 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. This is 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.

Monitoring

Monitor liver function tests (LFT), as well as levels 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 large increase in prothrombin times. Therefore, it is recommended 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 5 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 5 days. If patients are using theophylline and zileuton, physicians are advised to 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.

Toxicity

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 indicated for the elimination of any unabsorbed drug. However, when an overdose occurs, the experience is limited 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 prescribe zileuton should be familiar with the drug's indications and contraindications. Zileuton is only used for prophylaxis of asthma and never used alone. It also has several off label uses. Patients on zilueton should have their liver function monitored regularly. In addition, the drug can interact with beta-blockers and induce bradycardia.


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Zileuton - Questions

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A 19-year-old man with asthma is receiving treatment with fluticasone and salmeterol. The patient continues to experience daily bronchospasms. Zileuton treatment is added in order to further decrease the incidence of bronchospasms. Which of the following is the mechanism of action of zileuton?



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Which of the following describes the mechanism of action of zileuton?



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A 36-year-old man is receiving treatment with salmeterol and fluticasone to help control his asthma. The patient's daily bronchospasms have decreased with this treatment. The provider decides to add zileuton to the patient's therapy to help prevent daily bronchospasms. Which of the following represents a contraindication to therapy with zileuton?



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Which of the following drugs does not interact significantly with zileuton?



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A 17-year-old male patient with a history of asthma comes to the clinic for follow up. He was recently switched to a new asthma medication but now has complaints of new sleep disturbance. What is the most likely medication prescribed to this patient?



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Zileuton - References

References

Laidlaw TM, Clinical updates in aspirin-exacerbated respiratory disease. Allergy and asthma proceedings. 2019 Jan 1;     [PubMed]
Sharma S,Chakraborty RK, Asthma Medications 2018 Jan;     [PubMed]
Shameera Ahamed TK,Rajan VK,Sabira K,Muraleedharan K, QSAR classification-based virtual screening followed by molecular docking studies for identification of potential inhibitors of 5-lipoxygenase. Computational biology and chemistry. 2018 Dec;     [PubMed]
Zileuton 2006;     [PubMed]
Yanes DA,Mosser-Goldfarb JL, Emerging therapies for atopic dermatitis: The prostaglandin/leukotriene pathway. Journal of the American Academy of Dermatology. 2018 Mar;     [PubMed]
Bruno F,Spaziano G,Liparulo A,Roviezzo F,Nabavi SM,Sureda A,Filosa R,D'Agostino B, Recent advances in the search for novel 5-lipoxygenase inhibitors for the treatment of asthma. European journal of medicinal chemistry. 2018 Jun 10;     [PubMed]
Cingi C,Muluk NB,Ipci K,Şahin E, Antileukotrienes in upper airway inflammatory diseases. Current allergy and asthma reports. 2015 Nov;     [PubMed]
Zouboulis CC,Bettoli V, Management of severe acne. The British journal of dermatology. 2015 Jul;     [PubMed]

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