Continuing Education Activity

Zileuton is a 5-lipoxygenase inhibitor mainly used for the prophylaxis and treatment of chronic asthma for patients aged 12 and older. Zileuton is used along with inhaled corticosteroids for treatment. It can also be used in patients with aspirin-induced asthma. While It is not indicated for patients with an acute asthma attack, research has also shown zileuton to help treat patients with chronic obstructive pulmonary disease, upper airway inflammatory conditions, and dermatological conditions such as acne, pruritic in Sjogren-Larsson syndrome, and atopic dermatitis. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, toxicity, and monitoring, of zileuton. It also highlights the role of interprofessional teams so that providers can direct patient therapy using zileuton in asthma relief.

Objectives:

• 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.

Indications

Zileuton is a 5-lipoxygenase inhibitor primarily used for the prophylaxis and treatment of chronic asthma for patients aged 12 and older.[1] Clinicians can use zileuton along with inhaled corticosteroids for treatment. It can also play a therapeutic role in patients with aspirin-induced asthma.[2] It is not useful for patients with an acute attack of asthma.

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.[3] Studies have shown that those with exercise-induced asthma can also benefit from the drug if used one hour before exercise. In addition, zileuton has also been demonstrated to inhibit chronic myeloid leukemia when combined with imatinib or alone.[4] A recent study also suggested that zileuton can reduce sinus surgeries in aspirin-exacerbated respiratory disease(AERD).[5] Extensive clinical research is necessary before using zileuton for the indications mentioned above.

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.[6][7][8]

The second approach is that of zileuton. The enzyme 5-lipoxygenase is necessary for the biosynthesis of leukotrienes. Zileuton is a 5-lipoxygenase inhibitor that inhibits the formation of leukotrienes B4, C4, D4, and E4. In turn, limiting these leukotrienes helps reduce inflammation, edema, mucus secretion, and bronchoconstriction in the airways. This action reduces leukocyte adhesion, smooth muscle contraction, capillary permeability, and the migration and aggregation of neutrophils and eosinophils. As a result, patients benefit from a reduction in asthma exacerbations and an improvement in asthma symptoms.[3] Recent research suggests that the phosphatidylinositide 3-kinase (PI3K) pathway is a major determinant of clinical response to zileuton patients with asthma. Poor responders to zileuton would be anticipated to have increased activation of PIK3CA, resulting in increased leukotriene B4 production and resistance to zileuton therapy. Higher concentrations of leukotriene B4 can bind to GPCR, leading to increased PIK3CA signaling and proliferation of pro-inflammatory responses mediated by leukotriene activity. In contrast, 'good' responders would have limited leukotriene B4 production following zileuton treatment.[9]

Pharmacokinetics

Absorption: According to the manufacturer's labeling, zileuton is rapidly absorbed upon oral administration, and peak plasma concentration is attained in approximately 1.7 hours.

Distribution: Zileuton has an apparent volume of distribution of approximately 1.2 L/kg. Zileuton has high plasma protein binding (93%). It is primarily bound to albumin, and a small proportion is bound to alpha-1 acid glycoprotein.

Metabolism: Zileuton is primarily metabolized in the liver by the cytochrome P450 system, including CYP1A2, CYP2C9, and CYP3A4. Metabolites of zileuton include two  O-glucuronide conjugates (major metabolites) and an N-dehydroxylated metabolite. Pharmacodynamic activity is primarily due to the parent drug.

Excretion: Zileuton and its metabolites are primarily excreted in the urine (94.5%). The mean terminal half-life of zileuton is  2.5 hours.[10]

Administration

Zileuton is only available in a tablet dosage form. The tablets are available as single-strength, 600 mg white, oval, and film-coated tablets. Zileuton should be stored at room temperature 20C to 25C (68F to 77F).[11]

Administer two 600 mg extended-release tablets twice daily. Administer immediate-release tablets of 600 mg four times daily. [12] 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. In addition, patients should not take a double dose if they miss a scheduled drug dose. Patients are advised not to change the dosage of any other anti-asthma medication unless told by a clinician. Zileuton is not the preferred medication in GINA (global initiative for asthma) guidelines, although a study suggests that zileuton response varies across asthmatics, with low response rates associated with those with severe asthma and obesity. Consequently, zileuton could be considered along with leukotriene receptor antagonists(like montelukast) for non-severe asthma.[13]

Use in Specific Patient Populations

Patients with Renal Impairment: Dose adjustment in patients with renal impairment or hemodialysis is not required.

Patients with Hepatic Impairment: Zileuton is contraindicated in patients with active liver disease or constant ALT elevations ≥3 upper limits of normal. Hepatic injury due to zileuton has been self-limited, but the possibility of severe injury and hepatic failure must be evaluated, especially if the medication is not stopped.[12]

Pregnancy Considerations:  Severe asthma exacerbations, particularly during the first trimester of pregnancy, are associated with an increased risk of congenital malformations. According to Global Strategy for Asthma (GINA) guidelines, pregnant patients should be suggested that poorly controlled asthma and exacerbations expose their infants to a much greater risk than pharmacological treatments. Zileuton is a former FDA pregnancy category C drug. Zileuton should be used during pregnancy only after carefully considering the risk-benefit analysis. Other agents are preferred as controller and reliever medications.[14][15][16]

Breastfeeding Considerations: No medical information is available on using zileuton during breastfeeding; however, the manufacturer's data indicate that the concentration of zileuton in maternal milk is low. As there is no published experience with zileuton during breastfeeding, an alternate drug should be used, particularly while nursing a newborn or preterm infant.[17]

Adverse Effects

Serum alanine aminotransferase (ALT) concentration must be obtained from the patient before the zileuton treatment, as hepatotoxicity can occur. The pattern of liver injury is hepatocellular, and ALT is the most sensitive liver enzyme for liver injury with zileuton treatments.[12] Symptoms include jaundice, right upper abdominal pain, edema, or pruritus. If ALT concentration is normal, concentration must be monitored once a month for the first three months and then every three months for the year.[12]

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 consumption should use zileuton cautiously. Rechallenge of zileuton should be avoided as it leads to the recurrence of hepatotoxicity.[17][18][19]

Patients taking zileuton may experience sleep disorders or changes in behavior. If neuropsychiatric events occur, patients should contact their healthcare provider.[20]

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, these symptoms are 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 compared to the placebo group.[1] Other reported adverse events include sinusitis, nausea, headache, abdominal pain, or pharyngolaryngeal pain. Zileuton can also less commonly cause a decrease in white blood cell count. For most cases, the white count returned to normal or baseline without changing the zileuton treatment.[21]

Drug-Drug Interactions

Concurrent use of loxapine should be avoided due to the risk of severe bronchospasm.[22] CYP1A2 inhibitors like zileuton may increase the serum concentration of tizanidine and lead to adverse reactions such as bradycardia and hypotension. Avoid concurrent administration.[23] Monitor liver function tests (LFT) and plasma concentrations of theophylline, warfarin, and propranolol, as zileuton can increase serum concentrations of these medications when taken simultaneously.[12]

• 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 takes warfarin with zileuton.[24]
• Research has shown that patients taking zileuton immediate-release tablets and propranolol experienced an increase in serum propranolol concentration within five days, leading to bradycardia and 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.[25]
• In patients taking theophylline and zileuton concurrently, studies showed a decrease in theophylline clearance within five days. Therefore, if patients are using theophylline and zileuton, clinicians should reduce the theophylline dosage by half and have the plasma concentrations of theophylline monitored daily. Adjust the maintenance dose of theophylline if the patient is already on zileuton.[26]

Contraindications

Patients with active liver disease or a history of hypersensitivity to zileuton or excipients should not take zileuton. When using zileuton, patients with ALT elevations more than three times the normal upper limit should avoid taking zileuton and consider a different therapy course.[27][28]

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.[29]

Clinicians should avoid prescribing zileuton under the age of 12 years as its safety and effectiveness in the age group have not been established. Concerns in this group are primarily due to the risk of hepatoxicity.

Female patients over 65 must use zileuton cautiously as they are more susceptible to hepatotoxicity and liver injury.[30]

Monitoring

Monitor liver function tests (LFT) and plasma concentrations of theophylline, warfarin, and propranolol, as zileuton can increase serum concentrations of these medications when taken simultaneously.[12]

Monitor for neuropsychiatric adverse drug reactions such as sleep disorders and behavior changes. 

Monitor pulmonary function tests (typically reversible obstructive pattern) in patients with asthma.[31] NICE (national institute for clinical excellence) guidelines suggest spirometry for monitoring asthma at each clinic visit or at least after 3 or 6 months from the commencement of treatment and afterward every 1 to 2 years.[31]

Monitor estimated peak expiratory flow rate; measurements can be variable according to age, height, and race.[32][33] Repeated peak flow measurement is simple to execute in clinical settings.[34]

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 necessary to eliminate any unabsorbed drug. However, there is only limited experience with zileuton when an overdose occurs. A case report of a patient taking between 6.6 gm to 9.0 gm of zileuton and completely recovering without complication is reported. The clinician should consult a medical toxicologist or poison control center for up-to-date information on the management of zileuton overdose. The American association of poison control centers' (NPDS) national poison data system research reinforces the importance of expertise and the need for specialized medical toxicology knowledge to manage drug overdose.[35]

Enhancing Healthcare Team Outcomes

The interprofessional healthcare team should be familiar with the drug's indications and contraindications, including the primary care providers, physician assistants, and nurse practitioners who prescribe zileuton. Zileuton is only used for prophylaxis of asthma and is not recommended for monotherapy. It also has several off-label uses. Clinicians should monitor the patient's liver function on zileuton regularly. Nurses can monitor for any neuropsychiatric symptoms and report to the clinician team. According to CDC, moderate to severe asthma is a risk factor for severe COVID-19 infection.[36] Pharmacists can ensure the drug is dosed appropriately, check for interactions (as covered above), and counsel patients on the proper use and administration of the medication, reporting any concerns they may have to the prescribing clinician.

Pulmonologist consultation may be required if asthma is not controlled despite optimal medical therapy. The Asthma Quality of Life Questionnaire (AQLQ)(American thoracic society) can assess health-related quality of life.[37] Zileuton can interact with drugs like warfarin, theophylline, and propranolol; therefore, a pharmacist should thoroughly review the patient's medication profile to prevent drug interactions. In an overdose of zileuton, a medical toxicologist and intensivist consultation are necessary. A psychiatrist consultation is also necessary if the overdose is intentional. As depicted above, all healthcare members should use interprofessional team strategies, which improve care coordination and better patient outcomes to use zileuton in patients with asthma. [Level 5]