Continuing Education Activity

Zileuton, a 5-lipoxygenase inhibitor, is a primary intervention for the prophylaxis and treatment of chronic asthma in patients aged 12 and older. Although zileuton is frequently administered in conjunction with inhaled corticosteroids for chronic asthma, it is not effective for managing acute asthma attacks. 

Zileuton is also used off-label in patients with aspirin-induced asthma. The application of the drug extends to aspirin-induced asthma, with research supporting its efficacy in chronic obstructive pulmonary disease and dermatological conditions such as acne, pruritic manifestations in Sjögren-Larsson syndrome, and atopic dermatitis. This activity delves into the complexities of clinical toxicity, drug interactions, pharmacokinetics, and the importance of vigilant monitoring while administering zileuton to patients. This activity equips the interprofessional healthcare team with the necessary skills to manage diverse clinical scenarios and improve patient care in the context of respiratory and dermatological conditions using zileuton effectively.

Objectives:

• Identify appropriate candidates for zileuton therapy based on their age (12 and older) and a diagnosis of chronic asthma.

• Implement vigilant monitoring protocols for patients receiving zileuton, considering clinical toxicity, drug interactions, and pharmacokinetics.

• Select optimal combinations of zileuton with other medications for patients with chronic myeloid leukemia or aspirin-exacerbated respiratory disease.

• Collaborate with the interprofessional healthcare team to coordinate comprehensive patient care, integrating zileuton appropriately into treatment plans.

Indications

Zileuton is a 5-lipoxygenase inhibitor approved by the United States Food and Drug Administration (FDA) for the prophylaxis and treatment of chronic asthma in patients aged 12 and older.[1] 

FDA-Approved Indication

Zileuton is a primary intervention for the prophylaxis and treatment of chronic asthma in patients aged 12 or older. Although zileuton is frequently administered in conjunction with inhaled corticosteroids for chronic asthma, it is not effective for managing acute asthma attacks.

Off-Label Uses

Zileuton is also used off-label in patients with aspirin-induced asthma.[2] Research supports the effectiveness of zileuton in treating patients with chronic obstructive pulmonary disease, upper airway inflammatory conditions, and dermatological conditions such as acne, pruritus in Sjögren-Larsson syndrome, and atopic dermatitis.[3] 

Studies have demonstrated that individuals with exercise-induced asthma can derive benefits from the drug when administered 1 hour before exercise. In addition, zileuton has shown efficacy in inhibiting chronic myeloid leukemia, whether combined with imatinib or as a standalone treatment.[4] A recent study has also indicated that zileuton may decrease the necessity for sinus surgeries in aspirin-exacerbated respiratory disease.[5] In addition, a topical formulation of zileuton is currently under investigation for treating atopic dermatitis.[6] Clinicians are advised to conduct a thorough risk-benefit analysis before considering using zileuton for off-label indications.

Mechanism of Action

Currently, 2 primary approaches to leukotriene inhibition are recognized. One approach is antagonistic blockage of cys-LT1 receptors from cysteinyl leukotrienes on bronchial smooth muscle cells, which is the mechanism of action for montelukast and zafirlukast.[7][8][9] The second approach is the inhibition of 5-lipoxygenase. 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. 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. Consequently, a reduction in asthma exacerbations is evidenced by improving 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. Patients showing poor response to zileuton 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, patients with positive responses would have limited leukotriene B4 production following Zileuton treatment.[10]

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; a small proportion is bound to α-1-acid glycoprotein.

Metabolism: Zileuton is primarily metabolized in the liver by the cytochrome P450 system, including CYP1A2, CYP2C9, and CYP3A4. Zileuton's metabolites include 2 glucuronide conjugates (significant metabolites) and an N-dehydroxylated metabolite. Pharmacodynamic activity is primarily due to the parent drug.

Elimination: Zileuton and its metabolites are primarily excreted in the urine (94.5%). The mean terminal half-life of zileuton is 2.5 hours.[11]

Administration

Available Dosage Forms and Strengths

Zileuton is only available in a tablet formulation. The tablets are single-strength, 600 mg white, oval, and film-coated. Zileuton should be stored at room temperature 20 °C to 25 °C (68 °F to 77 °F).[12]

Adult Dosage

Administer 2 (600 mg) extended-release tablets twice daily. Administer immediate-release (IR) tablets of 600 mg 4 times daily. [13] Use within 1 hour of morning and evening meals. Zileuton 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. However, a study suggests that Zileuton response varies across asthmatics, with low response rates associated with those with severe asthma and obesity. Consequently, Zileuton and leukotriene receptor antagonists (like Montelukast) could be considered for non-severe asthma.[14]

Specific Patient Populations

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

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.[13]

Pregnancy considerations: Severe asthma exacerbations, particularly during the first trimester of pregnancy, are associated with an increased risk of congenital malformations. According to 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.[15][16][17]

Breastfeeding considerations: No medical information exists on using zileuton during breastfeeding; however, the manufacturer's data indicate that the concentration of zileuton in maternal milk is low. No published experience with zileuton during breastfeeding is evidenced, so accordingly, an alternate drug should be used, particularly while nursing a newborn or preterm infant.[18]

Pediatric patients: Zileuton is not FDA-approved for asthma management in pediatric patients aged 12 or younger.

Older patients: Patients aged 65 or older taking Zileuton IR are at a higher risk of developing elevated ALT levels.[19]

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.[13] 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 3 months and then every 3 months for the year.[13] 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.[18][20][21]

Patients undergoing long-term therapy (eg, taking zileuton for more than 6 months) may experience frequent headaches, upper respiratory tract infections, diarrhea, or myalgia. However, these symptoms are similar to placebo treatment in many cases, eg, headache: 25% for zileuton and 24% for placebo. In one study, dyspepsia was the most statistically significant adverse effect compared to the placebo group.[1] Other reported adverse events include sinusitis, nausea, headache, abdominal pain, or pharyngolaryngeal pain. Zileuton can infrequently cause a decrease in white blood cell count. In most cases, the white blood cell count returned to normal or baseline without changing the Zileuton treatment.[22]

Drug-Drug Interactions

• Concurrent use of Loxapine should be avoided due to the risk of severe bronchospasm.[23] CYP1A2 inhibitors like zileuton may increase the serum concentration of Tizanidine and lead to adverse reactions such as bradycardia and hypotension. Avoid concurrent administration.[24] 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.[13]

• Studies have shown a 15% decrease in Warfarin clearance, significantly increasing prothrombin times. Therefore, the recommendation is to monitor prothrombin times if the patient takes Warfarin with Zileuton.[25]

• Research has shown that patients taking zileuton IR tablets and Propranolol experienced an increase in serum level concentration within 5 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.[26]

• Concurrent administration of theophylline and zileuton leads to a reduction in Theophylline clearance within 5 days. Clinicians should monitor the plasma concentrations of theophylline in patients and reduce the dosage accordingly. Adjust the maintenance dose if the patient is already on zileuton.[27]

Contraindications

Box Warnings

Patients with active liver disease or a history of hypersensitivity to zileuton or excipients should not take the medication. When using zileuton, patients with ALT elevations more than 3 times the normal upper limit should avoid taking zileuton and consider a different therapy course.[28][29]

Warning and Precautions

Patients taking zileuton may experience sleep disorders or changes in behavior. If neuropsychiatric events occur, patients should contact their clinician.[30] No contraindications exist for use in pregnant patients. However, patients should not use zileuton unless the benefit to the mother justifies the risk to the fetus.[31] Clinicians should avoid prescribing zileuton to patients under 12 as its safety and effectiveness in the age group have not been established. Concerns in this group are primarily due to the risk of hepatotoxicity. Female patients aged over 65 must use zileuton cautiously as they are more susceptible to hepatotoxicity and liver injury.[19]

Monitoring

Monitor liver function tests and plasma concentrations of theophylline, warfarin, and propranolol, as zileuton can increase serum concentrations of these medications when taken simultaneously.[13] 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.[32] 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.[32] Monitor estimated peak expiratory flow rate; measurements can be variable according to age, height, and race.[33][34] Repeated peak flow measurement is simple to execute in clinical settings.[35]

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. Limited guidelines exist around the approach to overdose. According to product labeling, a case report of a patient taking between 6.6 and 9.0 g of zileuton and completely recovering without complications 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 and National Poison Data System research reinforces the importance of expertise and the need for specialized medical toxicology knowledge to manage drug overdose.[36]

Enhancing Healthcare Team Outcomes

The interprofessional healthcare team, including the primary care clinicians, physician assistants, and nurse practitioners who prescribe zileuton, should be familiar with the drug's indications and contraindications. 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 the CDC, moderate to severe asthma is a risk factor for severe COVID-19 infection.[37] Pharmacists can ensure the drug is dosed appropriately, check for interactions, and counsel patients on the proper use and administration of the medication.

A pulmonologist or immunologist consultation may be required if asthma is uncontrolled despite optimal medical therapy. The Asthma Quality of Life Questionnaire can assess quality of life.[38] 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 required if the overdose is intentional. All healthcare professionals, including clinicians, immunologists or pulmonologists, pharmacists, medical toxicologists, and nurses, should use interprofessional team strategies to improve care coordination and patient outcomes when using zileuton for asthma.