Zileuton is an oral leukotriene modifier that inhibits leukotriene synthesis. Zileuton inhibits the first enzyme in the lipoxygenase pathway, 5-lipoxygenase, and thereby limits the formation of potent leukotrienes (LTB4, LTC4, LTD4, and LTE4) which are implicated in the complicated inflammatory response that occurs in certain disease states. Zileuton is FDA-approved for the maintenance treatment of asthma in adult and pediatric patients 12 years and older. Due to the potential for hepatotoxicity, periodic monitoring of LFTs is required during zileuton treatment in all patients. Leukotriene modifiers are less effective than inhaled corticosteroids (ICSs) for asthma maintenance therapy; however, they may be of benefit in patients who are unwilling or unable to use ICS, experience intolerable ICS side effects, or have concomitant allergic rhinitis. Zileuton can be used as an add-on therapy for severe asthma in adults and adolescents. For the prevention of exercise-induced bronchoconstriction (EIB), zileuton may be considered as an alternative to LRTAs to add as a controller agent to an inhaled short-acting beta-2 agonist (SABA) to control EIB symptoms in patients who cannot be controlled by an inhaled SABA alone. Zileuton has been shown to inhibit the activity of several hepatic cytochrome isoenzymes, which increases the risk of drug-drug interactions; the drug is also associated with rare, but sometimes serious, hepatic toxicity.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
Regular-release tablets:
-For ease of the four times daily administration, may give with meals and at bedtime. Otherwise, may be given without regard to meals.
Extended-release tablets:
-Administer within 1 hour after morning and evening meals.
-Swallow whole. Do not chew, cut, or crush tablets.
Reversible cases of elevated hepatic enzymes have been reported; these laboratory abnormalities may progress, remain unchanged, or resolve with continued therapy. In placebo-controlled and long-term clinical trials of immediate-release zileuton, ALT elevations occurred in 1.9-4.6% of patients receiving zileuton versus 0.2-1.1% of patients receiving placebo or usual asthma care. In one clinical trial with extended-release zileuton, ALT elevations occurred in 2.5% of the zileuton group versus 0.5% in the placebo group. More than half occurred in the first month of treatment. Abnormal laboratory values returned to normal within approximately 1 month after discontinuation of the drug. During a 6 month trial of extended-release zileuton, most cases of elevated liver enzymes occurred within the first 3 months of treatment. Three patients developed mild hyperbilirubinemia in conjunction with elevated transaminases. A pharmacokinetic study in elderly patients revealed, through subset analysis, that females over the age of 65 may be at an increased risk for elevated hepatic enzymes, specifically alanine aminotransferase (ALT) elevations. Patients with pre-existing transaminase elevations may also be at increased risk for ALT elevations. In clinical trials, one patient developed symptomatic hepatitis with jaundice, which resolved upon discontinuation of therapy. Cases of severe liver injury have been reported in post-marketing experience with immediate-release zileuton including symptomatic jaundice, hyperbilirubinemia, ALT elevations greater than 8 times the upper limit of normal, life-threatening liver injury, and death. Liver function tests should be conducted at initiation of therapy then once monthly for three months, every two to three months for the remainder of the first year and periodically thereafter. Therapy should be discontinued if signs or symptoms of liver dysfunction develop or transaminase elevations > 5 times the upper limits of normal occur.
Most adverse reactions attributed to zileuton administration have been mild and self-limited. A flu-like syndrome (e.g., chills, fever, fatigue, myalgia) has been reported in 3.9% of healthy volunteers treated with immediate-release zileuton compared to 1.9% treated with placebo. Other adverse events reported for immediate-release zileuton vs. placebo in clinical trials include: headache (24.6% vs. 24%), asthenia (3.8% vs. 2.4%), dyspepsia (8.2% vs. 2.9%), abdominal pain (4.6% vs. 2.4%), pain (7.8% vs. 5.3%), nausea (5.5% vs 3.7%), myalgia (3.2% vs 2.9%), and accidental injury (3.4% vs 2%). Adverse events occurring in > 1% of patients receiving immediate-release zileuton and more often than patients receiving placebo include arthralgia, chest pain (unspecified), conjunctivitis, constipation, dizziness, fever, flatulence, hypertonia, lymphadenopathy, malaise, neck pain, nervousness, pruritus, drowsiness, urinary tract infection, vaginitis, and vomiting. Adverse effects (zileuton vs. placebo) reported from a trial of 21 patients with rheumatoid arthritis were as follows: headache (6% vs. 3%); nausea (3% vs. 0%); fatigue (2% vs. 0%); chills (1% vs. 0%); dizziness (2% vs. 0%); paresthesias (1% vs. 0%); and infection (2% vs. 1%). Rash and urticaria have also been reported with immediate-release zileuton in post-marketing experience. In clinical trials with extended-release zileuton, adverse effects occurring in at least 5% of patients and at a greater frequency than placebo included nausea (5% vs. 1.5%), sinusitis (6.5% vs. 4%), and pharyngolaryngeal pain (5% vs. 4%). Adverse effects occurring in at least 1% of patients receiving extended-release zileuton and more often than placebo included upper abdominal pain, diarrhea, dyspepsia, vomiting, rash (unspecified), hypersensitivity, and hepatotoxicity (unspecified). During a 6 month trial of extended-release zileuton, the following adverse events occurred in at least 5% of patients receiving active drug and more often than placebo: headache (23% vs. 21%), upper respiratory tract infection (9% vs. 7%), myalgia (7% vs. 5%), and diarrhea (5% vs. 2%). No evidence emerged of immunosuppression or bone marrow suppression in clinical trials, bone marrow suppression. Leukopenia has been reported. During clinical trials with immediate-release zileuton, a low white blood cell count (< 2.8 x 109/L) was reported in 1% of those receiving the drug versus 0.6% of those receiving placebo. During clinical trials with extended-release zileuton, a low white blood cell count (< 3 x 109/L) was reported in 2.6% of those receiving the drug versus 1.7% of those receiving placebo.
Zileuton and other leukotriene inhibitors are rarely associated with neuropsychiatric events. In clinical trials, insomnia has been reported more commonly during treatment with zileuton than with placebo (2.3% vs. 0.9%). Other post-market reports among patients on leukotriene inhibitor therapy have included agitation, aggressive behavior, dream abnormalities, drowsiness/sedation, hallucinations, irritability and restlessness, anxiety, seizures, tremor, depression, and suicidal ideation and behaviors. In March 2008, the FDA alerted healthcare professionals of an ongoing safety review investigating the possible association between the use of leukotriene inhibitors and behavior/mood changes, suicidality, and suicide. In June 2009, the FDA concluded that these events may be drug-related, possibly related to the leukotriene pathway. As a result the FDA has asked manufacturers of all leukotriene inhibitors, including zileuton, to include a precaution in the package labeling regarding the post-market reports. Advise patients to report changes in behavior and mood; consider alternate therapy if neuropsychiatric symptoms develop.
Zileuton is contraindicated in patients with hypersensitivity to zileuton or any of its inactive ingredients.
Zileuton is contraindicated in patients with active hepatic disease or with persistent hepatic transaminase elevations 3 times or more the upper limit of normal (ULN). Zileuton should be used cautiously in patients who consume substantial quantities of alcohol or who have a history of either alcoholism or previous hepatic disease. Zileuton undergoes hepatic metabolism and may increase 1 or more hepatic function enzymes and bilirubin. These laboratory abnormalities may progress to clinically significant liver injury, remain unchanged, or resolve with continued treatment, usually within 3 weeks. The ALT measurement is considered the most sensitive indicator of liver damage from zileuton. Cases of severe liver injury and hepatotoxicity have been reported in postmarketing experience with immediate-release zileuton including symptomatic jaundice, hyperbilirubinemia, ALT elevations greater than 8 times the ULN, life-threatening liver injury, and death. Monitor LFTs at the initiation of zileuton therapy and once monthly for 3 months, then every 2 to 3 months for the remainder of the first year, and periodically thereafter. If clinical signs and symptoms of liver dysfunction develop (e.g., right upper quadrant pain, nausea, fatigue, lethargy, pruritus, hepatitis, jaundice, or 'flu-like' symptoms), or transaminase values increase to 5 times the ULN or more, zileuton should be discontinued and appropriate follow-up of the condition instituted. In open-label and controlled studies of the immediate-release formula, subgroup analyses found that geriatric females 65 years and older appear to be at an increased risk for ALT elevations; while similar results were not found in trials of the extended-release formulation, the trial database may not have been large enough to detect such results. In the clinical studies involving more than 5,000 patients treated with zileuton immediate-release tablets, the overall rate of ALT elevation 3 times the ULN was 3.2%. In these trials, one patient developed symptomatic hepatitis with jaundice, which resolved upon discontinuation of therapy. An additional 3 patients with transaminase elevations developed mild hyperbilirubinemia that was less than 3 times the ULN. There was no evidence of hypersensitivity or other alternative etiologies for these findings.
Because of its relatively slow onset of action, zileuton should not be used to treat an acute asthmatic attack, including status asthmaticus or acute bronchospasm; an appropriate rescue medication (e.g., inhaled beta-agonist) should be available. However, zileuton therapy may be continued during the treatment of an acute asthmatic event. Patients should be advised not to stop taking or decrease the use of other asthma treatments when starting zileuton unless otherwise directed by their health care prescriber.
Neuropsychiatric events have been reported in adult and adolescent patients taking zileuton. The clinical details of some postmarketing psychiatric event reports involving zileuton appear consistent with a drug-induced effect. Postmarketing reports with zileuton include sleep disorders and behavioral changes. Suicidal ideation has been rarely reported. Patient and prescribers should be alert for these events during treatment. Patients should be advised to notify their prescriber if any other changes in mood or behavior occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with zileuton if such events occur.
Due to the risk of hepatotoxicity, the use of zileuton should be avoided in neonates, infants, and children less than 12 years of age.
The National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group recommend avoiding the use of zileuton in pregnancy. There are no adequate human data on zileuton use during human pregnancy to inform a drug associated risk. In animal studies, the oral administration of zileuton to pregnant rats and rabbits during organogenesis produced adverse developmental outcomes. A pregnancy registry has been established to monitor maternal and fetal outcomes; health care providers are encouraged to register pregnant women exposed to asthma medications during pregnancy. For more information, contact the MothersToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists at 1-877-311-8972 or visit http://mothertobaby.org/pregnancy-studies/. Animal studies indicate that zileuton and/or its metabolites cross the placental barrier of rats; therefore, zileuton may be transmitted from the mother to the developing fetus. Zileuton produced alterations to growth (reduced fetal body weight and increased skeletal variations) in rats when administered at 20 times greater than the maximum recommended human daily oral dose (MRHD). In a pre- and post-natal development study, oral administration of zileuton to pregnant rats from organogenesis through weaning at maternal plasma exposures 20 times greater than the MRHD resulted in reduced pup survival and body weights. In rabbits, doses equivalent to the human dose (based on body surface area) produced cleft palates in 3 of 118 rabbit fetuses.
Use zileuton with caution during breast-feeding. Zileuton and/or its metabolites are excreted in rat milk. It is not known if zileuton is excreted in human milk, nor are there data on the effects of the drug on the breastfed infant or effects on maternal milk production. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity of zileuton shown in animal studies, the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for zileuton and any potential adverse effects on the breastfed child from zileuton or the underlying maternal condition. Because there is no published experience with zileuton during breast-feeding, an alternate drug may be preferred. Montelukast may be a preferred alternative as no special precautions are needed during its use during lactation.
For asthma maintenance treatment:
Oral dosage (immediate-release):
Adults: 600 mg PO 4 times daily.
Children and Adolescents 12 to 17 years: 600 mg PO 4 times daily.
Oral dosage (extended-release):
Adults: 1,200 mg PO twice daily.
Children and Adolescents 12 to 17 years: 1,200 mg PO twice daily.
For the treatment of aspirin-induced asthma*:
Oral dosage (immediate-release tablets):
Adults: The usual dose, 600 mg PO four times daily with meals and at bedtime, has been studied and appears effective. Use with an established asthma treatment regimen that includes necessary medications such as bronchodilators and inhaled or systemic corticosteroids. Concomitant nasal corticosteroids or inhaled cromolyn were also used in some patients. Outcomes included FEV-1, patient-reported peak expiratory flow rates (PEFRs), beta-agonist use, and asthma symptom severity. Patient-reported peak nasal inspiratory flow rate (PNIFR) and nasal symptoms were assessed, as many patients with aspirin-induced asthma have chronic nasal problems. Zileuton significantly increased FEV-1 vs. placebo. Morning and evening PEFRs were significantly higher, and daily beta-agonist use was significantly reduced with zileuton vs. placebo; however, asthma symptom severity did not significantly differ between groups. PNIFR did improve with zileuton although changes were not significant compared to placebo; loss of smell and rhinorrhea occurred significantly less in those treated with zileuton, but there was no significant reduction in nasal congestion. Patients who underwent aspirin challenges tolerated higher aspirin dosages while taking zileuton compared to placebo.
For exercise-induced bronchospasm prophylaxis*:
Oral dosage (extended-release tablets):
Adults: 1,200 mg PO twice daily, taken within one hour after morning and evening meals, is the recommended dosage for controller therapy. Take at least 2 hours before exercise to have maximal prophylactic effect.
Oral dosage (immediate-release tablets):
Adults: 600 mg PO four times daily is the recommended dosage for controller therapy. Take at least 2 hours before exercise to have maximal prophylactic effect. The efficacy of zileuton for prevention of exercise-induced bronchospasm (EIB) was examined in a randomized, double-blind, placebo-controlled, crossover study.
Maximum Dosage Limits:
-Adults
2,400 mg/day PO.
-Geriatric
2,400 mg/day PO.
-Adolescents
2,400 mg/day PO.
-Children
12 years: 2,400 mg/day PO.
Less than 12 years: Safety and efficacy have not been established; not recommended due to toxicity risk.
-Infants
Safety and efficacy have not been established; not recommended due to toxicity risk.
Patients with Hepatic Impairment Dosing
Zileuton is contraindicated in patients with active hepatic disease and patients with liver transaminase elevations 3 times or more the upper limit of normal (ULN).
During therapy, if transaminase elevations occur or the patient has symptoms of hepatic disease, discontinue the drug and investigate the cause. During treatment, if clinical signs and/or symptoms of liver dysfunction develop or transaminase elevations more than 5 times the ULN occur, discontinue the drug and follow transaminase levels until normal.
Patients with Renal Impairment Dosing
No dosage adjustments are needed.
*non-FDA-approved indication
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Acetaminophen; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Anagrelide: (Moderate) Anagrelide is partially metabolized by and may inhibit CYP1A2. When anagrelide is coadministered with drugs that also are substrates of and inhibit CYP1A2, such as zileuton, patients should be monitored for increased adverse effects of either drug.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Bendamustine: (Major) Consider the use of an alternative therapy if zileuton treatment is needed in patients receiving bendamustine. Concomitant use of zileuton may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with zileuton is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Butalbital; Acetaminophen; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Caffeine: (Moderate) Inhibitors of CYP1A2, such as zileuton, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced. (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Caffeine; Sodium Benzoate: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Clomipramine: (Moderate) Monitor for an increase in clomipramine-related adverse reactions if concomitant use of zileuton is necessary; a clomipramine dose reduction may be necessary. Concomitant use may increase clomipramine exposure; clomipramine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with zileuton and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate. Zileuton is a weak CYP1A2 inhibitor.
Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as zileuton, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
Duloxetine: (Moderate) Co-administration of duloxetine and potent inhibitors of CYP1A2 should be avoided. Duloxetine is partially metabolized by CYP1A2. One study involving a potent CYP1A2 inhibitor in concomitant use with duloxetine showed that duloxetine exposure was significantly increased. Concurrent use of duloxetine and zileuton, a CYP1A2 inhibitor, may result in excessive serotonin activity. Careful monitoring is recommended if concurrent therapy is considered necessary.
Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP1A2. The significance of administering inhibitors of CYP1A2, such as zileuton, on the systemic exposure of eltrombopag has not been established. Monitor patients for signs of eltrombopag toxicity if these drugs are coadministered.
Ergotamine; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Fezolinetant: (Contraindicated) Concomitant use of fezolinetant and zileuton is contraindicated due to the risk of increased fezolinetant exposure which may increase the risk of fezolinetant-related adverse effects. Fezolinetant is a CYP1A2 substrate; zileuton is a weak CYP1A2 inhibitor. Concomitant use with another weak CYP1A2 inhibitor increased fezolinetant overall exposure by 100%.
Green Tea: (Moderate) Some, but not all, green tea products contain caffeine. Inhibitors of the hepatic CYP450 isoenzyme CYP1A2, such as zileuton, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with zileuton is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with zileuton is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with zileuton is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Melatonin: (Moderate) CYP1A2 inhibitors such as zileuton may increase melatonin exposure. Melatonin is primarily metabolized by CYP1A2, with lesser contributions by CYP1A1, CYP2C9 and CYP2C19.
Mexiletine: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with zileuton. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 substrate and zileuton is a weak CYP1A2 inhibitor.
Pimozide: (Major) Avoid concomitant use of pimozide and zileuton as use may increase pimozide exposure and the risk for pimozide-related adverse reactions, including QT prolongation and ventricular arrhythmias.
Pirfenidone: (Major) Avoid concomitant administration of zileuton and pirfenidone because it may increase exposure to pirfenidone. If concurrent use cannot be avoided, closely monitor for adverse effects of pirfenidone, like elevated hepatic enzymes, arthralgia, or nausea. Dosage redution, interruption of therapy, or discontinuation may be necessary. Zileuton is a moderate inhibitor of CYP1A2, and pirfenidone is primarily metabolized by CYP1A2.
Pomalidomide: (Moderate) Use pomalidomide and zileuton together with caution; increased pomalidomide exposure may occur increasing the risk of pomalidomide adverse events. If these drugs are used together, monitor for pomalidomide adverse events; a pomalidomide dose adjustment may be necessary. Pomalidomide is a CYP1A2 substrate and zileuton is a moderate CYP1A2 inhibitor. The Cmax increased by 73% and the AUC value approximately doubled for a sensitive CYP1A2 substrate when zileuton was co-administered with a sensitive CYP1A2 substrate in healthy volunteers.
Propranolol: (Moderate) Concomitant administration of zileuton and propranolol results in a significant increase in propranolol serum concentrations, AUC, and elimination half-life. Bradycardia is also potentiated by the drug combination. Clinicians should monitor vital signs carefully if zileuton is added to a regimen containing propranolol and adjust dosages as needed.
Rasagiline: (Moderate) Monitor for dopaminergic adverse effects during concurrent use of rasagiline and zileuton. Coadministration may result in increased rasagiline concentrations. A dose reduction of rasagiline may be necessary. Rasagiline is primarily metabolized by CYP1A2; zileuton is a weak CYP1A2 inhibitor.
Ropinirole: (Major) Zileuton inhibits cytochrome P450 CYP1A2 isoenzymes, which can potentially lead to increased plasma concentrations of CYP1A2 substrates, such as ropinirole. If these drugs are coadministered, adjustment of ropinirole dose may be required.
Ropivacaine: (Major) Concomitant use of ropivacaine and zileuton may result in increased systemic concentrations of ropivacaine and subsequent toxicity. Ropivacaine is metabolized primarily by CYP1A2. Zileuton is a competitive inhibitor of CYP1A2.
Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and zileuton. Because tasimelteon is partially metabolized via CYP1A2, use with a CYP1A2 inhibitor, such as zileuton, may increase exposure to tasimelteon and the potential for adverse reactions.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering zileuton. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP1A2; zileuton is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
Theophylline, Aminophylline: (Major) Concurrent use of zileuton and theophylline results in an approximate doubling of theophylline serum concentrations and increased frequency of theophylline-related adverse effects. Aminophylline is a salt form of theophylline. It has been recommended to reduce the theophylline dose by approximately 50% and monitor theophylline plasma concentrations when zileuton is prescribed to an existing regimen; a similar strategy may be employed with aminophylline. When initiating therapy with aminophylline in a patient receiving zileuton, adjust the maintenance dose and/or dosing interval of aminophylline based on serum theophylline concentrations. Theophylline is primarily metabolized by CYP1A2, with secondary pathways by CYP2E1 and CYP3A4; zileuton is a CYP1A2 inhibitor. (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with zileuton is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and zileuton is a CYP1A2 inhibitor.
Tizanidine: (Major) Avoid concomitant use of tizanidine and zileuton as increased tizanidine exposure may occur. If use together is necessary, initiate tizanidine at 2 mg and increase by 2 to 4 mg/day based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate and zileuton is a weak CYP1A2 inhibitor.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with zileuton is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor. Concomitant use has been observed to increase R-warfarin AUC by 22%. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zileuton is a leukotriene modifier which selectively inhibits 5-lipoxygenase; cyclooxygenase is not affected, thus limiting leukotriene formation. The drug inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in vitro and in vivo systems. Leukotrienes are mediators found in soluble fractions of leukocyte cultures. Cell stimulation promotes the synthesis of leukotrienes from fatty acid precursors. Unlike cyclooxygenase, 5-lipoxygenase is not stored in tissues or widely distributed, being found mainly in neutrophils, eosinophils, monocytes, macrophages, and mast cells. Leukotrienes cause smooth muscle contraction and increase blood vessel permeability, allowing plasma fluid to pass into the extravascular space, further swelling inflamed tissue. As a response to inflammation, leukocytes migrate to the damaged area. There also appears to be synergism between leukotrienes and prostaglandins. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction. LTB4, a chemoattractant for neutrophils and eosinophils, and cysteinyl leukotrienes (LTC4, LTD4, LTE4) can be measured in some biological fluids including bronchoalveolar lavage fluid (BALF), blood, urine, and sputum from asthmatic patients. Zileuton inhibits the synthesis of cysteinyl leukotrienes as demonstrated by reduced urinary LTE4 levels. Additionally, zileuton reduces nasal congestion in allergic rhinitis and produces a significant improvement in asthmatic patients exposed to cold, dry air. The long-term improvement in airflow obstruction after treatment with zileuton did not affect the response to beta-agonists.
Zileuton is an orally active inhibitor of ex vivo LTB4 formation in humans. The inhibition of LTB4 formation in whole blood is directly related to zileuton plasma levels. In patients with asthma, the IC50 is estimated to be 0.46 mcg/mL, and maximum inhibition of 80% or more is reached at a zileuton concentration of 2 mcg/mL. In patients with asthma receiving zileuton immediate-release tablets 600 mg four times daily, peak plasma levels averaging 5.9 mcg/mL were associated with a mean LTB4 inhibition of 98%. Zileuton inhibits the synthesis of cysteinyl leukotrienes as demonstrated by reduced urinary LTE4 levels.
Zileuton is administered orally. The volume of distribution is approximated at 1.2 L/kg. Zileuton is highly bound to plasma protein (93%). It is not easily displaced by other drugs. Zileuton undergoes first-pass metabolism in the liver, primarily by glucuronidation. Some dehydroxylation occurs in the intestine. In vitro studies have shown that zileuton and its inactive N-dehydroxylated metabolite may be oxidized by CYP 1A2, 2C9, and 3A4. The N-dehydroxylated metabolite is formed in the GI tract, and delayed absorption of zileuton increases its formation. Excretion is mainly renal (87-95%) as the glucuronide, with about 2% appearing in the feces. No unchanged drug has been detected in urine. The mean elimination half-life after multiple oral doses of 600 mg 4 times a day ranged from 1 to 2.3 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2C9, CYP3A4
Zileuton, according to in vitro data, is both a substrate and weak inhibitor of the hepatic cytochrome isoenzyme CYP1A2. In vitro studies utilizing human liver microsomes have shown that zileuton and its N-dehydroxylated metabolite can be oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9, and 3A4.
-Route-Specific Pharmacokinetics
Oral Route
Following administration of immediate-release zileuton, absorption is rapid with a mean Cmax of 4.98 mcg/ml and a mean Tmax of 1.7 hours. Administration with food resulted in a small but statistically significant increase in Cmax, however no significant changes in AUC or Tmax were noted. Comparison data between immediate-release and extended-release zileuton indicate that at steady state under fed conditions, the Cmax of the extended-release formulation is 35% lower than the immediate-release formulation, while Cmin and AUC are similar for both. Therefore, it is recommended to administer extended-release zileuton with food. The AUC does appear to increase in proportion to dose increases. Multiple dosing did not change the pharmacokinetic constants significantly.
-Special Populations
Hepatic Impairment
Zileuton is contraindicated in patients with active liver disease.
Geriatric
Zileuton pharmacokinetics have been found to be similar in healthy elderly subjects (>= 65 years) compared to healthy younger adults (18 to 40 years) following single and multiple oral doses of 600 mg every 6 hours.