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  • CLASSES

    Systemic Leukotriene Antagonists

    DEA CLASS

    Rx

    DESCRIPTION

    Oral 5-lipoxygenase inhibitor; limits leukotriene production
    Primarily used for the prophylaxis and chronic maintenance treatment of asthma in adult and pediatric patients 12 years and older
    Due to a potential for hepatotoxicity, periodic monitoring of liver function tests is required

    COMMON BRAND NAMES

    Zyflo, Zyflo CR

    HOW SUPPLIED

    Zileuton/Zyflo CR Oral Tab ER: 600mg
    Zyflo Oral Tab: 600mg

    DOSAGE & INDICATIONS

    For the prophylaxis and chronic maintenance treatment of asthma.
    Oral dosage (extended-release tablets)
    Adults

    1,200 mg PO twice daily, within one hour after morning and evening meals.

    Children and Adolescents 12 years and older

    1,200 mg PO twice daily, within one hour after morning and evening meals.

    Oral dosage (immediate-release tablets)
    Adults

    600 mg PO 4 times per day, taken with meals and at bedtime.

    Children and Adolescents 12 years and older

    600 mg PO 4 times per day, taken with meals and at bedtime.

    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.[55894]

    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, has been effective. The American Thoracic Society recommends daily administration of zileuton or a leukotriene receptor antagonist (LTRA) in patients who continue to have exercise-induced symptoms despite using an inhaled short-acting beta-2 agonist (SABA) before exercise, or in those who require daily (or more frequent) SABA use. In clinical practice, zileuton may be the first-line choice for a controller agent to be added to SABAs; inhaled corticosteroids (ICS) may also be used. The choice between the two classes is made on an individual basis considering patient preferences and baseline lung function. Patients with EIB associated with greater airway inflammation (e.g., asthma) may benefit more from ICS therapy.[56291]

    Oral dosage (immediate-release tablets)
    Adults

    600 mg PO four times daily with meals and at bedtime has been effective. The American Thoracic Society recommends daily administration of zileuton or a leukotriene receptor antagonist (LTRA) in patients who continue to have exercise-induced symptoms despite using an inhaled short-acting beta-2 agonist (SABA) before exercise, or in those who require daily (or more frequent) SABA use. In clinical practice, zileuton is a first-line option for a controller agent to be added to SABAs; inhaled corticosteroids (ICS) may also be used. The choice between the two classes is made on an individual basis considering patient preferences and baseline lung function. Patients with EIB associated with greater airway inflammation (e.g., asthma) may benefit more from ICS therapy.[56291] The efficacy of zileuton for prevention of exercise-induced bronchospasm (EIB) was examined in a randomized, double-blind, placebo-controlled, crossover study. Adult subjects (n = 24) had an asthma history with wheezing, dyspnea, or a cough with exercise and an FEV-1 of 70% or more of predicted. Inhaled corticosteroids, NSAIDs, theophylline, and antihistamines were discontinued 2 days before screening and study entry. All subjects had an FEV-1 decrease of 20% or more following exercise before study enrollment. Subjects received zileuton 600 mg four times daily or placebo for 2 days, followed by an exercise treadmill challenge. EIB was assessed as the percent change in FEV-1 compared to baseline values 90 minutes after medication receipt at screening visits. Zileuton produced a shorter duration of and less severe bronchoconstriction compared to placebo. The FEV-1 of subjects who received zileuton remained significantly greater than placebo for 45 minutes following the exercise challenge. Approximately 80% of subjects had some improvement in EIB after zileuton treatment.[56331]

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    No dosage adjustments are needed.

    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.

    STORAGE

    Zyflo:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Zyflo CR:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Zileuton is contraindicated in patients with hypersensitivity to zileuton or any of its inactive ingredients.

    Alcoholism, geriatric, hepatic disease, hepatitis, hepatotoxicity, jaundice

    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). [51120] 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. [51120] 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. [51120]

    Acute bronchospasm, status asthmaticus

    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.

    Behavioral changes, psychiatric event, suicidal ideation

    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.

    Children, infants, neonates

    Due to the risk of hepatotoxicity, the use of zileuton should be avoided in neonates, infants, and children less than 12 years of age.

    Pregnancy

    The National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group recommend avoiding the use of zileuton in pregnancy.[31822] 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.[46824] [51120] 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/.[46824] [51120] 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.[46824] [51120]

    Breast-feeding

    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.[46824] [51120] 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.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 1.9-4.6
    leukopenia / Delayed / 0-2.6
    hypertonia / Delayed / 1.0
    lymphadenopathy / Delayed / 1.0
    chest pain (unspecified) / Early / 1.0
    constipation / Delayed / 1.0
    vaginitis / Delayed / 1.0
    conjunctivitis / Delayed / 1.0
    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    hallucinations / Early / Incidence not known

    Mild

    headache / Early / 6.0-24.6
    myalgia / Early / 3.2-7.0
    sinusitis / Delayed / 6.5-6.5
    nausea / Early / 3.0-5.5
    fatigue / Early / 2.0-3.9
    chills / Rapid / 1.0-3.9
    asthenia / Delayed / 3.8-3.8
    insomnia / Early / 2.3-2.3
    paresthesias / Delayed / 1.0-1.0
    arthralgia / Delayed / 1.0
    fever / Early / 1.0
    vomiting / Early / 1.0
    pruritus / Rapid / 1.0
    diarrhea / Early / 1.0
    rash / Early / 1.0
    dizziness / Early / 1.0
    dyspepsia / Early / 1.0
    drowsiness / Early / 1.0
    malaise / Early / 1.0
    infection / Delayed / 1.0
    abdominal pain / Early / 1.0
    flatulence / Early / 1.0
    anxiety / Delayed / Incidence not known
    irritability / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    agitation / Early / Incidence not known
    tremor / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; 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.
    Acetaminophen; Butalbital; 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.
    Acetaminophen; Butalbital; Caffeine; Codeine: (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.
    Acetaminophen; 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.
    Acetaminophen; Caffeine; Dihydrocodeine: (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.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (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.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (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.
    Alfentanil: (Moderate) Alfentanil is metabolized by the cytochrome P450 3A4 isoenzyme. Zileuton is an inhibitor of CYP3A4 and may decrease systemic clearance of alfentanil leading to increased or prolonged effects.
    Alosetron: (Major) Concomitant use of alosetron with zileuton should be avoided due to the risk for increased alosetron serum concentrations and serious adverse reactions. Alosetron is metabolized by CYP1A2; zileuton is a moderate inhibitor of this enzyme.
    Alprazolam: (Moderate) Zileuton may inhbit the CYP3A isoenzymes and reduce the metabolism of alprazolam, potentially increasing the risk for benzodiazepine toxicity. Consider alprazolam dose reduction of up to 50%. Monitor for an increase in CNS and/or respiratory depression.
    Amiodarone: (Minor) Amiodarone inhibits cytochrome P450 CYP1A2 isoenzymes, which can potentially lead to increased plasma concentrations of CYP1A2 substrates like zileuton.
    Amitriptyline; Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as zileuton, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Amoxicillin; Clarithromycin; Lansoprazole: (Minor) Zileuton is metabolized by CYP3A4 and may also inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates, including clarithromycin.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) Zileuton is metabolized by CYP3A4 and may also inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates, including clarithromycin.
    Amprenavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    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.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if zileuton and aprepitant are used concurrently and monitor for an increase in zileuton-related adverse effects for several days after administration of a multi-day aprepitant regimen. Zileuton is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of zileuton. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Aprepitant is also a CYP2C9 inducer and zileuton is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
    Aspirin, ASA; Butalbital; 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.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (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.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (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.
    Aspirin, ASA; Caffeine; Orphenadrine: (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.
    Atazanavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with zileuton as there is a potential for elevated zileuton concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Zileuton is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor. (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Azelastine; Fluticasone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Beclomethasone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Zileuton is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Bendamustine: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as zileuton may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
    Bepridil: (Minor) Caution should be used when other CYP3A4 inhibitors, such as zileuton, are co-administered with bepridil; monitor clinical response. The metabolism of bepridil may be reduced and its effect increased. Dosage adjustments of bepridil may be necessary if CYP3A4 inhibitors are added or discontinued.
    Betamethasone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering zileuton with boceprevir due to an increased potential for zileuton-related adverse events. If zileuton dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of zileuton. Zileuton is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated zileuton plasma concentrations.
    Bosentan: (Minor) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, such as zileuton.
    Bromocriptine: (Major) Bromocriptine is a cytochrome P450 3A4 substrate. In theory, inhibitors of this isoenzyme, such as zileuton, may decrease the metabolism of bromocriptine.
    Budesonide: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Budesonide; Formoterol: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Bupivacaine; Lidocaine: (Minor) Concomitant use of systemic lidocaine and zileuton may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; in vitro data indicates zileuton is both a substrate and inhibitor of CYP1A2.
    Buspirone: (Moderate) CYP3A4 inhibitors, such as zileuton, may decrease systemic clearance of buspirone leading to increased or prolonged effects. If buspirone is to be administered concurrently with significant CYP3A4 inhibitors, a low dose of buspirone (i.e., 2.5 mg PO twice daily) is recommended initially. Subsequent dosage adjustments should be based on clinical response.
    Cabergoline: (Major) Cabergoline is a cytochrome P450 3A4 substrate. In theory, inhibitors of this isoenzyme, such as zileuton, may decrease the metabolism of cabergoline.
    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) 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.
    Caffeine; Ergotamine: (Major) Zileuton is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible. (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.
    Carbamazepine: (Moderate) Carbamazepine is metabolized by the hepatic isoenzyme CYP3A4. Zileuton is known to inhibit CYP3A4 and may decrease carbamazepine metabolism and increase carbamazepine plasma concentrations.
    Ceritinib: (Moderate) Monitor for an increase in zileuton-related adverse reactions if coadministration with ceritinib is necessary. Zileuton is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
    Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as zileuton, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Chlordiazepoxide; Clidinium: (Moderate) CYP3A4 inhibitors, such as zileuton, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Ciclesonide: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Cinacalcet: (Moderate) Caution is recommended when coadministering cinacalcet with other CYP3A4 enzyme inhibitors, such as zileuton.
    Ciprofloxacin: (Minor) Zileuton is primarily metabolized by CYP1A2. Zileuton metabolism may be reduced by coadministration with inhibitors of CYP1A2 such as ciprofloxacin.
    Cisapride: (Severe) Although administration of zileuton with cisapride has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with cisapride, as both are CYP3A4 substrates. Avoid concomitant use, as increased plasma cisapride concentrations and QT prolongation could occur.
    Clarithromycin: (Minor) Zileuton is metabolized by CYP3A4 and may also inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates, including clarithromycin.
    Clonazepam: (Moderate) Zileuton is a CYP3A4 inhibitor and may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity.
    Clorazepate: (Moderate) Zileuton is a CYP3A4 inhibitor and may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity.
    Clozapine: (Moderate) Caution is advisable during concurrent use of zileuton and clozapine. Zileuton is an inhibitor of CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. When initiating clozapine or adding a mild or moderate CYP1A2 inhibitor to clozapine treatment, monitor for adverse reactions and consider reducing the clozapine dose if necessary. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with zileuton as there is a potential for elevated zileuton concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Zileuton is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.
    Corticosteroids: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Corticotropin, ACTH: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Cortisone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Crizotinib: (Minor) Monitor for an increase in zileuton-related adverse reactions if coadministration with crizotinib is necessary. Zileuton is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Although formal drug-drug interaction studies have not been conducted, it is reasonable to monitor these patients clinically.
    Cyclosporine: (Minor) Zileuton is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to reduce cyclosporine dosage requirements or cause cyclosporine toxicity. This potential interaction may result in increased serum concentrations of cyclosporine.
    Darifenacin: (Moderate) The serum concentration of darifenacin may be increased if coadministered with CYP3A4 inhibitors including zileuton.
    Darunavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with zileuton as there is a potential for elevated zileuton concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Zileuton is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor. (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with zileuton as there is a potential for elevated zileuton concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Zileuton is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor. (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Deflazacort: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Dexamethasone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Dextromethorphan; Quinidine: (Moderate) Zileuton is metabolized by the hepatic isoenzyme CYP3A4 and may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates, including quinidine.
    Diazepam: (Moderate) Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4. As a result, diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes. Zileuton may inhibit the metabolism of diazepam. While diazepam clearance may be inhibited, diazepam pharmacodynamics are not always affected. Consider dose reduction of diazepam if clinically indicated. Monitor for an increase in CNS or respiratory depression.
    Dihydroergotamine: (Major) Coadministration of dihydroergotamine with inhibitors of CYP3A4, such as zileuton, may potentially increase the risk of ergot toxicity. Symptoms of ergot toxicity include: vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects.
    Diltiazem: (Minor) Zileuton is a respiratory antiinflammatory agent which can theoretically inhibit CYP3A4 metabolism of diltiazem, a CYP3A4 substrate.
    Disopyramide: (Minor) Zileuton may inhibit CYP3A4 isoenzymes and could potentially compete with other CYP3A4 substrates, such as disopyramide.
    Donepezil: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4 and may inhibit CYP3A4 isoenzymes. Zileuton could also potentially compete with other CYP3A4 substrates, such as donepezil.
    Donepezil; Memantine: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4 and may inhibit CYP3A4 isoenzymes. Zileuton could also potentially compete with other CYP3A4 substrates, such as donepezil.
    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.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Zileuton is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    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.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as zileuton. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Elbasvir; Grazoprevir: (Moderate) Administering zileuton with elbasvir; grazoprevir may result in elevated zileuton plasma concentrations. Zileuton is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    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.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with zileuton as there is a potential for elevated zileuton concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Zileuton is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with zileuton as there is a potential for elevated zileuton concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Zileuton is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor.
    Enalapril; Felodipine: (Minor) Zileuton is a CYP3A4 inhibitors which theoretically may decrease hepatic clearance and enhance oral bioavailability of felodipine, a CYP3A4 substrate.
    Ergoloid Mesylates: (Major) Ergot alkaloids are cytochrome P450 3A4 substrates. In theory, inhibitors of this isoenzyme, such as zileuton, may decrease the metabolism of ergot alkaloids.
    Ergonovine: (Major) Coadministration of certain ergot alkaloids with inhibitors of CYP3A4, such as zileuton, may increase the risk of ergot toxicity and result in severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities and/or other serious effects. Use together with caution and employ appropriate clinical monitoring.
    Ergotamine: (Major) Zileuton is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Estazolam: (Moderate) Zileuton may inhibit CYP3A4 and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity. Consider a dose reduction of estazolam if clinically warranted. Monitor for an increase in CNS or respiratory depression.
    Ezetimibe; Simvastatin: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates, including simvastatin.
    Felodipine: (Minor) Zileuton is a CYP3A4 inhibitors which theoretically may decrease hepatic clearance and enhance oral bioavailability of felodipine, a CYP3A4 substrate.
    Fludrocortisone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Flunisolide: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Fluoxetine; Olanzapine: (Minor) Zileuton is an inhibitor of CYP1A2 and could potentially reduce the elimination of olanzapine.
    Flurazepam: (Moderate) Zileuton is a CYP3A4 inhibitor and may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity.
    Fluticasone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Fluticasone; Salmeterol: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Fluticasone; Vilanterol: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Fluvoxamine: (Minor) Zileuton is primarily metabolized by CYP1A2 isoenzymes, while fluvoxamine inhibits this isoenzyme. Fluvoxamine may reduce CYP1A2 mediated metabolism of zileuton.
    Formoterol; Mometasone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Fosamprenavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    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.
    Halofantrine: (Moderate) ZIleuton significantly inhibits cytochrome CYP3A4, and may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity.
    Hydrochlorothiazide, HCTZ; 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.
    Hydrocortisone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with zileuton, a CYP3A substrate, as zileuton toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Indinavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with zileuton may result in increased serum concentrations of zileuton. Zileuton is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isradipine: (Minor) Zileuton ia a CYP3A4 inhibitors and may inhibit the metabolism of and increase the effect of isradipine.
    Levomethadyl: (Major) Agents that inhibit hepatic cytochrome P450 3A4, such as zileuton, may decrease the metabolism of levomethadyl, increase levomethadyl levels, and may precipitate severe arrhythmias including torsade de pointes.
    Lidocaine: (Minor) Concomitant use of systemic lidocaine and zileuton may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; in vitro data indicates zileuton is both a substrate and inhibitor of CYP1A2.
    Lomitapide: (Major) Concomitant use of lomitapide and zileuton may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Zileuton is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Lovastatin: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4 and could potentially compete with other CYP3A4 substrates including lovastatin.
    Lovastatin; Niacin: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4 and could potentially compete with other CYP3A4 substrates including lovastatin.
    Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Zileuton is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
    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.
    Methylergonovine: (Major) Zafirlukast is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Methylprednisolone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Methysergide: (Major) The risk of ergot toxicity, e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects, is potentially increased by the use of zileuton, a CYP3A4 inhibitor.
    Mexiletine: (Moderate) Zileuton and mexiletine are both substrates and inhibitors of CYP1A2. Coadministration may result in increased serum concentrations of either agent.
    Midazolam: (Moderate) Zileuton may inhibit CYP3A4 and may potentially reduce the metabolism of midazolam. When midazolam is co-administered with zileuton, monitor for an increase in CNS or respiratory depression. Consider midazolam dose reduction if clinically warranted.
    Mitotane: (Moderate) Use caution if mitotane and zileuton are used concomitantly, and monitor for decreased efficacy of zileuton and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and zileuton is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of zileuton.
    Mometasone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Nelfinavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Niacin; Simvastatin: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates, including simvastatin.
    Nicardipine: (Minor) Zileuton is a CYP3A4 inhibitor and may decrease the metabolism and increase the effect of nicardipine.
    Nifedipine: (Minor) Zileuton is a CYP3A4 inhibitor which theoretically may decrease hepatic clearance and enhance oral bioavailability of nifedipine, a CYP3A4 substrate.
    Nimodipine: (Minor) Zileuton is a CYP3A4 inhibitor which theoretically may decrease hepatic metabolism and increase the effect of nimodipine, a CYP3A4 substrate.
    Nisoldipine: (Minor) Because nisoldipine is metabolized by CYP3A4, inhibitors of these enzymes, such as zileuton, have the potential to increase the bioavailability of nisoldipine.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as zileuton. Therapeutic monitoring is recommended with coadministration.
    Olanzapine: (Minor) Zileuton is an inhibitor of CYP1A2 and could potentially reduce the elimination of olanzapine.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Oritavancin: (Moderate) Coadministration of oritavancin and zileuton may result in increases or decreases in zileuton exposure and may increase side effects or decrease efficacy of zileuton. Zileuton is metabolized by CYP3A4 and CYP2C9. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Inhibitors of the CYP3A4 enzyme, such as zileuton, may increase the serum concentrations of oxybutynin. The manufacturer recommends caution when oxybutynin is co-administered with CYP3A4 inhibitors.
    Paricalcitol: (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as zileuton. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and zileuton, a CYP3A4 substrate, may cause an increase in systemic concentrations of zileuton. Use caution when administering these drugs concomitantly.
    Peginterferon Alfa-2b: (Moderate) Caution is warranted with the use of peginterferon alfa-2b and zileuton. Peginterferon alfa-2b is a CYP2D6 inhibitor and zileuton and its N-dehydroxylated metabolite can be oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9, and 3A4.
    Pimozide: (Major) Concurrent use of pimozide and zileuton should be avoided, if possible. If not possible, consider the potential for elevated pimozide concentrations and associated side effects, including the potential for QT prolongation. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Zileuton is a CYP1A2 inhibitor.
    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.
    Posaconazole: (Major) Posaconazole and zileuton should be coadministered with caution due to an increased potential for zileuton-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of zileuton. These drugs used in combination may result in elevated zileuton plasma concentrations, causing an increased risk for zileuton-related adverse events.
    Prednisolone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Prednisone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Propafenone: (Moderate) Zileuton is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of propafenone.
    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.
    Protease inhibitors: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Quazepam: (Moderate) Concurrent use of zileuton and quazepam may increase the serum concentration of quazepam and increase the potential for benzodiazepine toxicity. Zileuton is a CYP3A4 inhibitor and quazepam is a CYP3A4 substrate.
    Quinidine: (Moderate) Zileuton is metabolized by the hepatic isoenzyme CYP3A4 and may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates, including quinidine.
    Ramelteon: (Major) Ramelteon should be avoided in combination with potent CYP1A2 inhibitors, such as zileuton, if possible. CYP1A2 is the major isozyme involved in the metabolism of ramelteon. Strong CYP1A2 inhibitors have been shown to have significant interactions with ramelteon, leading to elevated ramelteon AUC > 190-fold and Cmax > 70-fold. If zileuton must be administered with ramelteon, monitor the patient closely for toxicity due to elevated ramelteon serum concentrations.
    Rasagiline: (Major) Rasagiline plasma concentrations may increase up to 2-fold in patients using concomitant zileuton; do not exceed a rasagiline dose of 0.5 mg PO once daily with concomitant use. Closely monitor for increased adverse effects including postural hypotension, hallucinations, dyskinesias, weight loss, or xerostomia. If zileuton is subsequently discontinued, the dose of rasagiline may need to be adjusted upward. Zileuton is a CYP1A2 inhibitor. Rasagiline is a CYP1A2 substrate and does not have an alternate metabolic pathway.
    Riluzole: (Moderate) Coadministration of riluzole with zileuton may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
    Ritonavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Rofecoxib: (Minor) Rofecoxib may produce a modest inhibition of cytochrome P450 CYP1A2. Therefore, there is a potential for an interaction with other drugs metabolized via CYP1A2, such as zileuton.
    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.
    Saquinavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Sildenafil: (Minor) Sildenafil is metabolized principally by CYP3A4. Inhibitors of these isoenzymes like zileuton may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects.
    Silodosin: (Moderate) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4 such as zileuton may cause significant increases in silodosin plasma concentrations.
    Simvastatin: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates, including simvastatin.
    Simvastatin; Sitagliptin: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates, including simvastatin.
    Sirolimus: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates including sirolimus.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system and co-administration of St. John's Wort could decrease the efficacy of zileuton, which is metabolized by these enzymes.
    Tacrine: (Minor) The principal isoenzyme involved in initial hepatic oxidative metabolism of zileuton is CYP1A2. Tacrine is an inhibitor of CYP1A2 and could potentially increase plasma concentrations of zileuton.
    Tacrolimus: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4 and could potentially compete with other CYP3A4 substrates, including tacrolimus. Clinical documentation of interactions is lacking; the manufacturer recommends appropriate clinical monitoring if these drugs are used concomitantly due to the lack of data.
    Tadalafil: (Minor) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 CYP3A4 isoenzyme. Zileuton is an Inhibitor of CYP3A4 and may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as zileuton. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    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.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering zileuton with telaprevir due to an increased potential for zileuton-related adverse events. If zileuton dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of zileuton. Zileuton is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated zileuton plasma concentrations.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and zileuton is necessary, as the systemic exposure of zileuton may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of zileuton; consider increasing the dose of zileuton if necessary. Zileuton is a CYP3A4 substrate in vitro. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    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.
    Terfenadine: (Severe) The combination of zileuton and terfenadine is contraindicated due to the potential for increased terfenadine concentrations, which increases the risk for torsade de pointes (TdP) secondary to QT prolongation. Zileuton inhibits CYP3A4; terfenadine is a CYP3A4 substrate. Torsade de pointes secondary to QT prolongation has been associated with terfenadine therapy. In some cases, this cardiac arrhythmia occurred when drugs thought to inhibit terfenadine hepatic metabolism were administered concomitantly. In a drug interaction study in 16 healthy volunteers, co-administration of multiple doses of terfenadine (60 mg every 12 hours) and zileuton (600 mg every 6 hours) for 7 days resulted in a decrease in clearance of terfenadine by 22% leading to a statistically significant increase in mean AUC and Cmax of terfenadine of approximately 35%; prolongation of the QTc interval did not occur. Although there was no cardiac effect in this small number of healthy volunteers, given the high inter-individual pharmacokinetic variability of terfenadine, co-administration of zileuton and terfenadine is not recommended.
    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. (Major) Concurrent use of zileuton and theophylline results in an approximate doubling of theophylline serum concentrations and increased frequency of theophylline-related adverse effects. Reduce the theophylline dose by approximately 50% and monitor theophylline plasma concentrations when zileuton is prescribed to an existing regimen. When initiating therapy with theophylline in a patient receiving zileuton, adjust the maintenance dose and/or dosing interval of theophylline based on serum theophylline concentrations. Theophylline is primarily metabolized by CYP1A2, with secondary pathways by CYP2E1 and CYP3A4; zileuton is a CYP1A2 inhibitor.
    Thiabendazole: (Moderate) Thiabendazole is a potent inhibitor of CYP1A2 hepatic enzymes. Zileuton is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Although data are lacking, zileuton metabolism may be reduced by coadministration with inhibitors of CYP1A2 such as thiabendazole.
    Tipranavir: (Moderate) Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
    Tizanidine: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors, such as zileuton, as concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Trandolapril; Verapamil: (Minor) Caution should be used when CYP3A4 inhibitors, such as zileuton, are co-administered with verapamil, a CYP3A4 substrate and inhibitor.
    Triamcinolone: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Triazolam: (Moderate) CYP3A4 inhibitors, such as zileuton, may reduce the metabolism of triazolam and increase the potential for benzodiazepine toxicity. Consider a triazolam dose reduction of up to 50% Monitor for an increase in CNS or respiratory depression.
    Vardenafil: (Minor) Vardenafil is metabolized by CYP3A4. Inhibitors of CYP3A4, such as zileuton, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.
    Vemurafenib: (Minor) Concomitant use of vemurafenib and zileuton may result in altered concentrations of zileuton. Vemurafenib is an inhibitor of CYP1A2 and an inducer of CYP3A4. Zileuton is a substrate of CYP1A2 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Verapamil: (Minor) Caution should be used when CYP3A4 inhibitors, such as zileuton, are co-administered with verapamil, a CYP3A4 substrate and inhibitor.
    Voriconazole: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates.
    Warfarin: (Moderate) Concomitant administration of zileuton and warfarin resulted in a 15% decrease in the clearance of R-warfarin but no change in the clearance of the more potent S-isomer. These pharmacokinetic changes were accompanied by a significant prolongation of prothrombin time. Prothrombin times should be monitored very carefully if zileuton is either added or discontinued during warfarin therapy.
    Zonisamide: (Minor) Zonisamide is metabolized by hepatic cytochrome P450 isoenzyme 3A4. Inhibitors of this enzyme, such as zileuton, may decrease the clearance of zonisamide. Inhibitors can increase the systemic exposure of zonisamide by decreasing the metabolism of the drug.

    PREGNANCY AND LACTATION

    Pregnancy

    The National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group recommend avoiding the use of zileuton in pregnancy.[31822] 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.[46824] [51120] 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/.[46824] [51120] 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.[46824] [51120]

    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.[46824] [51120] 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.

    MECHANISM OF ACTION

    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.[24329] [24330] [24331] [51119] [51120]
     
    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.[51119] [51120]

    PHARMACOKINETICS

    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—2.3 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP1A2, CYP2C9, CYP3A4
    Zileuton, according to in vitro data, is both a substrate and 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.

    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.