Zileuton Er

Drug overview for ZILEUTON ER (zileuton):

Generic name: ZILEUTON (zye-LOO-ton)
Drug class: Leukotriene Modulators
Therapeutic class: Respiratory Therapy Agents

Zileuton, a leukotriene synthesis inhibitor, is an antiasthmatic agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

ZILEUTON ER 600 MG TABLET

The following indications for ZILEUTON ER (zileuton) have been approved by the FDA:

Indications:
Maintenance therapy for asthma

Professional Synonyms:
Therapy to achieve long-term asthma control

The following dosing information is available for ZILEUTON ER (zileuton):

Dosing
Administration
ZILEUTON ER
ZILEUTON ER

For the prevention and long-term symptomatic control of asthma, the usual dosage of immediate-release zileuton for adults and children 12 years of age or older is 600 mg 4 times daily. Limited evidence from clinical trials suggests that a smaller dosage of the drug (400 mg 4 times daily) does not produce consistent improvements in asthma control (i.e., as determined by changes in FEV1, FVC, asthma symptoms, or reduction in supplemental use of beta-agonist bronchodilators). For the prevention and long-term symptomatic control of asthma, the usual dosage of extended-release zileuton for adults and children 12 years of age or older is 1.2

g twice daily.

Limited data suggest that renal impairment does not affect the pharmacokinetics of zileuton, and the manufacturer states that dosage adjustment in patients with impaired renal function or in those undergoing hemodialysis is not necessary.

Since hepatic metabolism is the principal means of elimination of zileuton, the drug is contraindicated in patients with active liver disease or serum aminotransferase concentrations of at least 3 times the upper limit of normal; zileuton should be used with caution in patients with mild hepatic impairment (serum ALT less than 3 times the upper limit of normal) or in those with a history of liver disease and/or excessive alcohol consumption. The manufacturer states that liver function tests should be performed prior to initiation of zileuton therapy and monitored periodically during therapy.

Zileuton is administered orally as conventional (immediate-release) and extended-release tablets. Immediate-release zileuton is usually given in 4 equally divided doses daily. Administration of immediate-release zileuton with food does not appreciably affect the rate or extent of absorption; therefore, for ease of administration, the drug may be taken with meals and at bedtime.

Extended-release zileuton is usually given in 2 equally divided doses daily. Administration of extended-release zileuton with food increases the rate and extent of absorption; therefore, for ease of administration, the drug should be taken within 1 hour after morning and evening meals.

Dosing information for ZILEUTON ER
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
ZILEUTON ER 600 MG TABLET	Maintenance	Adults take 2 tablets (1,200 mg) by oral route 2 times per day within 1 hr after morning and evening meals

Generic dosing information for ZILEUTON ER
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
ZILEUTON ER 600 MG TABLET	Maintenance	Adults take 2 tablets (1,200 mg) by oral route 2 times per day within 1 hr after morning and evening meals

The following drug interaction information is available for ZILEUTON ER (zileuton):

Contraindicated
Severe
Moderate

There are 2 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Pimozide/Zileuton SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Zileuton may inhibit the metabolism of pimozide at CYP3A.(1) CLINICAL EFFECTS: Concurrent administration may result in elevated levels of pimozide, which may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4) PATIENT MANAGEMENT: The concurrent administration of pimozide and zileuton is contraindicated by the manufacturer of pimozide.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: An in vitro study indicates that pimozide is metabolized at CYP3A.(2) Because elevated levels of pimozide may prolong the QTc interval, resulting in life-threatening ventricular arrhythmias, the manufacturer of pimozide states that the concurrent administration of pimozide with inhibitors of CYP3A such as zileuton is contraindicated.(1)	PIMOZIDE
Fezolinetant/CYP1A2 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of fezolinetant.(1) CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of fezolinetant states that concurrent use with CYP1A2 inhibitors is contraindicated.(1) DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include allopurinol, artemisinin, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, verapamil, zileuton.(2-4)	VEOZAH

Drug Interaction

Drug Names

Pimozide/Zileuton

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Zileuton may inhibit the metabolism of pimozide at CYP3A.(1)

CLINICAL EFFECTS: Concurrent administration may result in elevated levels of pimozide, which may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The concurrent administration of pimozide and zileuton is contraindicated by the manufacturer of pimozide.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: An in vitro study indicates that pimozide is metabolized at CYP3A.(2) Because elevated levels of pimozide may prolong the QTc interval, resulting in life-threatening ventricular arrhythmias, the manufacturer of pimozide states that the concurrent administration of pimozide with inhibitors of CYP3A such as zileuton is contraindicated.(1)

PIMOZIDE

Fezolinetant/CYP1A2 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of fezolinetant.(1)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of fezolinetant states that concurrent use with CYP1A2 inhibitors is contraindicated.(1)

DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1)

Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include allopurinol, artemisinin, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, verapamil, zileuton.(2-4)

VEOZAH

There are 2 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Tizanidine/Zileuton SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Zileuton may inhibit the metabolism of tizanidine by CYP1A2.(1) CLINICAL EFFECTS: Concurrent use of zileuton may result in elevated levels of and effects from tizanidine, including hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor function. PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2) PATIENT MANAGEMENT: The US manufacturer of tizanidine states that concurrent use of tizanidine with inhibitors of CYP1A2, such as zileuton, should be avoided. If concurrent use is warranted, tizanidine should be initiated with 2 mg dose and increased in 2-4 mg steps daily based on patient response to therapy.(1) If adverse reactions such as hypotension, bradycardia or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(1) DISCUSSION: In a study in 10 healthy subjects, concurrent fluvoxamine, another inhibitor of CYP1A2, increased tizanidine maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold, and 3-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(1) In a study in 10 healthy subjects, concurrent ciprofloxacin, another inhibitor of CYP1A2, increase tizanidine Cmax and AUC by 7-fold and 10-fold, respectively. Significant decreases in blood pressure and and increases in drowsiness and psychomotor impairment occurred.(1) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	TIZANIDINE HCL, ZANAFLEX
Lomitapide (Less Than or Equal To 30 mg)/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of lomitapide.(1) Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Thus even weak CYP3A4 inhibitors may affect lomitapide exposure (AUC, area-under-curve). CLINICAL EFFECTS: Concurrent use of a weak inhibitor of CYP3A4 may result in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1) PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1) PATIENT MANAGEMENT: The maximum lomitapide dose should be 30 mg daily for patients taking concomitant weak CYP3A4 inhibitors. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction. When initiating a weak CYP3A4 inhibitor in patients taking lomitapide 10 mg daily or more, decrease the dose of lomitapide by 50%. In patients taking lomitapide 5 mg daily, continue current dose. DISCUSSION: Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Based upon interactions with stronger inhibitors, weak inhibitors of CYP3A4 are predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1) Weak CYP3A4 inhibitors linked to this interaction include alprazolam, amiodarone, amlodipine, asciminib, atorvastatin, azithromycin, Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab, cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin, chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant, delavirdine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, larotrectinib, lacidipine, lapatinib, lazertinib, leflunomide, levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib, selpercatinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, vonoprazan, and zileuton.(1-3)	JUXTAPID

Drug Interaction

Drug Names

Tizanidine/Zileuton

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Zileuton may inhibit the metabolism of tizanidine by CYP1A2.(1)

CLINICAL EFFECTS: Concurrent use of zileuton may result in elevated levels of and effects from tizanidine, including hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor function.

PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: The US manufacturer of tizanidine states that concurrent use of tizanidine with inhibitors of CYP1A2, such as zileuton, should be avoided. If concurrent use is warranted, tizanidine should be initiated with 2 mg dose and increased in 2-4 mg steps daily based on patient response to therapy.(1) If adverse reactions such as hypotension, bradycardia or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(1)

DISCUSSION: In a study in 10 healthy subjects, concurrent fluvoxamine, another inhibitor of CYP1A2, increased tizanidine maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) by 12-fold, 33-fold, and 3-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(1) In a study in 10 healthy subjects, concurrent ciprofloxacin, another inhibitor of CYP1A2, increase tizanidine Cmax and AUC by 7-fold and 10-fold, respectively.

Significant decreases in blood pressure and and increases in drowsiness and psychomotor impairment occurred.(1) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S.

Office of the National Coordinator (ONC) for Health Information Technology.

TIZANIDINE HCL, ZANAFLEX

Lomitapide (Less Than or Equal To 30 mg)/Weak CYP3A4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of lomitapide.(1) Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Thus even weak CYP3A4 inhibitors may affect lomitapide exposure (AUC, area-under-curve).

CLINICAL EFFECTS: Concurrent use of a weak inhibitor of CYP3A4 may result in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1)

PATIENT MANAGEMENT: The maximum lomitapide dose should be 30 mg daily for patients taking concomitant weak CYP3A4 inhibitors. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction. When initiating a weak CYP3A4 inhibitor in patients taking lomitapide 10 mg daily or more, decrease the dose of lomitapide by 50%. In patients taking lomitapide 5 mg daily, continue current dose.

DISCUSSION: Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Based upon interactions with stronger inhibitors, weak inhibitors of CYP3A4 are predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1) Weak CYP3A4 inhibitors linked to this interaction include alprazolam, amiodarone, amlodipine, asciminib, atorvastatin, azithromycin, Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab, cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin, chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant, delavirdine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, larotrectinib, lacidipine, lapatinib, lazertinib, leflunomide, levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib, selpercatinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, vonoprazan, and zileuton.(1-3)

JUXTAPID

There are 2 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Theophylline/Zileuton SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Zileuton may inhibit the metabolism of theophylline(1). CLINICAL EFFECTS: Concurrent administration may result in increased levels of theophylline (up to two-fold) with possible theophylline toxicity.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of zileuton recommends that patients receiving concurrent therapy have their theophylline dosages reduced by one-half and that these patients be monitored for theophylline toxicity.(2) DISCUSSION: In a study in 16 subjects, the concurrent administration of theophylline and zileuton resulted in increased levels of theophylline and adverse effects. During concurrent administration, theophylline area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) increased 92%, 73%, and 125%, respectively. During administration of theophylline with placebo, eight of 16 subjects reported a single adverse effect, while 14 subjects reported a total of 44 adverse effects during administration of theophylline with zileuton.(1)	AMINOPHYLLINE, DYPHYLLINE, ELIXOPHYLLIN, THEO-24, THEOPHYLLINE, THEOPHYLLINE ANHYDROUS, THEOPHYLLINE ER, THEOPHYLLINE ETHYLENEDIAMINE
Propranolol/Zileuton SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Zileuton may inhibit the metabolism of propranolol by CYP1A2.(1) CLINICAL EFFECTS: Concurrent use of zileuton may result in increased levels of and effects from propranolol.(2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patient receiving concurrent therapy with zileuton and propranolol should be closely monitored for adverse effects. The dosage of propranolol may need to be adjusted if zileuton is initiated or discontinued.(2) DISCUSSION: In a study in 16 healthy males, pretreatment with zileuton (600 mg ever 6 hours for 5 days) increased the maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a single dose of propranolol (80 mg) by 52%, 104%, and 25%, respectively. During concurrent administration, beta-blockade was increased and heart rate was decreased.(2) A study in human liver microsomes showed that zileuton inhibited the metabolism of propranolol by CYP1A2.(1)	HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID

Drug Interaction

Drug Names

Theophylline/Zileuton

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Zileuton may inhibit the metabolism of theophylline(1).

CLINICAL EFFECTS: Concurrent administration may result in increased levels of theophylline (up to two-fold) with possible theophylline toxicity.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of zileuton recommends that patients receiving concurrent therapy have their theophylline dosages reduced by one-half and that these patients be monitored for theophylline toxicity.(2)

DISCUSSION: In a study in 16 subjects, the concurrent administration of theophylline and zileuton resulted in increased levels of theophylline and adverse effects. During concurrent administration, theophylline area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) increased 92%, 73%, and 125%, respectively. During administration of theophylline with placebo, eight of 16 subjects reported a single adverse effect, while 14 subjects reported a total of 44 adverse effects during administration of theophylline with zileuton.(1)

AMINOPHYLLINE, DYPHYLLINE, ELIXOPHYLLIN, THEO-24, THEOPHYLLINE, THEOPHYLLINE ANHYDROUS, THEOPHYLLINE ER, THEOPHYLLINE ETHYLENEDIAMINE

Propranolol/Zileuton

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Zileuton may inhibit the metabolism of propranolol by CYP1A2.(1)

CLINICAL EFFECTS: Concurrent use of zileuton may result in increased levels of and effects from propranolol.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patient receiving concurrent therapy with zileuton and propranolol should be closely monitored for adverse effects. The dosage of propranolol may need to be adjusted if zileuton is initiated or discontinued.(2)

DISCUSSION: In a study in 16 healthy males, pretreatment with zileuton (600 mg ever 6 hours for 5 days) increased the maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a single dose of propranolol (80 mg) by 52%, 104%, and 25%, respectively. During concurrent administration, beta-blockade was increased and heart rate was decreased.(2) A study in human liver microsomes showed that zileuton inhibited the metabolism of propranolol by CYP1A2.(1)

HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID

The following contraindication information is available for ZILEUTON ER (zileuton):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

No enhanced Contraindications information available for this drug.

There are 1 contraindications. Absolute contraindication.

Contraindication List
Disease of liver

There are 0 severe contraindications.

There are 8 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Anxiety disorder
Depression
Dream disorder
Hallucinations
Mood changes
Nervousness
Suicidal ideation
Tremor

The following adverse reaction information is available for ZILEUTON ER (zileuton):

Overview
Severe
Less Severe

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

There are 5 severe adverse reactions.

More Frequent	Less Frequent
None.	Abnormal hepatic function tests Increased alanine transaminase

Rare/Very Rare
Hyperbilirubinemia Suicidal Suicidal ideation

There are 23 less severe adverse reactions.

More Frequent	Less Frequent
Dyspepsia Nasal passage irritation Nausea Sinusitis Sore throat	Abdominal pain with cramps Diarrhea Headache disorder Myalgia Skin rash Upper respiratory infection Vomiting

Rare/Very Rare
Aggressive behavior Agitation Behavioral disorders Depression Dream disorder Hallucinations Insomnia Irritability Nervousness Symptoms of anxiety Tremor

The following precautions are available for ZILEUTON ER (zileuton):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

No enhanced Pregnancy information available for this drug.

No enhanced Lactation information available for this drug.

No enhanced Geriatric Use information available for this drug.

Maintenance therapy for asthma
J45	Asthma
J45.2	Mild intermittent asthma
J45.20	Mild intermittent asthma, uncomplicated
J45.3	Mild persistent asthma
J45.30	Mild persistent asthma, uncomplicated
J45.4	Moderate persistent asthma
J45.40	Moderate persistent asthma, uncomplicated
J45.5	Severe persistent asthma
J45.50	Severe persistent asthma, uncomplicated
J45.9	Other and unspecified asthma
J45.90	Unspecified asthma
J45.909	Unspecified asthma, uncomplicated