Zileuton Er (zileuton)

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.

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

Cyp1a2 Inhibitors/Fezolinetant

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.(1-4)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for concurrent use of fezolinetant with CYP1A2 inhibitors differ in different regions. The US manufacturer of fezolinetant states that concurrent use with strong, moderate, and weak CYP1A2 inhibitors is contraindicated.(1) The Australian, Canadian, and UK manufacturers of fezolinetant state that concurrent use with strong and moderate CYP1A2 inhibitors is contraindicated, while weak CYP1A2 inhibitors are not predicted to cause clinically relevant changes in fezolinetant exposure.(2-4)

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, centanafadine, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include acyclovir, allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, valacyclovir, verapamil, and zileuton.(5-7)

Zileuton/Pimozide

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)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Weak Cyp3a4 Inhibitors/Lomitapide

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: When initiating lomitapide in patients taking a stable dose of a weak CYP3A4 inhibitor, follow the recommended dose and titration schedule per labeling. When initiating a weak CYP3A4 inhibitor in patients taking lomitapide, decrease the dose of lomitapide by 50%. The maximum recommended lomitapide dose with concurrent weak CYP3A4 inhibitors should be: -Adults (age 18 years and older): 30 mg daily, -Age group 11 to 17 years: 20 mg daily, -Age group 2 to 10 years: 10 mg daily. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

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: amiodarone, amlodipine, anamorelin, asciminib, atorvastatin, avapritinib, azithromycin, Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab, camizestrant, cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin, chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant, delavirdine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, sevabertinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, ziftomenib, and zileuton.(1-3)

Zileuton/Astemizole; Terfenadine

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 astemizole and terfenadine.(1-3)

CLINICAL EFFECTS: Concurrent administration may result in elevated levels of astemizole and terfenadine, which may result in life-threatening cardiotoxicity including QT prolongation or torsades de pointes.

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.(4) 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).(4)

PATIENT MANAGEMENT: Evaluate all patients for predisposing risk factors. The manufacturers of zileuton(1) and terfenadine(2) state that concurrent administration of terfenadine and zileuton is not recommended. The manufacturer of astemizole states that concurrent administration of astemizole and zileuton is not recommended.(3) If concurrent therapy is warranted, 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: There is no published documentation substantiating this possible drug interaction. In a study in 16 subjects, the concurrent administration of terfenadine and zileuton resulted in a decrease in terfenadine clearance by 22% and a 35% increase in terfenadine area-under-curve (AUC) and maximum concentration (Cmax).(1) Although there were no significant prolongations of the QTc interval in this small study, the manufacturers of zileuton(1) and terfenadine(2) state that concurrent administration is not recommended. The manufacturer of astemizole states that concurrent administration of astemizole and zileuton is not recommended.(3)

Zileuton/Tizanidine

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.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Zileuton/Propranolol

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)

Zileuton/Theophylline

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)

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• Disease of liver

There are no severe contraindications for this drug.

• Anxiety disorder
• Depression
• Dream disorder
• Hallucinations
• Mood changes
• Nervousness
• Suicidal ideation
• Tremor

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Less Frequent

• Abnormal hepatic function tests
• Increased alanine transaminase

Rare or Very Rare

• Hyperbilirubinemia
• Suicidal
• Suicidal ideation

More Frequent

• Dyspepsia
• Nasal passage irritation
• Nausea
• Sinusitis
• Sore throat

Less Frequent

• Abdominal pain with cramps
• Diarrhea
• Headache disorder
• Myalgia
• Skin rash
• Upper respiratory infection
• Vomiting

Rare or Very Rare

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

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