Version November 2024
Asthma:
Immediate release: Oral: 600 mg 4 times daily
Extended release: Oral: 1,200 mg twice daily
No dosage adjustment necessary.
Use is contraindicated in patients with active liver disease or persistent transaminase elevations ≥3 times the upper limit of normal.
Refer to adult dosing.
(For additional information see "Zileuton: Pediatric drug information")
Asthma: Note: Current guidelines do not describe a role for zileuton in the management of asthma (Ref); not routinely used. Children ≥12 years and Adolescents:
Immediate release: Oral: 600 mg 4 times daily; maximum daily dose: 2,400 mg/day
Extended release: Oral: 1,200 mg twice daily; maximum daily dose: 2,400 mg/day
No dosage adjustment necessary in renal impairment or with hemodialysis; dialysis: <0.5% removed by hemodialysis.
Contraindicated in patients with active liver disease or persistent transaminase elevations ≥3 times the upper limit of normal.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Central nervous system: Headache (23% to 25%)
1% to 10%:
Cardiovascular: Chest pain
Central nervous system: Pain (8%), dizziness, drowsiness, hypertonia, insomnia, malaise, nervousness
Dermatologic: Pruritus, skin rash
Gastrointestinal: Dyspepsia (8%), nausea (5% to 6%), abdominal pain (5%), diarrhea (5%), constipation, flatulence, vomiting
Genitourinary: Urinary tract infection, vaginitis
Hematologic & oncologic: Leukopenia (1% to 3%), lymphadenopathy
Hepatic: Increased serum ALT (≥3 x ULN: 2% to 5%), hepatotoxicity
Hypersensitivity: Hypersensitivity reaction
Neuromuscular & skeletal: Myalgia (7%), weakness (4%), arthralgia, neck pain, neck stiffness
Ophthalmic: Conjunctivitis
Respiratory: Upper respiratory tract infection (9%), sinusitis (7%), pharyngolaryngeal pain (5%)
Miscellaneous: Fever
<1%, postmarketing, and/or case reports: Behavioral changes, hepatic failure, hepatitis, hyperbilirubinemia, jaundice, mood changes, sleep disorder, suicidal tendencies, urticaria
Hypersensitivity to zileuton or any component of the formulation; active liver disease or transaminase elevations ≥3 times ULN
Concerns related to adverse effects:
• Hepatotoxicity: There have been reports of hepatic adverse effects (elevated transaminase levels); serum ALT should be monitored. Females >65 years and patients with pre-existing elevated transaminases may be at greater risk. Discontinue therapy and follow transaminases until normal if patients develop clinical signs/symptoms of liver dysfunction or with transaminase levels >5 times ULN; use caution with history of liver disease and/or in those patients who consume substantial quantities of ethanol.
• Neuropsychiatric events: Postmarketing reports of behavioral changes and sleep disorders have been noted.
Concurrent drug therapy issues:
• Sedatives: CNS effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
• Older adult: Females >65 years of age may be at increased risk for ALT elevations. Pharmacokinetics were similar in older adults (≥65 years) compared to younger adults.
• Pediatric: Due to the risk of hepatotoxicity, the manufacturer does not recommend use of zileuton in children <12 years of age.
Other warnings/precautions:
• Reversal of bronchospasm: Not indicated for the reversal of bronchospasm in acute asthma attacks, including status asthmaticus; therapy may be continued during acute asthma exacerbations.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Zyflo: 600 mg [scored]
Tablet Extended Release 12 Hour, Oral:
Generic: 600 mg
May be product dependent
Tablet, 12-hour (Zileuton ER Oral)
600 mg (per each): $32.22
Tablets (Zyflo Oral)
600 mg (per each): $37.59
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Immediate release: Administer without regard to meals.
Extended release: Swallow tablet whole; do not crush, cut, or chew; administer within 1 hour after morning and evening meals.
Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet formulation is available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.
Oral:
Immediate release: May administer daily doses at meals and bedtime.
Extended release: Do not crush, cut, or chew tablet; administer within 1 hour after morning and evening meals. If dose is missed, it does not need administered; at the next scheduled time administer the next dose; do not double the dose.
Asthma: Prophylaxis and chronic treatment of asthma in adults and children ≥12 years of age
Limitations of use: Not indicated for relief of acute bronchospasm
Substrate of CYP1A2 (minor), CYP2C9 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Fezolinetant. Risk X: Avoid combination
Lomitapide: Zileuton may increase the serum concentration of Lomitapide. Management: Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half with concurrent zileuton; the lomitapide dose may then be increased to a max adult dose of 30 mg/day (patients on lomitapide 5 mg/day may continue that dose). Risk D: Consider therapy modification
Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Risk X: Avoid combination
Propranolol: Zileuton may increase the serum concentration of Propranolol. Risk C: Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification
Warfarin: Zileuton may increase the serum concentration of Warfarin. Risk C: Monitor therapy
Zyflo CR: Improved absorption when administered with food. Management: Administer with food.
Uncontrolled asthma is associated with adverse events in pregnancy (increased risk of perinatal mortality, preeclampsia, preterm birth, low birth weight infants, cesarean delivery, and the development of gestational diabetes). Poorly controlled asthma or asthma exacerbations may have a greater fetal/maternal risk than what is associated with appropriately used asthma medications. Maternal treatment improves pregnancy outcomes by reducing the risk of some adverse events (eg, preterm birth, gestational diabetes). Maternal asthma symptoms should be monitored monthly during pregnancy. Agents other than zileuton are preferred for the treatment of asthma during pregnancy (ERS/TSANZ [Middleton 2020]; GINA 2021).
Data collection to monitor pregnancy and infant outcomes associated with asthma and the medications used to treat asthma in pregnancy is ongoing. Health care providers are encouraged to enroll exposed pregnant patients in the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (877-311-8972 or https://mothertobaby.org). Patients may also enroll themselves.
It is not known if zileuton is present in breast milk.
According to the manufacturer, due to the potential tumorigenicity of zileuton in animal studies, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Immediate release: Take without regard to meals.
Extended release: Take with food.
Hepatic transaminases (prior to initiation and during therapy), specifically monitor serum ALT (prior to initiation, once-a-month for the first 3 months, every 2 to 3 months for the remainder of the first year, and periodically thereafter for patients receiving long-term therapy)
Specific 5-lipoxygenase inhibitor which inhibits leukotriene formation. Leukotrienes augment neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction (which contribute to inflammation, edema, mucous secretion, and bronchoconstriction in the airway of the asthmatic).
Absorption: Well-absorbed
Distribution: 1.2 L/kg
Protein binding: 93%, primarily albumin
Metabolism: Hepatic and gastrointestinal; zileuton and N-dehydroxylated metabolite can be metabolized by CYP1A2, 2C9, and 3A4
Half-life elimination: ~3 hours
Time to peak: Immediate release: 1.7 hours
Excretion: Urine (~95% primarily as metabolites); feces (~2%)
Hepatic function impairment: The mean apparent plasma clearance of zileuton in subjects with hepatic impairment was approximately half the value of the healthy subjects. The percent binding of zileuton to plasma proteins after multiple dosing was significantly reduced in patients with moderate hepatic impairment.
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