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Zileuton

Pronunciation

(zye LOO ton)

Dosage Forms

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:

Zyflo CR: 600 mg

Brand Names: U.S.

  • Zyflo
  • Zyflo CR

Pharmacologic Category

  • 5-Lipoxygenase Inhibitor

Pharmacology

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

Metabolism

Hepatic and gastrointestinal; zileuton and N-dehydroxylated metabolite can be metabolized via CYP1A2, 2C9, and 3A4

Excretion

Urine (~95% primarily as metabolites); feces (~2%)

Time to Peak

Immediate release: 1.7 hours

Half-Life Elimination

~3 hours

Protein Binding

93%, primarily albumin

Use: Labeled Indications

Prophylaxis and chronic treatment of asthma

Contraindications

Hypersensitivity to zileuton or any component of the formulation; active liver disease or transaminase elevations ≥3 times ULN

Dosing: Adult

Asthma: Oral:

Immediate release: 600 mg 4 times/day

Extended release: 1200 mg twice daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Asthma: Oral: Children ≥12 years: Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Contraindicated with hepatic impairment.

Administration

Immediate release: Administer without regard to meals.

Extended release: Do not crush, cut, or chew tablet; administer within 1 hour after morning and evening meals.

Dietary Considerations

Immediate release: Take without regard to meals.

Extended release: Take with food.

Storage

Store tablets at 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Aminophylline: Zileuton may increase the serum concentration of Aminophylline. Management: Reduce aminophylline dose by 50% upon initiation of zileuton therapy. If aminophylline is added to existing zileuton therapy, use a lower starting dose. Monitor for increased theophylline serum concentrations and effects. 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. Avoid combination

Pimozide: Zileuton may increase the serum concentration of Pimozide. Avoid combination

Propranolol: Zileuton may increase the serum concentration of Propranolol. Monitor therapy

Theophylline: Zileuton may increase the serum concentration of Theophylline. Management: Reduce theophylline dose by 50% upon initiation of zileuton therapy. If theophylline is added to existing zileuton therapy, use a lower starting dose. Monitor for increased serum concentrations and effects of theophylline. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Warfarin: Zileuton may increase the serum concentration of Warfarin. Monitor therapy

Adverse Reactions

>10%: Central nervous system: Headache (23% to 25%)

1% to 10%:

Cardiovascular: Chest pain

Central nervous system: Pain (8%), dizziness, fever, insomnia, malaise, nervousness, somnolence

Dermatologic: Pruritus, rash

Gastrointestinal: Dyspepsia (8%), diarrhea (5%), nausea (5% to 6%), abdominal pain (5%), constipation, flatulence, vomiting

Genitourinary: Urinary tract infection, vaginitis

Hematologic: Leukopenia (1% to 3%)

Hepatic: ALT increased (≥3 x ULN: 2% to 5%), hepatotoxicity

Neuromuscular & skeletal: Myalgia (7%), weakness (4%), arthralgia, hypertonia, neck pain/rigidity

Ocular: Conjunctivitis

Respiratory: Upper respiratory tract infection (9%), sinusitis (7%), pharyngolaryngeal pain (5%)

Miscellaneous: Hypersensitivity reactions, lymphadenopathy

<1% (Limited to important or life-threatening): Behavior/mood changes, hepatitis, hyperbilirubinemia, jaundice, liver failure, suicidality, suicide

Warnings/Precautions

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:

• Elderly: 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.

Monitoring Parameters

Hepatic transaminases (prior to initiation and during therapy), specifically monitor serum ALT (prior to initiation, once-a-month for the first 3 months, every 2-3 months for the remainder of the first year, and periodically thereafter for patients receiving long-term therapy)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. If a leukotriene modifier is needed during pregnancy, other agents are preferred (ACOG, 2008).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, dyspepsia, pyrosis, pharyngitis, rhinitis, rhinorrhea, or sternutation. Have patient report immediately to prescriber signs of depression (eg, depression, suicidal ideation, anxiety, emotional instability, illogical thinking), signs of hepatic impairment, angina, insomnia, or behavioral changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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