ZYFLO CR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZYFLO CR (ZYFLO CR).
Zileuton is a selective inhibitor of 5-lipoxygenase (5-LO), thereby inhibiting leukotriene biosynthesis, including leukotrienes LTB4, LTC4, LTD4, and LTE4, which are bronchoconstrictors and pro-inflammatory mediators.
| Metabolism | Primarily metabolized by CYP1A2, CYP2C9, and CYP3A4 to inactive metabolites; also undergoes glucuronidation and sulfation. |
| Excretion | Primarily hepatic metabolism; approximately 10% excreted unchanged in urine, 80% as metabolites in feces via biliary elimination. |
| Half-life | Terminal elimination half-life is approximately 5.5 hours in healthy adults; may be prolonged in patients with hepatic impairment. |
| Protein binding | Approximately 93% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 1.5 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 40-50% due to first-pass metabolism. |
| Onset of Action | Therapeutic effect on asthma symptoms typically begins within 1-2 weeks of oral administration. |
| Duration of Action | Duration of effect is 12 hours; requires twice-daily dosing for continuous asthma control. |
Adults: 600 mg orally twice daily (total daily dose 1200 mg).
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | No dose adjustment required for renal impairment; drug is hepatically metabolized. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B or C: Reduce dose to 600 mg once daily or avoid use; not recommended in severe hepatic impairment. |
| Pediatric use | Not approved for patients <12 years. Safety and efficacy not established. |
| Geriatric use | No specific dose adjustment; monitor for hepatic effects and drug interactions due to CYP inhibition; use with caution. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ZYFLO CR (ZYFLO CR).
| Breastfeeding | Zileuton is excreted in human milk; the milk-to-plasma ratio is not reported. Due to potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, considering the importance of the drug to the mother. |
| Teratogenic Risk | FDA Pregnancy Category C. In animal studies, zileuton (active ingredient) caused fetal malformations and developmental delays at doses below human exposure. There are no adequate and well-controlled studies in pregnant women. Zileuton should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Risks may be higher during the first trimester due to organogenesis, but potential adverse effects persist throughout pregnancy. |
■ FDA Black Box Warning
ZYFLO CR can cause hepatotoxicity. Serum ALT should be monitored prior to initiation and periodically during therapy. Discontinue if evidence of liver injury or ALT > 3 times upper limit of normal persists.
| Serious Effects |
Active liver disease or ALT > 3 times upper limit of normal, history of hypersensitivity to zileuton or any component of the formulation, concomitant use with CYP1A2 substrates (e.g., theophylline, tizanidine) without dose adjustment.
| Precautions | Hepatotoxicity (elevated liver enzymes), neuropsychiatric events (sleep disorders, behavior changes), increased risk of infections (especially varicella-zoster), hypersensitivity reactions, including eosinophilic conditions. |
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| Fetal Monitoring | Monitor liver function tests (ALT, AST) at baseline and periodically during therapy, especially in pregnancy due to potential hepatic toxicity. Monitor fetal growth and development via ultrasound and fetal heart rate monitoring as clinically indicated. Observe for any signs of maternal hepatotoxicity or adverse fetal effects. |
| Fertility Effects | No specific human studies on fertility with zileuton. Animal studies have shown no impairment of fertility at clinically relevant exposures. However, due to potential hormonal or metabolic effects, caution is advised in patients attempting conception. |