ZYFLO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZYFLO (ZYFLO).
Zyflo (zileuton) is a specific inhibitor of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. This reduces the synthesis of leukotrienes (LTA4, LTB4, LTC4, LTD4, LTE4), which are potent bronchoconstrictors and pro-inflammatory mediators.
| Metabolism | Zileuton is extensively metabolized primarily via cytochrome P450 isoenzymes, including CYP1A2, CYP2C9, and CYP3A4. The major metabolites are inactive glucuronide conjugates. |
| Excretion | Renal (approximately 0.5% unchanged); biliary/fecal (approximately 75% as metabolites); the remainder is metabolized and eliminated via other routes. |
| Half-life | Terminal half-life is approximately 2.5 hours in healthy adults; clinical context: requires dosing 4 times daily due to short half-life. |
| Protein binding | Approximately 93% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 1.2 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 100% (well absorbed, but extensive first-pass metabolism). |
| Onset of Action | Oral: clinical improvement in asthma symptoms may be observed within 2 to 4 weeks; not indicated for acute bronchospasm. |
| Duration of Action | Duration is approximately 8-12 hours; requires t.i.d. or q.i.d. dosing to maintain therapeutic effect. |
| Molecular Weight | 236.29 |
600 mg orally four times daily.
| Dosage form | TABLET |
| Renal impairment | No dosage adjustment required for renal impairment. |
| Liver impairment | Contraindicated in patients with active liver disease or transaminase elevations >3x ULN. For mild hepatic impairment (Child-Pugh A), no adjustment; moderate to severe (Child-Pugh B or C) not studied, use with caution. |
| Pediatric use | Approved for age >=12 years: 600 mg orally four times daily. For age <12 years, safety and efficacy not established. |
| Geriatric use | No specific dose adjustment, but monitor for hepatic effects due to age-related decline in liver function. |
| 1st trimester | Insufficient data; avoid use unless benefit outweighs risk. Zileuton is a 5-lipoxygenase inhibitor; animal studies show fetal harm at high doses. |
| 2nd trimester | Limited data; avoid use unless benefit outweighs risk. Potential for constriction of ductus arteriosus theoretically but not reported. |
| 3rd trimester | Avoid use near term; potential for premature closure of ductus arteriosus and other adverse effects. |
Clinical note
Comprehensive clinical and safety monograph for ZYFLO (ZYFLO).
| Placental transfer | Data suggest low placental transfer in animal studies; human data absent. Molecular weight (236.29 Da) < 500 Da suggests potential for transfer. |
| Breastfeeding | Zileuton is excreted into breast milk in low concentrations; however, no adverse effects in infants have been reported. Use with caution, especially in preterm or ill infants. |
■ FDA Black Box Warning
None
| Serious Effects |
Active liver diseaseElevated transaminases (≥3 times upper limit of normal)Hypersensitivity to zileuton or any component
| Precautions | Hepatotoxicity: Elevations of liver enzymes have been reported; monitoring of hepatic function (ALT) is recommended before and during therapy. Zileuton should be discontinued if signs of liver injury occur., Neuropsychiatric events: Cases of sleep disorders, behavior changes, and depression have been reported, especially in adolescents., Not for reversal of acute bronchospasm or status asthmaticus., May interfere with the metabolism of drugs metabolized by CYP1A2 (e.g., theophylline, warfarin, tacrine), requiring dose adjustment or monitoring. |
| Food/Dietary | No significant food interactions. Avoid alcohol due to hepatotoxicity risk. Maintain consistent intake of caffeine-containing products as zileuton may increase caffeine levels. |
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| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Pregnancy Category B. Animal studies have not demonstrated fetal risk, but there are no adequate and well-controlled studies in pregnant women. Zileuton should be used during pregnancy only if clearly needed. |
| Fetal Monitoring | Monitor liver function tests (ALT, AST) at baseline and periodically during therapy due to risk of hepatotoxicity. Monitor for signs of bronchospasm and asthma exacerbation. |
| Fertility Effects | In animal studies, no impairment of fertility was observed. There are no human data regarding effects on fertility. |
| Clinical Pearls | ZYFLO (zileuton) is a 5-lipoxygenase inhibitor used for prophylaxis of chronic asthma. It is not a rescue therapy. Monitor hepatic function (ALT) at initiation and periodically; discontinue if ALT >3x ULN. Cytochrome P450 (CYP1A2) inhibitor; reduce dose of theophylline, warfarin, and propranolol. Contraindicated in active liver disease or transaminase elevation >3x ULN. May cause dyspepsia and headache. |
| Patient Advice | Take ZYFLO exactly as prescribed, usually 4 times daily with or without food. · Do not use to treat acute asthma attacks; have a rescue inhaler available. · Report signs of liver problems: yellowing skin/eyes, dark urine, abdominal pain, fatigue. · Avoid alcohol and other hepatotoxic substances. · Inform all healthcare providers you are taking zileuton. · Do not stop or change dose without consulting your doctor. |