Zyflo Drug Interactions: What to Avoid and What to Tell Your Doctor

Zyflo (zileuton) interacts with a number of other medications in ways that can be serious if not managed properly. Understanding these interactions before you start Zyflo — and making sure your entire care team is aware — is essential to safe treatment. This guide covers the most important Zyflo drug interactions for 2026, how they happen, and what steps to take.

Why Does Zyflo Interact With Other Drugs?

Zyflo (zileuton) is a weak inhibitor of CYP1A2 — a liver enzyme that metabolizes many other medications. When Zyflo slows down CYP1A2 activity, drugs that depend on this enzyme for clearance accumulate to higher-than-expected blood levels. Higher drug levels mean increased effects and increased risk of toxicity.

Zileuton is also metabolized by CYP1A2, 2C9, and 3A4 itself, meaning other drugs that affect these enzymes can alter zileuton levels. The result is a two-way interaction risk that requires attention from your prescriber and pharmacist.

Major Interaction #1: Theophylline

Severity: Major

Co-administration of Zyflo with theophylline is one of the most clinically significant drug interactions in pulmonary medicine. In a study of 16 healthy volunteers, adding zileuton to theophylline therapy:

Decreased theophylline clearance by approximately 50%

Approximately doubled theophylline AUC (area under the curve — total drug exposure)

Increased theophylline maximum concentration (Cmax) by 73%

Increased theophylline elimination half-life by 24%

Theophylline toxicity can cause serious symptoms including nausea, vomiting, seizures, and cardiac arrhythmias. If you take theophylline for asthma or COPD and your doctor wants to start Zyflo, your theophylline dose will need to be reduced by approximately one-half, and your theophylline blood levels will need to be monitored.

Note: Caffeine is closely related to theophylline (both are methylxanthines, and theophylline is a caffeine metabolite). Zileuton may also reduce caffeine metabolism, though no formal interaction studies exist. High caffeine intake while on Zyflo may lead to caffeine accumulation — consider moderating caffeine consumption.

Major Interaction #2: Propranolol (Beta-Blockers)

Severity: Major

Adding Zyflo to propranolol therapy dramatically increases propranolol exposure. In a study, a single 80 mg dose of propranolol in subjects taking zileuton resulted in:

42% decrease in propranolol clearance

52% increase in propranolol Cmax (maximum blood concentration)

104% increase in propranolol AUC (total drug exposure)

25% increase in propranolol elimination half-life

This significantly increases beta-blocking effects: slowing heart rate and lowering blood pressure more than intended. Patients on propranolol for hypertension, migraines, tremor, or heart rate control who start Zyflo will need their propranolol dose reduced and closely monitored.

Other beta-blockers: No formal interaction studies have been conducted with beta-blockers other than propranolol, but caution is warranted since they share similar metabolic pathways.

Moderate Interaction: Warfarin

Severity: Moderate

Zileuton affects the metabolism of the R-isomer of warfarin via CYP1A2 inhibition. This can increase warfarin's blood-thinning effect, raising bleeding risk. The S-isomer (the more potent anticoagulant) is metabolized by CYP2C9 and is not significantly affected.

If you take warfarin (Coumadin) for blood clot prevention or atrial fibrillation, your doctor should monitor your PT/INR (clotting time) more closely when you start or stop Zyflo. Warfarin dose adjustments may be needed.

Contraindicated Combinations

Certain drug combinations with Zyflo are contraindicated — meaning they should not be used together:

Fezolinetant (Veozah): Used for menopausal hot flashes. Zileuton increases fezolinetant blood levels via CYP1A2 inhibition, which can cause serious toxicity. These two drugs cannot be used together.

Flibanserin (Addyi): Used for hypoactive sexual desire disorder. Zileuton can increase flibanserin levels, causing severe hypotension (low blood pressure) and syncope. Contraindicated.

Other Drugs to Be Cautious With

Zileuton's CYP1A2 inhibition can affect several other medications. Discuss these with your doctor if you take any of them:

Duloxetine (Cymbalta): Antidepressant; zileuton may increase duloxetine levels via CYP1A2.

Alosetron (Lotronex): IBS medication; avoid concurrent use.

Melatonin: Zileuton increases melatonin levels via CYP1A2. If using melatonin supplements while on Zyflo, use with caution — effects may be stronger than expected.

Alcohol: Increases risk of both liver toxicity and CNS depression. Avoid alcohol entirely during Zyflo treatment.

Other hepatotoxic drugs: Drugs known to cause liver damage should be used with special caution alongside Zyflo. Discuss any medications that carry liver warnings with your prescriber.

What to Tell Your Doctor and Pharmacist Before Starting Zyflo

Before starting Zyflo, provide your prescriber and pharmacist with a complete list of:

All prescription medications (especially theophylline, propranolol or other beta-blockers, warfarin, and antidepressants)

Over-the-counter medications (including antihistamines, pain relievers, antacids)

Vitamins and supplements (melatonin, herbal supplements, fish oil)

Any history of liver disease, excessive alcohol use, or current liver enzyme abnormalities

See also: Zyflo Side Effects: What to Expect and When to Call Your Doctor