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

Like all prescription medications, Zyflo (zileuton) can cause side effects. Most people who take Zyflo tolerate it well, but there are a few important risks you and your doctor need to monitor closely — particularly regarding your liver and mental health. This guide gives you a clear, straightforward picture of what to expect.

Common Side Effects of Zyflo

In clinical trials of Zyflo CR (the extended-release formulation), the most frequently reported side effects occurring in at least 5% of patients and more often than placebo were:

Sinusitis (6.5%): Inflammation or infection of the sinuses, which can cause sinus pressure, congestion, and facial pain.

Nausea (5%): Stomach upset and nausea, particularly when starting the medication. Taking it with food may help.

Pharyngolaryngeal pain (5%): Soreness or pain in the throat and voice box area.

Other side effects reported in clinical trials (occurring in more than 1% of patients) include:

Headache

Abdominal pain and upset stomach

Dizziness

Arthralgia (joint pain)

Constipation or flatulence

Rash or urticaria (hives)

Serious Side Effect #1: Liver Problems (Hepatotoxicity)

The most important serious side effect of Zyflo is potential damage to the liver (hepatotoxicity). In placebo-controlled clinical trials, approximately 1.9-2.5% of Zyflo-treated patients showed ALT (a liver enzyme) elevations of 3 times the upper limit of normal or greater. In most cases, stopping the medication caused liver enzymes to return to normal.

Post-marketing reports have documented more serious liver injury, including jaundice, hyperbilirubinemia, ALT elevations greater than 8 times the upper limit of normal, and rare cases of life-threatening liver injury requiring hospitalization.

Call your doctor immediately if you experience any of these liver warning signs:

Yellowing of the skin or whites of the eyes (jaundice)

Dark yellow or brown urine

Light-colored or clay-colored stools

Pain or tenderness in the upper right side of your abdomen

Unusual tiredness or weakness

Loss of appetite accompanied by persistent nausea

This is why regular liver function testing is required while on Zyflo. Your doctor should check your ALT levels before you start, then every 2-3 months for the first year, then periodically. Never skip these lab appointments.

Important: Avoid alcohol completely while taking Zyflo. Alcohol adds to the liver stress from zileuton and significantly increases your risk of liver toxicity.

Serious Side Effect #2: Neuropsychiatric Events

Like other leukotriene modifiers, Zyflo has been associated with neuropsychiatric events in post-marketing reports. These include sleep disorders and behavioral changes. These effects can occur in people with or without a prior history of mental health conditions and may persist even after stopping the medication.

Notify your doctor promptly if you notice:

Unusual changes in mood, behavior, or thinking

Trouble sleeping (insomnia) or very vivid dreams

Anxiety, depression, or agitation that is new or worsening

Thoughts of self-harm (seek emergency care immediately)

Serious Side Effect #3: Allergic Reactions

Rarely, Zyflo can cause serious allergic reactions. Get emergency medical help right away if you have:

Hives, rash, or severe itching

Difficulty breathing or swallowing

Swelling of the face, lips, tongue, or throat

Who Should Not Take Zyflo?

Zyflo is contraindicated in:

People with active liver disease

People with liver transaminases (ALT/AST) already elevated to ≥3x the upper limit of normal

People who are allergic to zileuton or any ingredient in Zyflo

Children under 12 years old (not approved for this age group)

Tips for Reducing Side Effects

For GI side effects (nausea, abdominal pain): Take Zyflo CR with food, within 1 hour of morning and evening meals.

For liver protection: Avoid alcohol completely. Keep all liver monitoring appointments. Report any symptoms promptly.

For neuropsychiatric symptoms: Let family members or caregivers know you're starting a new medication and ask them to let you know if they notice mood or behavior changes you might not be aware of.

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