Zileuton

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take zileuton with a full glass of water.

Zileuton tablets and extended-release tablets contain the same amount of the drug, but they are not taken in the same way. Follow your doctor's instructions.

Zileuton tablets are usually taken 4 times daily, with meals and at bedtime. Zileuton tablets may be swallowed whole or split in half to make swallowing easier.

Zileuton extended-release tablets are usually taken twice daily, within 1 hour after your morning and evening meals.

Do not crush, chew, or break an extended-release tablet. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time.

Do not use zileuton to treat an asthma attack that has already begun. It will not work fast enough. Use only a fast acting inhalation medication. Talk with your doctor if any of your asthma medications do not seem to work as well in treating or preventing attacks.

It may take up to a few weeks before your symptoms improve. Keep using the medication as directed even if you feel fine or have no symptoms. Having no asthma symptoms is a sign that the medication is working.

Asthma is often treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice, even if you have no asthma symptoms.

Call your doctor right away if you feel that this medicine is not working as well as usual, or if it makes your condition worse. If it seems like you need to use more of any of your medications in a 24-hour period, talk with your doctor.

You may need regular medical tests to be sure this medication is not causing harmful effects. Visit your doctor regularly.

Store at room temperature away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe forms of some of the side effects listed in this medication guide.

Avoid situations or activities that may trigger an asthma attack.

Avoid drinking alcohol. It may increase your risk of liver damage.

Storage

Oral

Conventional (immediate-release) tablets: 20–25°C; protect from light.1

Extended-release tablets: 20–25°C (may be exposed to 15–30°C); protect from light.46

Zileuton is used by patients with mild-to-moderate chronic asthma to decrease the symptoms of asthma and the number of acute asthma attacks. However, zileuton should not be taken to relieve an asthma attack that has already started.

zileuton is available only with your doctor's prescription.

Zileuton immediate-release tablets (Zyflo(R)) were withdrawn from the U. S. market by Critical Therapeutics on February 12, 2008. The extended-release formulation of zileuton (Zyflo CR(R)), also manufactured by Critical Therapeutics, Inc, is still available.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For zileuton, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to zileuton or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of zileuton in children younger than 12 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of zileuton in the elderly. However, elderly patients are more likely to have age-related liver disease, and zileuton should not be used in patients with this condition.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking zileuton, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using zileuton with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amiodarone
• Anagrelide
• Astemizole
• Ceritinib
• Clarithromycin
• Eliglustat
• Eltrombopag
• Idelalisib
• Pimozide
• Piperaquine
• Pixantrone
• Theophylline
• Tizanidine

Using zileuton with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Propranolol
• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using zileuton with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use zileuton, or give you special instructions about the use of food, alcohol, or tobacco.

• Tobacco

Other Medical Problems

The presence of other medical problems may affect the use of zileuton. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol use, severe or
• Liver disease, history of—Use with caution. The chance of serious side effects may be increased.

• Liver disease, active—zileuton should not be used with this condition.

The use of Zileuton Extended-Release Tablets is contraindicated in patients with:

• Active liver disease or persistent hepatic function enzyme elevations greater than or equal to 3 times the upper limit of normal (≥3xULN) [see Warnings and Precautions (5), and Use in Specific Populations (8.7)].
• A history of allergic reaction to Zileuton or any of the ingredients of Zileuton Extended-Release Tablets (e.g., rash, eosinophilia, etc.).

Hepatotoxicity:  Elevations of one or more hepatic function enzymes and bilirubin may occur during Zileuton Extended-Release Tablets therapy [see Warnings and Precautions (5)].

The most commonly occurring adverse reactions (≥5%) with Zileuton Extended-Release Tablets are sinusitis, nausea, and pharyngolaryngeal pain.

6.1   Short-Term Clinical Studies Experience

The safety data described below reflect exposure to Zileuton Extended-Release Tablets in 199 patients for 12 weeks duration.  In a 12-week, randomized, double-blind, placebo-controlled trial in adults and adolescents 12 years of age and older with asthma, patients received Zileuton Extended-Release Tablets two 600 mg tablets (n=199) or placebo (n=198) twice daily by mouth.  Eighty-three percent of patients were white, 48% were male, and the mean age was 34 years.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The most commonly reported adverse reactions (occurring at a frequency of ≥5%) in Zileuton Extended-Release Tablets-treated patients and at a frequency greater than placebo-treated patients are reflected in Table 1.

Less common adverse reactions occurring at a frequency ≥1% and more often in the Zileuton Extended-Release Tablets group than in the placebo group included gastrointestinal disorders (upper abdominal pain, diarrhea, dyspepsia, vomiting), rash, hypersensitivity, and hepatotoxicity.

There were no differences in the incidence of adverse reactions based upon gender.  The clinical trials did not include sufficient numbers of patients <18 years of age or non-Caucasians to determine whether there is any difference in adverse reactions based upon age or race.

Hepatotoxicity

In the 12-week placebo-controlled trial, the incidence of ALT elevations (≥3xULN) was 2.5% (5 of 199) in the Zileuton Extended-Release Tablets group, compared to 0.5% (1 of 198) in the placebo group.  In the Zileuton Extended-Release Tablets group, the majority of ALT elevations (60%) occurred in the first month of treatment, and in 2 of the 5 patients in the Zileuton Extended-Release Tablets group, ALT elevations were detected 14 days after completion of the 3-month study treatment.  The levels returned to <2xULN or normal within 9 and 12 days, respectively.  The ALT elevations in the other 3 patients were observed to return to <2xULN or normal within 15, 19, and 31 days after Zileuton Extended-Release Tablets discontinuation.  There appeared to be no clinically relevant relationship between the time of onset and the magnitude of the first elevation or the magnitude of first elevation and time to resolution.  The hepatic function enzyme elevations attributed to Zileuton Extended-Release Tablets did not result in any cases of jaundice, development of chronic liver disease, or death in this clinical trial.

6.2   Long-Term Clinical Studies Experience

The safety of Zileuton Extended-Release Tablets was evaluated in one 6-month, randomized, double-blind, placebo-controlled clinical trial in adults and adolescents 12 years of age and older with asthma.  Patients received two 600 mg Zileuton Extended-Release Tablets (n=619) or placebo (n=307) twice daily by mouth along with usual asthma care.  Eighty-six percent of patients were white, 40% were male, and the overall mean age was 36.

The rate and type of adverse reactions observed in this study were comparable to the adverse reactions observed in the 12-week study.  Other commonly reported adverse reactions (occurring at a frequency of ≥5%) in Zileuton Extended-Release Tablets-treated patients and at a frequency greater than placebo-treated patients included the following: headache (23%), upper respiratory tract infection (9%), myalgia (7%), and diarrhea (5%) compared to 21%, 7%, 5% and 2%, respectively, in the placebo-treated group.

ALT elevations (≥3xULN) were observed in 1.8% of patients treated with Zileuton Extended-Release Tablets compared to 0.7% in patients treated with placebo.  The majority of elevations (82%) were reported within the first 3 months of treatment and resolved within 21 days for most of these patients after discontinuation of the drug.  The hepatic function enzyme elevations attributed to Zileuton Extended-Release Tablets did not result in any cases of jaundice, development of chronic liver disease, or death in this clinical trial.

Occurrences of low white blood cell (WBC) count (<3.0 x 109/L) were observed in 2.6% (15 of 619) of the Zileuton Extended-Release Tablets-treated patients and in 1.7% (5 of 307) of the placebo-treated patients. The WBC counts returned to normal or baseline following discontinuation of Zileuton Extended-Release Tablets.  The clinical significance of these findings is not known.

6.3   Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Zileuton immediate-release tablets and may be applicable to Zileuton Extended-Release Tablets.  Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship. 

Cases of severe hepatic injury have been reported in patients taking Zileuton immediate-release tablets.  These cases included death, life-threatening liver injury with recovery, symptomatic jaundice, hyperbilirubinemia, and elevations of ALT >8xULN.

Cases of sleep disorders and behavior changes have also been reported [see Warnings and Precautions (5.2.)]. 

(zye LOO ton)

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

Generic: 600 mg

• Zyflo
• Zyflo CR

• 5-Lipoxygenase Inhibitor

Asthma: Prophylaxis and chronic treatment of asthma in adults and children ≥12 years of age

Limitations of use: Not indicated for relief of acute bronchospasm

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.

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

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

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 is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 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

Applies to zileuton: oral tablet, oral tablet extended release

Along with its needed effects, zileuton may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking zileuton:

• Flu-like symptoms
• itching
• right upper stomach pain
• unusual tiredness or weakness
• yellow eyes or skin

• Attack, assault, or force
• attempts at killing oneself
• discouragement
• dry mouth
• fear or nervousness
• feeling sad or empty
• hyperventilation
• irregular heartbeats
• irritability
• lack of appetite
• loss of interest or pleasure
• restlessness
• seeing, hearing, or feeling things that are not there
• shakiness in the legs, arms, hands, or feet
• shortness of breath
• sleeplessness
• tiredness
• trembling or shaking of the hands or feet
• trouble with concentrating
• trouble with sleeping
• unable to sleep

Some side effects of zileuton may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Cough
• fever
• headache
• nausea
• pain or tenderness around the eyes and cheekbones
• stuffy or runny nose
• tightness of the chest or wheezing
• troubled breathing
• upset stomach

• Abdominal or stomach pain
• sore throat
• weakness