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ZILEUTON

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Zileuton is an orally active 5-lipoxygenase redox inhibitor. 5-Lipoxygenase is the first enzymatic step in the conversion of arachidonic acid to leukotrienes, and the inhibition of this pathway prevents generation of all leukotrienes as well as other biologically-active 5-lipoxygenase metabolites, such as 5-hydroxyeicosatetraenoic acid (5-HETE) and 5-hydroxyperoxyeicosatetraenoic acid (5-HPETE).

Specific Substances

    1) A-64077
    2) Abbott-64077
    3) Molecular Formula: C11-H12-N2-O2-S
    4) CAS 111406-87-2

Available Forms Sources

    A) FORMS
    1) Zileuton is available as 600-milligram immediate-release and extended-release tablets (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014; Prod Info ZYFLO(R) oral tablets, 2009).
    B) USES
    1) Zileuton is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014; Prod Info ZYFLO(R) oral tablets, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Zileuton, an orally active leukotriene synthesis inhibitor, is used for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Zileuton is NOT intended for the treatment of an acute asthma attack.
    B) PHARMACOLOGY: Zileuton is an inhibitor of 5-lipoxygenase and can inhibit leukotriene (ie, LTB(4), LTC(4), LTD(4) and LTE(4)) formation. Leukotrienes have many biologic effects. In asthmatic patients, leukotrienes can promote inflammation, edema, mucus secretions and bronchoconstriction.
    C) EPIDEMIOLOGY: Exposure may occur.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects (5% or greater) include sinusitis, nausea, and pharyngolaryngeal pain.
    2) SERIOUS: Other potentially serious adverse events include liver function abnormalities (increased liver enzymes ) leading to clinically significant liver injury. Neuropsychiatric events (ie, sleep disorders and behavioral changes) have also been reported.
    3) DRUG INTERACTIONS: A significant risk for drug interactions exist via P450 CYP3A4. Zileuton has been shown to decrease the clearance and increase the free concentration of the following drugs: theophylline, warfarin, propranolol and terfenadine.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited human data. ANIMAL OVERDOSE: (Dogs): Nephritis developed at 1000 mg/kg (approximately 12 times the daily human dose). No deaths occurred.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Sinusitis and pharyngolaryngeal pain are commonly reported with zileuton therapy.
    0.2.20) REPRODUCTIVE
    A) Zileuton is classified as US FDA Pregnancy Category C. In animal developmental studies, reduced body weight and increased skeletal variations have been observed. Cleft palate and stillbirths have also been observed in animal studies.

Laboratory Monitoring

    A) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    B) Monitor liver enzymes after a significant overdose or as indicated. The ALT (SGPT) liver enzyme test is considered the most sensitive indicator of liver injury for extended-release zileuton.
    C) Monitor neurologic function as necessary.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Limited overdose information. Hepatic injury has been reported with therapeutic use. Obtain baseline liver enzymes following a significant exposure or as indicated. Monitor fluids and electrolyte status in patients that develop significant vomiting and/or diarrhea. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Treat persistent diarrhea with antidiarrheals.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Neuropsychiatric (ie, sleep disorders, behavior changes) events have also developed with therapy. Monitor neurologic function. HYPERSENSITIVITY has been reported infrequently. MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    C) DECONTAMINATION
    1) PREHOSPITAL: Zileuton is unlikely to cause significant toxicity following a minor exposure; prehospital gastrointestinal decontamination may not be necessary. Vomiting may develop following a significant exposure.
    2) HOSPITAL: Severe toxicity is not anticipated. Gastrointestinal decontamination may not be necessary. Consider activated charcoal following a recent significant overdose, the patient is not vomiting and airway can be maintained or protected.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary unless underlying respiratory disease is exacerbated or poorly controlled.
    E) ANTIDOTE
    1) There is no known antidote for zileuton.
    F) PHARMACOKINETICS
    1) IMMEDIATE RELEASE: Rapidly absorbed following oral administration. Highly bound to plasma proteins (93%), mainly to albumin with minor binding to alpha-1-acid glycoprotein. Volume of distribution is 1.2 L/kg. EXCRETION: Following oral administration, 94.5% of the a radiolabeled dose was recovered in the urine and 2.2% was recovered in the feces. METABOLISM: Metabolized in the liver, primarily via glucuronide conjugation. In vitro data have demonstrated that zileuton and its N-dehydroxylated metabolite is oxidatively metabolized by the cytochrome P450 isoenzymes CYP1A2, CYP2C9, and CYP3A4.
    2) Immediate-release: Cmax: 4.98 mcg/mL; Tmax: 1.7 hours. Extended-release: Tmax: Following a single 1200 mg dose is 2.1 hours under fasting conditions and 4.3 hours under fed conditions.
    3) ELIMINATION HALF-LIFE: Immediate-release: Predominantly limited by the rate of metabolism; terminal half-life is 2.5 hours. Extended-release: Terminal half-life is 3.2 hours.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent minor exposure (1 to 2 tablets) that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolytes, fluid balance and liver enzymes. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for ongoing severe vomiting, profuse diarrhea, electrolyte abnormalities and elevations in liver enzymes. Patients with evidence of significant neuropsychiatric changes may require close monitoring and drug therapy as needed.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected zileuton overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are limited but are anticipated to be similar to reported side effects of the medication. Patients taking zileuton may have significant respiratory disease and may be receiving other drugs that may produce significant adverse events.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hepatotoxicity or neuropsychiatric changes (eg, toxic alcohols, antipsychotic medications).

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. An ingestion by an adult of 11 to 15 immediate release zileuton tablets (6.6 to 9 g) produced no permanent clinical events. THERAPEUTIC DOSE: ADULTS and CHILDREN 12 YEARS OF AGE AND OLDER: IMMEDIATE-RELEASE: 600 mg orally 4 times daily for a total daily dose of 2400 mg. EXTENDED-RELEASE: Two 600 mg extended-release tablets twice daily for a total daily dose of 2400 mg.

Clinical Effects

Summary Of Exposure

    A) USES: Zileuton, an orally active leukotriene synthesis inhibitor, is used for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Zileuton is NOT intended for the treatment of an acute asthma attack.
    B) PHARMACOLOGY: Zileuton is an inhibitor of 5-lipoxygenase and can inhibit leukotriene (ie, LTB(4), LTC(4), LTD(4) and LTE(4)) formation. Leukotrienes have many biologic effects. In asthmatic patients, leukotrienes can promote inflammation, edema, mucus secretions and bronchoconstriction.
    C) EPIDEMIOLOGY: Exposure may occur.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects (5% or greater) include sinusitis, nausea, and pharyngolaryngeal pain.
    2) SERIOUS: Other potentially serious adverse events include liver function abnormalities (increased liver enzymes ) leading to clinically significant liver injury. Neuropsychiatric events (ie, sleep disorders and behavioral changes) have also been reported.
    3) DRUG INTERACTIONS: A significant risk for drug interactions exist via P450 CYP3A4. Zileuton has been shown to decrease the clearance and increase the free concentration of the following drugs: theophylline, warfarin, propranolol and terfenadine.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited human data. ANIMAL OVERDOSE: (Dogs): Nephritis developed at 1000 mg/kg (approximately 12 times the daily human dose). No deaths occurred.

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Sinusitis and pharyngolaryngeal pain are commonly reported with zileuton therapy.
    3.4.2) HEAD
    A) WITH THERAPEUTIC USE
    1) Sinusitis was a common adverse reaction (equal to or greater than 5%) reported with zileuton therapy (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Pharyngolaryngeal pain was common adverse reaction (equal to or greater than 5%) reported with zileuton therapy (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Phlebitis was described in 1 of 132 asthmatic patients treated with zileuton 600 mg 4 times daily (Israel et al, 1996).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) In a long-term randomized, double-blind, placebo-controlled clinical trial in adults and children 12 years of age and older with asthma, upper respiratory tract infection was reported in 9% of patients (n=619) treated with 1200 mg extended-release zileuton compared to 7% in the placebo-treated group (n=307) (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a long-term randomized, double-blind, placebo-controlled clinical trial in adults and children 12 years of age and older with asthma, headache was reported in 23% of patients (n=619) receiving 1200 mg extended-release zileuton compared to 21% in the placebo-treated group (n=307) (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Abdominal pain, vomiting, dyspepsia and diarrhea have been reported infrequently during zileuton therapy (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea (5%) was one of the most common adverse effects (equal to or greater than 5%) reported with zileuton therapy (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a long-term randomized, double-blind, placebo-controlled clinical trial in adults and children 12 years of age and older with asthma, diarrhea was reported in 5% of patients (n=619) receiving 1200 mg extended-release zileuton compared to 2% in the placebo-treated group (n=307) (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevations in liver enzymes and bilirubin may develop during zileuton therapy. In postmarketing experience, zileuton immediate-release tablets have resulted in cases of severe hepatic injury including death, life-threatening liver injury with recovery, symptomatic jaundice, hyperbilirubinemia, and elevations of ALT of greater than 8 times the upper limits of normal (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    b) In controlled and uncontrolled clinical trials involving more than 5,000 patients treated with immediate-release zileuton tablets, the overall rate of ALT elevations three times the upper limit of normal or greater was 3.2%. One patient developed symptomatic hepatitis with jaundice which resolved with the discontinuation of zileuton. Three patients with elevated transaminases developed mild hyperbilirubinemia that was less than 3 times the upper limit of normal. There was no evidence of hypersensitivity or other clinical findings that would explain the events observed (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) IMPOTENCE
    1) WITH THERAPEUTIC USE
    a) Impotence was described in 1 of 134 asthmatic patients treated with zileuton 400 mg 4 times daily (Israel et al, 1996).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHRITIS
    a) Nephritis was reported in dogs after administration of 1000 mg/kg of zileuton (approximately 12 times the systemic exposure achieved at the maximum recommended human daily oral dose) (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia was described in 2 of 132 asthmatic patients treated with zileuton 600 mg 4 times daily (Israel et al, 1996).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Hives in association with abnormal liver function tests were described in 1 of 92 asthmatic patients treated with zileuton (Israel et al, 1993).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash has been reported at a frequency of greater than 1% in patients treated with extended release zileuton (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) In a long-term randomized, double-blind, placebo-controlled clinical trial in adults and children 12 years of age and older with asthma, myalgia was reported in 7% of patients (n=619) receiving 1200 mg extended-release zileuton compared to 5% in the placebo-treated group (n=307) (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity has been reported at a frequency of greater than 1% in patients treated with extended release zileuton (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Zileuton is classified as US FDA Pregnancy Category C. In animal developmental studies, reduced body weight and increased skeletal variations have been observed. Cleft palate and stillbirths have also been observed in animal studies.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) SKELETAL MALFORMATION
    a) RATS: Developmental studies have indicated adverse effects (reduced body weight and increased skeletal variations) in rats at an oral dose of 300 mg/kg/day (providing approximately 10 times the systemic exposure achieved at the maximum recommended human daily oral dose) (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    b) In animal studies, zileuton and/or its metabolites cross the placental barrier (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    2) CLEFT PALATE
    a) Three of 118 (2.5%) rabbit fetuses had cleft palates at an oral dose of 150 mg/kg/day (equivalent to the maximum recommended human daily oral dose on a mg/M(2) basis) (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) SUMMARY
    1) There are no adequate and well controlled studies in pregnant women (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    B) PREGNANCY CATEGORY
    1) Zileuton is classified as US FDA Pregnancy Category C (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    C) ANIMAL STUDIES
    1) In a perinatal/postnatal animal study, reduced pup survival and growth were observed at an oral dose at approximately 10 times the maximum recommended human daily oral dose (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) SUMMARY
    1) It is unknown if zileuton is excreted in human breast milk; however, zileuton and its metabolites are excreted in rat milk. Because of the potential for tumorigenicity in animal studies, a decision to discontinue nursing or zileuton should be taken into consideration given the importance of the drug to the mother (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LIVER CARCINOMA
    1) MICE - In 2-year carcinogenicity studies, increases in the incidence of liver, kidney, and vascular tumors in female mice and a trend towards an increase in the incidence of liver tumors in male mice were observed at 450 milligrams/kilogram/day (providing approximately 4 times [females] or 7 times [males] the systemic exposure achieved at the maximum recommended human daily oral dose) (Prod Info Zyflo(TM) Filmtab(R), zileuton, 1999).
    B) RENAL CARCINOMA
    1) RATS - Increased incidence of kidney tumors were observed in both sexes at 170 milligrams/kilogram/day (providing approximately 14 times [females] or 6 times [males] the systemic exposure achieved at the maximum recommended human daily oral dose) (Prod Info Zyflo(TM) Filmtab(R), zileuton, 1999).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    B) Monitor liver enzymes after a significant overdose or as indicated. The ALT (SGPT) liver enzyme test is considered the most sensitive indicator of liver injury for extended-release zileuton.
    C) Monitor neurologic function as necessary.
    4.1.2) SERUM/BLOOD
    A) Monitor liver enzymes after a significant overdose or as indicated. The ALT (SGPT) liver enzyme test is considered the most sensitive indicator of liver injury for extended-release zileuton (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for ongoing severe vomiting, profuse diarrhea, electrolyte abnormalities and elevations in liver enzymes. Patients with evidence of significant neuropsychiatric changes may require close monitoring and drug therapy as needed.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent minor exposure (1 to 2 tablets) that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolytes, fluid balance and liver enzymes. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    B) Monitor liver enzymes after a significant overdose or as indicated. The ALT (SGPT) liver enzyme test is considered the most sensitive indicator of liver injury for extended-release zileuton.
    C) Monitor neurologic function as necessary.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Zileuton is unlikely to cause significant toxicity following a minor exposure; prehospital gastrointestinal decontamination may not be necessary.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Limited overdose information. Hepatic injury has been reported with therapeutic use. Obtain baseline liver enzymes following a significant exposure or as indicated. Monitor fluids and electrolyte status in patients that develop significant vomiting and/or diarrhea. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Treat persistent diarrhea with antidiarrheals.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Neuropsychiatric (ie, sleep disorders, behavior changes) events have also developed with therapy. Monitor neurologic function. HYPERSENSITIVITY has been reported infrequently. MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    B) MONITORING OF PATIENT
    1) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    2) Monitor liver enzymes after a significant overdose or as indicated. The ALT (SGPT) liver enzyme test is considered the most sensitive indicator of liver injury for extended-release zileuton (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    3) Monitor neurologic function as necessary.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis is UNLIKELY to be effective because of extensive protein binding (93%) of zileuton (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. An ingestion by an adult of 11 to 15 immediate release zileuton tablets (6.6 to 9 g) produced no permanent clinical events. THERAPEUTIC DOSE: ADULTS and CHILDREN 12 YEARS OF AGE AND OLDER: IMMEDIATE-RELEASE: 600 mg orally 4 times daily for a total daily dose of 2400 mg. EXTENDED-RELEASE: Two 600 mg extended-release tablets twice daily for a total daily dose of 2400 mg.

Therapeutic Dose

    7.2.1) ADULT
    A) ASTHMA
    1) IMMEDIATE-RELEASE TABLETS: 600 mg orally 4 times daily; a total daily dose of 2400 mg (Prod Info ZYFLO(R) oral tablets, 2012).
    2) EXTENDED-RELEASE TABLETS: 1200 mg orally twice daily within 1 hour after morning and evening meals; a total daily dose of 2400 mg. Do NOT chew, crush or cut the tablets (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    7.2.2) PEDIATRIC
    A) ASTHMA
    1) IMMEDIATE-RELEASE TABLETS: 12 years and older, 600 mg orally 4 times daily; a total daily dose of 2400 mg (Prod Info ZYFLO(R) oral tablets, 2012).
    2) EXTENDED-RELEASE TABLETS: 12 years and older, 1200 mg orally twice daily within 1 hour after morning and evening meals; a total daily dose of 2400 mg. Do NOT chew, crush or cut the tablets (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    3) The safety and efficacy of immediate-release and extended-release zileuton have not been established in children under 12 years of age (Prod Info ZYFLO(R) oral tablets, 2012; Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Minimum Lethal Exposure

    A) SUMMARY
    1) At the time of this review, a toxic dose has not been established.

Maximum Tolerated Exposure

    A) CASE REPORT
    1) One person ingested between 11 and 15 tablets (6.6 and 9.0 grams) immediate release zileuton tablets. Vomiting was induced and the patient recovered without sequelae (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).
    B) ANIMAL DATA
    1) Nephritis was reported in dogs after administration of 1000 mg/kg of zileuton (approximately 12 times the maximum recommended human daily oral dose) (Prod Info ZYFLO CR(R) oral extended-release tablets, 2014).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Zileuton is an orally active 5-lipoxygenase inhibitor which inhibits leukotriene (LT) formation (eg, LTB4, LTC4, LTD4, and LTE4). Leukotrienes exert their effects by augmenting neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. The production of leukotrienes ultimately leads to inflammation, edema, mucus secretion, and bronchoconstriction. Zileuton would be beneficial in asthmatic patients, especially when leukotriene production would worsen or exacerbate the underlying pathology contributing to hyperactive airway disease. Animal studies have shown that zileuton blocks the physiologic effects of leukotrienes (Prod Info ZYFLO(R) oral tablets, 2012).

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    3) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    4) Dube LM, Swanson LJ, & Awni W: Zileuton, a leukotriene synthesis inhibitor in the management of chronic asthma. Clin Rev Allergy Immun 1999; 17:213-221.
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