zileuton (Rx)

>10%

Headache (24.6%)

1-10%

Abdominal pain (5%)

ALT elevation ≥3 times ULN (1.9-5%)

Asthenia (3.8%)

Dyspepsia (8.2%)

Diarrhea (5%)

Generalized pain (7.8%)

Nausea (5.5%)

Leukopenia (1-3%)

Myalgia (7%)

Weakness (4%)

Sinusitis (7%)

Pharyngolaryngeal pain (5%)

< 1%

Hepatitis

Behavioral changes

Jaundice

Liver failure

Suicidality

Suicide

Contraindications

Hypersensitivity

Liver disease, LFT's ≥3x ULN

Cautions

Not indicated for use in acute bronchospasm

History of liver disease, heavy alcohol use

Behavioral changes and sleep disorders reported

Not recommended for patients <12 years due to risk of hepatotoxicity

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications during pregnancy; for more information, contact the MothersToBaby Pregnancy Studies conducted by Organization of Teratology Information Specialists at 1- 877-311-8972 or visit http://mothertobaby.org/pregnancy-studies

There are no adequate human data on use in pregnant women to inform a drug associated risk

Animal data

• In animal studies, oral administration to pregnant rats and rabbits during organogenesis produced adverse developmental outcomes; structural abnormalities (cleft palate) were observed in rabbits at a dose similar to maximum recommended human daily oral dose (MRHD), alterations to growth (reduced fetal body weight and increased skeletal variations) were observed in rats at maternal plasma exposures 20 times greater than at MRHD; in a pre- and post-natal development study, oral administration to pregnant rats from organogenesis through weaning at maternal plasma exposures 20 times greater than MRHD resulted in reduced pup survival and body weights; the drug and/or its metabolites cross placental barrier of rats; therefore, drug may be transmitted from mother to developing fetus

Lactation

The drug and metabolites are excreted in rat milk; it is not known if zileuton is excreted in human milk, nor are there data on effects of drug on breastfed infant or effects on maternal milk production; because many drugs are excreted in human milk, and because of potential for tumorigenicity shown in animal studies, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for drug and any potential adverse effects on breastfed child from drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Inhibitor of 5-lipoxygenase, which inhibits formation of LTB4, LTC4, LTD4, & LTE4

Inhibition of leukotriene formation reduces eosinophil and neutrophil migration, neutrophil and monocyte aggregation, capillary permeability, and smooth muscle contraction

Pharmacokinetics

Half-Life: 2.5 hr

Onset: 2-5 hr

Peak Plasma Time: 1.7 hr

Protein Bound: 93%

Vd: 1.2 L/kg

Metabolites: O-glucuronide conjugate & N-dehydroxylated metabolite

Clearance: 7 mL/min/kg

Excretion: Urine (95%); feces (2%)

Enzymes inhibited: hepatic CYP1A2, CYP3A4, and CYP2C9