Section 1 - CHEMICAL PRODUCT AND COMPANY IDENTIFICATION

PRODUCT NAME

ZAFIRLUKAST

NFPA

PRODUCT USE

Antiasthmatic. Given by mouth for the prophylaxis and chronic treatment of asthma. A
selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4),
components of slow- reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene
production and receptor occupation are thought to be associated with the pathophysiology
of asthma, including airway oedema, smooth muscle constriction and altered cell activity
associated with the inflammatory process (patients with asthma have been found to be 25-
100 times more sensitive to the bronchoconstricting activity of inhaled LTD4 than non-
asthmatic subjects). In vitro studies indicate that zafirlukast antagonises the
contractile activity of three leukotrienes (LTC4, LTD4 and LTE4) in conducting airway
smooth muscle of humans and laboratory animals. The drug also prevented intradermal LTD- 4
increases in cutaneous vascular permeability and inhibited inhaled LTD4- induced influx of
eosinophils into animal lungs. Inhalation challenge studies in sensitised sheep
demonstrate that the drug suppressed airway responses to antigen. In humans the drug
inhibited bronchoconstriction by several types of inhalational challenge.

SYNONYMS

C31-H33-N3-O6-S, "[3-((2-methoxy-4-((((2-
methylphenyl)sulfonyl)amino)carbonyl)phenyl)methyl)-1-methyl-1H-indol-5-yl]carbamic acid
cyclopentyl ester", "[3-((2-methoxy-4-((((2-
methylphenyl)sulfonyl)amino)carbonyl)phenyl)methyl)-1-methyl-1H-indol-5-yl]carbamic acid
cyclopentyl ester", "cyclopentyl 3-[2-methoxy-4-((o-tolylsulfonyl)carbamoyl)benzyl]-1-
methylindole-5-carbamate", "cyclopentyl 3-[2-methoxy-4-((o-
tolylsulfonyl)carbamoyl)benzyl]-1-methylindole-5-carbamate", N-[4-(5-
(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl)-3-methoxybenzoyl]-2-
methylbenzenesulfonamide, N-[4-(5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl)-
3-methoxybenzoyl]-2-methylbenzenesulfonamide, 4-(5-cyclopentyloxycarbonylamino-1-
methylindol-3-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide, 4-(5-
cyclopentyloxycarbonylamino-1-methylindol-3-ylmethyl)-3-methoxy-N-o-
tolylsulfonylbenzamide, Accolate, ICI-204219, "antiasthmatic/ leukotriene D4/ E4
antagonist/ SRSA antagonist"

Section 2 - HAZARDS IDENTIFICATION

CANADIAN WHMIS SYMBOLS

EMERGENCY OVERVIEW

RISK

POTENTIAL HEALTH EFFECTS

ACUTE HEALTH EFFECTS

SWALLOWED

  Considered an unlikely route of entry in commercial/industrial environments.  At sufficiently high doses the material may be hepatotoxic(i.e. poisonous to the liver).  Sulfonamides and their derivatives can cause extensive kidney damage, and destroy red blood cells. Overdose may cause an accumulation of acid in the blood or a diminished blood sugar level with confusion and coma resulting. Predisposed persons can develop hypersensitivity reactions, including for topical application. Deaths have occurred due to hypersensitivity, anemia, imbalances in blood cell distribution and kidney and liver damage. 2-5 grams can be fatal. Sulfonamides cross the placental barrier, are excreted in the breast milk and may produce adverse effects in the fetus/ embryo and newborn, including loss of certain white blood cells causing immune function deficiency, anemia, jaundice and kernicterus.  

EYE

  The material may be irritating to the eye, with prolonged contact causing inflammation. Repeated or prolonged exposure to irritants may produce conjunctivitis.  

INHALED

  Persons with impaired respiratory function, airway diseases and conditions such as emphysema or chronic bronchitis, may incur further disability if excessive concentrations of particulate are inhaled.  

CHRONIC HEALTH EFFECTS

  Principal routes of exposure are usually by skin contact/absorption and inhalation of generated dust.  Repeated exposure by inhalation at relatively high levels have produced  adverse blood effects.  Exposure to small quantities may induce hypersensitivity reactions characterized by acute bronchospasm, hives (urticaria), deep dermal wheals (angioneurotic edema), running nose (rhinitis) and blurred vision . Anaphylactic shock and skin rash (non-thrombocytopenic purpura) may occur. An individual may be predisposed to such anti-body mediated reaction if other chemical agents have caused prior sensitization (cross-sensitivity).  There has been concern that this material can cause cancer or mutations, but there is not enough data to make an assessment.  Male mice given 300 mg/kg/day of zafirlukast had a greater incidence of  hepatocellular carcinomas; female mice given the same dose showed a  greater incidence of whole body histocytic sarcomas. Male and female rats  given 2000 mg/kg/day had a greater incidence of urinary bladder  transitional cell papillomas. Tumourigenic levels of the drug are more  than 50 times those attained in human therapies.  In mutagenicity studies, there was no evidence of mutagenic potential in  reverse (S. typhimurium and E. coli) or forward point mutation (CHO-HGPRT  and mouse lysosyme) assays or in two assays for chromosomal aberration  (human peripheral blood lymphocyte clastogenic assay and the rat bone  marrow micronucleus assay).  No teratogenicity was observed at oral doses up to 1600 mg/kg/day in  mice, 2000 mg/kg/day in rats and 2000 mg/kg/day in cynomolgus monkeys.  At 2000 mg/kg/day in rats, maternal toxicity and deaths were seen with  increased incidence of early foetal resorption. Spontaneous abortions  occurred in cynomolgus monkeys at maternally toxic doses (2000 mg/kg).  Zafirlukast is excreted in breast milk; because of the potential for  tumourigenicity shown in rodent studies and the enhanced sensitivity for  neonatal rats and dogs to adverse effects of the drug, zafirlukast should  not be given to nursing mothers.  Prolonged oral treatment with sulfonamides has caused nausea, vomiting, diarrhea, abdominal pain, loss of appetite, inflammation of the mouth cavity, impaired folic acid absorption, exacerbation of porphyria, acidosis, liver damage with impaired blood clotting, jaundice and inflammation of the pancreas. Effects on the kidney include blood and crystals in the urine, painful and frequent urination or lack of urine with nitrogen retention. Nervous system symptoms include headache, drowsiness, trouble sleeping, dizziness, ringing in the ears, hearing loss, depression, hallucinations, inco-ordination,  paralysis of muscles, numbness in the extremities, spinal cord damage and inflammation, convulsions and unconsciousness. Effects on the blood includes a change in blood cell distribution with loss of white blood cells and platelets, and anemia, which Africans seem to be more prone to developing than Europeans. Cyanosis can occur owing to complexes being formed by hemoglobin. Eye effects include inflamed cornea and conjunctiva with eyelid swelling and in severe cases, fear of the light. Allergies and cross-sensitivity is common, and can cause itches, wheals and sometimes a severe red rash with blisters that is often fatal. This class of drugs can scar the cornea and conjunctiva, swelling around the eyes, painful and inflamed joints, reduced sperm counts, pneumonia, fever, chills, hair loss, inflammation of vessels, lupus, reduced lung function, infertility, hypothyroidism and goiter, and increased urinary output. More seriously, the lungs may become permanently scarred and there may be irreversible damage to the nervous system and muscles. Inflammation of the skin has occurred after the drug is ingested and has traveled through the bloodstream. Skin effects often occur when there has been exposure in conjunction with UV light. Clothed areas are initially less likely to be affected but may be in later stages. Rarely there may be persistence of inflammation on light contact even after the drug has been removed.