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ZAFIRLUKAST

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Zafirlukast is a selective and competitive receptor antagonist of the cysteinyl leukotrienes D4 and E4. The cysteinyl leukotrienes, originally described as slow-reacting substances of anaphylaxis, produce airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, all of which are associated with the pathophysiology of asthma.

Specific Substances

    A) PRANLUKAST
    1) ONO-1078
    2) CAS 103177-37-3
    ZAFIRLUKAST
    1) ICI-204219
    2) Molecular Formula: C31-H33-N3-O6-S
    3) CAS 107753-78-6

Available Forms Sources

    A) FORMS
    1) Zafirlukast is available as 10 and 20 mg tablets (Prod Info ACCOLATE(R) film coated oral tablets, 2009).
    2) Pranlukast is not available in the United States.
    B) USES
    1) Zafirlukast is used for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older (Prod Info ACCOLATE(R) film coated 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: Zafirlukast is used for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.
    B) PHARMACOLOGY: Zafirlukast is a selective and competitive receptor antagonist of the cysteinyl leukotrienes D4 and E4. The cysteinyl leukotrienes, originally described as slow-reacting substances of anaphylaxis, produce airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, all of which are associated with the pathophysiology of asthma.
    C) EPIDEMIOLOGY: Exposure is common, but severe toxicity is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects associated with therapeutic zafirlukast use include headache, somnolence, pharyngitis, rhinitis, nausea, diarrhea, elevation of liver enzymes, and asthma exacerbation; however, the incidence of most of these effects has been similar in placebo-treated patients.
    2) Zafirlukast and the other leukotriene antagonists have been associated with the development of Churg-Strauss Syndrome, a potentially fatal eosinophilic vasculitis, in adult asthma patients in most of whom concomitant oral steroid dose was reduced. Effects have included worsening pulmonary symptoms, eosinophilia, vasculitic rash, cardiac complications and/or neuropathy. This is a rare effect.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Four patients developed minimal adverse effects (eg, rash, upset stomach) after ingesting zafirlukast doses as high as 200 mg.
    0.2.20) REPRODUCTIVE
    A) Zafirlukast has been classified as FDA pregnancy category B. No teratogenic effects have been observed in human or animal studies, however, maternal toxicity, death, and spontaneous abortions have been reported. Zafirlukast is excreted in human breast milk. The manufacturer recommends caution when zafirlukast is used during pregnancy.

Laboratory Monitoring

    A) Serum zafirlukast levels are not readily available and are not clinically useful.
    B) Monitor vital signs and liver enzymes in all symptomatic patients.
    C) Monitor fluid and electrolyte levels in patients with severe vomiting or diarrhea.
    D) In rare cases, systemic eosinophilia has been reported, sometimes presenting with the clinical features of Churg-Strauss syndrome. Monitor CBC in patients with worsening of pulmonary symptoms, vasculitic rash or cardiac complications while receiving zafirlukast therapy.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Treatment is symptomatic and supportive.
    B) DECONTAMINATION
    1) PREHOSPITAL: Serious toxicity is not expected after ingestion of zafirlukast alone, and prehospital gastrointestinal decontamination is not routinely required.
    2) HOSPITAL: Significant toxicity is not expected after overdose; gastrointestinal decontamination is generally not necessary. Activated charcoal should be considered after extremely large ingestions or if more toxic coingestants are involved.
    C) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may be required in patients with severe allergic reactions, but this is rare.
    D) ANTIDOTE
    1) None.
    E) ACUTE ALLERGIC REACTION
    1) MILD to MODERATE EFFECTS: Monitor airway. Administer antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE EFFECTS: Administer oxygen, aggressive airway management may be necessary. Administer antihistamines, epinephrine, corticosteroids as needed. Treatment includes IV fluids and ECG monitoring.
    F) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the high degree of protein binding.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with a minor unintentional exposure who are asymptomatic or have mild symptoms can likely be managed at home.
    2) OBSERVATION CRITERIA: Moderate to severely symptomatic patients should be sent to a health care facility for evaluation and treated until symptoms resolve.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) Pitfalls in managing these patients include missing alternative diagnoses or not recognizing iatrogenic overdoses. When managing a suspected zafirlukast overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Zafirlukast is more than 99% bound to plasma proteins. The mean terminal elimination half-life of zafirlukast is approximately 10 hours. Metabolism of zafirlukast is most likely via hepatic mechanisms. Approximately 90% of a radiolabeled dose of zafirlukast is recovered in the feces.
    J) DIFFERENTIAL DIAGNOSIS
    1) Differential diagnosis included other drugs and conditions that can cause altered mental status, elevated liver enzymes, or symptoms similar to Churg-Strauss syndrome (eg, rash, vasculitis, fever, seizures).

Range Of Toxicity

    A) TOXICITY: No toxic dose established in humans. Four patients developed minimal adverse effects (eg, rash, upset stomach) after ingesting zafirlukast doses as high as 200 mg.
    B) ANIMALS: No deaths occurred at oral doses of 2000 mg/kg in mice, 2000 mg/kg in rats, or 500 mg/kg in dogs (approximately 200, 400 and 350 times the maximum recommended human daily oral dose on a mg/m(2) basis, respectively).
    C) THERAPEUTIC DOSE: ADULTS AND CHILDREN OVER 12 YEARS OF AGE: 20 mg twice daily. CHILDREN 5 TO 11 YEARS OF AGE: 10 mg twice daily. CHILDREN LESS THAN 5 YEARS OF AGE: The safety and efficacy of zafirlukast in patients younger than 5 years of age have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Zafirlukast is used for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.
    B) PHARMACOLOGY: Zafirlukast is a selective and competitive receptor antagonist of the cysteinyl leukotrienes D4 and E4. The cysteinyl leukotrienes, originally described as slow-reacting substances of anaphylaxis, produce airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, all of which are associated with the pathophysiology of asthma.
    C) EPIDEMIOLOGY: Exposure is common, but severe toxicity is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects associated with therapeutic zafirlukast use include headache, somnolence, pharyngitis, rhinitis, nausea, diarrhea, elevation of liver enzymes, and asthma exacerbation; however, the incidence of most of these effects has been similar in placebo-treated patients.
    2) Zafirlukast and the other leukotriene antagonists have been associated with the development of Churg-Strauss Syndrome, a potentially fatal eosinophilic vasculitis, in adult asthma patients in most of whom concomitant oral steroid dose was reduced. Effects have included worsening pulmonary symptoms, eosinophilia, vasculitic rash, cardiac complications and/or neuropathy. This is a rare effect.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: Four patients developed minimal adverse effects (eg, rash, upset stomach) after ingesting zafirlukast doses as high as 200 mg.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) Pharyngitis (20%) and rhinitis (9%) have been reported in asthmatic patients receiving oral zafirlukast. However, a similar incidence of these complications were observed in the placebo group (Spector et al, 1994).
    B) DISORDER OF RESPIRATORY SYSTEM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: One subject developed mild wheezing associated with 12% and 10% falls in the FEV1 after inhalation of zafirlukast and placebo, respectively (Maaker et al, 1992).
    b) Adverse respiratory effects reported less frequently during oral zafirlukast administration include exacerbation of asthma, cough, and upper respiratory tract infection (Findlay et al, 1992).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) The most common adverse event reported was headache reported in 12.9% of volunteers and patients (n=4058) treated with zafirlukast, versus 11.7% in the placebo group (Prod Info ACCOLATE(R) film coated oral tablets, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea occurred in 3.1% and diarrhea in 2.8% of volunteers and patients (n=4058) treated with zafirlukast versus 2% and 2.1% for those treated with placebo (n=2032), respectively (Prod Info ACCOLATE(R) film coated oral tablets, 2009).
    B) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH POISONING/EXPOSURE
    a) Four patients developed minimal adverse effects (eg, rash, upset stomach) after ingesting zafirlukast doses as high as 200 mg (Prod Info ACCOLATE(R) film coated oral tablets, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Although the frequency of hepatic transaminase elevations was comparable between zafirlukast and placebo-treated patients, a case of symptomatic hepatitis and hyperbilirubinemia, without other attributable cause, occurred in a patient who had received 40 mg/day of zafirlukast for 100 days.
    b) In this patient, the liver enzymes returned to normal within 3 months of stopping zafirlukast (Prod Info Accolate(R), zafirlukast, 2000).
    c) CASE REPORT: A 55-year-old female developed severe hepatitis after taking zafirlukast 20 mg twice daily for 5 months and albuterol sulfate nasal spray. Elevated hepatic enzymes were observed. A liver biopsy revealed submassive hepatic necrosis with abundant eosinophilic infiltration typical of toxin-related liver injury. The patient's symptoms resolved upon discontinuation of the drug (Danese et al, 2001).
    d) In an analysis of 9 reported cases of zafirlukast-associated hepatotoxicity, jaundice was reported in 7 of 9 cases (78%). Rash and eosinophilia were reported in 3 of 9 cases (33%). There were no fatalities reported, although 2 patients underwent liver transplantation. Liver histological findings varied from moderate portal infiltrates to submassive hepatic necrosis. The authors suggested that serum ALT levels should be monitored in patients taking zafirlukast (Davern & Bass, 2003).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) Four patients developed minimal adverse effects (eg, rash, upset stomach) after ingesting zafirlukast doses as high as 200 mg (Prod Info ACCOLATE(R) film coated oral tablets, 2009).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions, including urticaria, angioedema and rashes, with or without blistering have been reported in patients receiving zafirlukast (Prod Info ACCOLATE(R) film coated oral tablets, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Zafirlukast has been classified as FDA pregnancy category B. No teratogenic effects have been observed in human or animal studies, however, maternal toxicity, death, and spontaneous abortions have been reported. Zafirlukast is excreted in human breast milk. The manufacturer recommends caution when zafirlukast is used during pregnancy.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) MICE - No teratogenicity was observed in mice at oral doses up to 1,600 mg/kg/day (approximately 160 times the maximum recommended human daily oral dose on a mg/m(2) basis) (Prod Info ACCOLATE(R) oral tablets, 2004).
    2) MONKEYS - No teratogenicity was observed in cynomolgus monkeys at oral doses up to 2,000 mg/kg/day (approximately 20 times the exposure to the drug plus its metabolites compared to the maximum recommended human daily oral dose on a mg/m(2) basis) (Prod Info ACCOLATE(R) oral tablets, 2004).
    3) RATS - No teratogenicity was observed in rats at oral doses up to 2,000 mg/kg/day (approximately 400 times the maximum recommended human daily oral dose on a mg/m(2) basis) (Prod Info ACCOLATE(R) oral tablets, 2004).
    3.20.3) EFFECTS IN PREGNANCY
    A) MATERNAL TOXICITY
    1) There was no association between use of leukotriene receptor antagonists (LTRAs) and increased risk of perinatal adverse effects according to a clinical study of participants of the Asthma Medications in Pregnancy Study conducted by the Organization of Teratology Information Specialists (OTIS) from 1998 to 2003. Of the 564 pregnant women studied, 96 treated asthma with an LTRA (72, montelukast 10 mg/day; 22, zafirlukast 20 mg twice daily) with or without other medications, 122 treated asthma exclusively with a short-acting beta(2)-agonist, and 346 women without asthma served as a comparison group. There was no significant difference between the LTRA, beta(2)-agonist, and comparison groups for percentage of overall pregnancy loss (6.7%, 5.6%, and 3.4%, respectively [p=0.338]), including loss due to spontaneous abortion (5.6%, 5.6%, and 2.5%, respectively), ectopic pregnancy (0%, 0%, and 0.3%, respectively), and stillbirth (1.1%, 0%, and 0.6%, respectively). In addition, LTRA use was not associated with an increased risk of preterm delivery, low Apgar scores, or reduced infant birth length and head circumference. The incidence of major structural anomalies was significantly higher in the LTRA group compared with the no-treatment group (p=0.007), but was similar compared to the beta(2)-agonist group (p=0.524) (Bakhireva et al, 2007).
    B) PREGNANCY CATEGORY
    1) Zafirlukast has been classified as FDA pregnancy category B (Prod Info ACCOLATE(R) oral tablets, 2004).
    C) ANIMAL STUDIES
    1) ABORTION
    a) RATS - Maternal toxicity and deaths were seen in rats with increased incidence of early fetal resorption at an oral dose of 2,000 mg/kg/day (Prod Info ACCOLATE(R) oral tablets, 2004).
    b) MONKEYS - Spontaneous abortions occurred in cynomolgus monkeys at a maternally toxic dose of 2,000 mg/kg/day orally (Prod Info ACCOLATE(R) oral tablets, 2004).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Zafirlukast is excreted in breast milk. When healthy women were given repeated doses of zafirlukast 40 mg twice daily, average steady-state breast milk concentrations were 50 ng/mL compared to plasma concentrations of 255 ng/mL. The manufacturer recommends that zafirlukast should not be administered to mothers who are breast feeding (Prod Info ACCOLATE(R) oral tablets, 2004).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS107753-78-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Zafirlukast was orally administered to mice at daily doses of 10, 100 and 300 milligrams/kilogram during 2-year carcinogenicity studies (Prod Info Accolate(R), 2001).
    a) MALE - The incidence of hepatocellular adenomas was greater in mice given 300 milligrams/kilogram/day compared to controls. A 100-milligram/kilogram/day dosage was non-tumorigenic.
    b) FEMALE - The incidence of whole body histocytic sarcomas was greater in mice given 300 milligrams/kilogram/day compared to controls. A 100-milligram/kilogram/day dosage was non-tumorigenic.
    2) Zafirlukast was orally administered at daily doses of 40, 400 and 2000 milligrams/kilogram during 2-year carcinogenicity studies (Prod Info Accolate(R), 2001).
    a) MALE and FEMALE - The incidence of transitional cell papillomas of the urinary bladder was greater in mice given 2000 milligrams/kilogram/day compared to controls. A 400-milligram/kilogram/day dosage was non-tumorigenic in rats (approximately 200 and 170 times, respectively the plasma concentration in humans at the maximum recommended human daily oral dose) (Prod Info Accolate(R), 2001).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum zafirlukast levels are not readily available and are not clinically useful.
    B) Monitor vital signs and liver enzymes in all symptomatic patients.
    C) Monitor fluid and electrolyte levels in patients with severe vomiting or diarrhea.
    D) In rare cases, systemic eosinophilia has been reported, sometimes presenting with the clinical features of Churg-Strauss syndrome. Monitor CBC in patients with worsening of pulmonary symptoms, vasculitic rash or cardiac complications while receiving zafirlukast therapy.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Serum zafirlukast levels are not readily available and are not clinically useful.
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor fluid and electrolyte levels in patients with severe vomiting or diarrhea.
    2) In rare cases, systemic eosinophilia has been reported, sometimes presenting with the clinical features of Churg-Strauss syndrome (Prod Info Accolate(R), 2001). Monitor CBC in patients with worsening of pulmonary symptoms, vasculitic rash or cardiac complications while receiving zafirlukast therapy.
    C) LIVER FUNCTION
    1) Elevation of total bilirubin and liver aminotransferases (ALT, AST) have been reported during zafirlukast therapy (Prod Info Accolate(R), 2001).

Treatment

Monitoring

    A) Serum zafirlukast levels are not readily available and are not clinically useful.
    B) Monitor vital signs and liver enzymes in all symptomatic patients.
    C) Monitor fluid and electrolyte levels in patients with severe vomiting or diarrhea.
    D) In rare cases, systemic eosinophilia has been reported, sometimes presenting with the clinical features of Churg-Strauss syndrome. Monitor CBC in patients with worsening of pulmonary symptoms, vasculitic rash or cardiac complications while receiving zafirlukast therapy.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Serious toxicity is not expected after ingestion of zafirlukast alone, and prehospital gastrointestinal decontamination is not routinely required.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Significant toxicity is not expected after overdose; gastrointestinal decontamination is generally not necessary. Activated charcoal should be considered after extremely large ingestions or if more toxic coingestants are involved.
    B) 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) Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Serum zafirlukast levels are not readily available and are not clinically useful.
    2) Monitor vital signs and liver enzymes in all symptomatic patients.
    3) Monitor fluid and electrolyte levels in patients with severe vomiting or diarrhea.
    4) In rare cases, systemic eosinophilia has been reported, sometimes presenting with the clinical features of Churg-Strauss syndrome. Monitor CBC in patients with worsening of pulmonary symptoms, vasculitic rash or cardiac complications while receiving zafirlukast therapy.
    C) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

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 who remain symptomatic despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with a minor unintentional exposure who are asymptomatic or have mild symptoms can likely be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Moderate to severely symptomatic patients should be sent to a health care facility for evaluation and treated until symptoms resolve.

Range Of Toxicity

Summary

    A) TOXICITY: No toxic dose established in humans. Four patients developed minimal adverse effects (eg, rash, upset stomach) after ingesting zafirlukast doses as high as 200 mg.
    B) ANIMALS: No deaths occurred at oral doses of 2000 mg/kg in mice, 2000 mg/kg in rats, or 500 mg/kg in dogs (approximately 200, 400 and 350 times the maximum recommended human daily oral dose on a mg/m(2) basis, respectively).
    C) THERAPEUTIC DOSE: ADULTS AND CHILDREN OVER 12 YEARS OF AGE: 20 mg twice daily. CHILDREN 5 TO 11 YEARS OF AGE: 10 mg twice daily. CHILDREN LESS THAN 5 YEARS OF AGE: The safety and efficacy of zafirlukast in patients younger than 5 years of age have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose of zafirlukast is 20 mg twice daily (Prod Info ACCOLATE(R) oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) 12 YEARS OF AGE AND OLDER: The recommended dose is 20 mg twice daily (Prod Info ACCOLATE(R) oral tablets, 2013).
    B) 5 TO 11 YEARS OF AGE: The recommended dose is 10 mg twice daily (Prod Info ACCOLATE(R) oral tablets, 2013).
    C) LESS THAN 5 YEARS OF AGE: The safety and efficacy of zafirlukast in patients less than 5 years of age have not been established (Prod Info ACCOLATE(R) oral tablets, 2013).

Minimum Lethal Exposure

    A) ANIMAL STUDIES
    1) No deaths occurred at oral doses of 2000 mg/kg in mice, 2000 mg/kg in rats, or 500 mg/kg in dogs (approximately 200, 400 and 350 times the maximum recommended human daily oral dose on a mg/m(2) basis, respectively) (Prod Info ACCOLATE(R) film coated oral tablets, 2009).

Maximum Tolerated Exposure

    A) Four patients developed minimal adverse effects (eg, rash, upset stomach) after ingesting zafirlukast doses as high as 200 mg (Prod Info ACCOLATE(R) film coated oral tablets, 2009).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Plasma levels greater than 5 nanograms/milliliter have correlated with protection from antigen induced bronchoconstriction (Smith et al, 1993).

Workplace Standards

    A) ACGIH TLV Values for CAS107753-78-6 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS107753-78-6 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS107753-78-6 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS107753-78-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

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