LEUKOTRIENE MODIFIERS








Montelukast (Singulair®)

Dosage forms

Tablet
  • 10 mg
Chewable tablet
  • 4 mg
  • 5 mg
Granule
  • 4 mg packet

Dosing

Asthma
  • 1 - 5 years of age
    • 4 mg once daily in the evening
  • 6 - 14 years of age
    • 5 mg once daily in the evening
  • ≥ 15 years of age
    • 10 mg once daily in the evening
Exercise-induced asthma
  • 6 - 14 years of age
    • 5 mg at least 2 hours before exercise
  • ≥ 15 years old
    • 10 mg at least 2 hours before exercise
Allergic rhinitis
  • 6 - 23 months
    • 4 mg once daily in the evening
  • 2 - 5 years of age
    • 4 mg once daily in the evening
  • 6 - 14 years of age
    • 5 mg once daily in the evening
  • ≥ 15 years of age
    • 10 mg once daily in the evening

Efficacy

Generic / Price

  • Tablet - YES/$
  • Chewable Tablet - YES/$
  • Granule - YES/$

Other

Tablets
  • May take without regard to food
Granules
  • 4 mg oral granules can be administered either directly in the mouth, dissolved in 1 teaspoonful (5 mL) of cold or room temperature baby formula or breast milk, or mixed with a spoonful of cold or room temperature soft foods; based on stability studies, only applesauce, carrots, rice, or ice cream should be used
  • After opening the packet, the full dose (with or without mixing with baby formula, breast milk, or food) must be administered within 15 minutes

Mechanism of action

  • Leukotriene Receptor Antagonist (LTRA) - blocks leukotriene receptors and inhibits leukotriene-induced airway edema, smooth muscle contraction, and other inflammatory actions

FDA-approved indications

  • Asthma - prevention and prophylaxis in patients 12 months of age and older. Montelukast does NOT treat acute bronchospasm.
  • Exercise-induced asthma - in patients 6 years of age and older
  • Allergic rhinitis - seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 6 months of age and older

Side effects



Side effect Montelukast Placebo
Headache 18.4% 18.1%
Influenza 4.2% 3.9%
Abdominal pain 2.9% 2.5%
Cough 2.7% 2.4%
Upset stomach 2.1% 1.1%

Drug interactions

  • No clinically relevant drug interactions have been identified
  • Montelukast is a CYP2C8, CYP3A4, and CYP2C9 substrate (in vitro data)

Contraindications / Precautions

  • Phenylketonuria (chewable tablet) - each 4 mg and 5 mg chewable tablet contains 0.674 mg and 0.842 mg of phenylalanine, respectively.
  • Neuropsychiatric events - neuropsychiatric events including agitation, aggressive behavior, memory problems, depression, hallucinations, etc. have been reported in some patients. In 2020, the FDA strengthened its warning for these events by placing them in a boxed warning. The reasoning for their action was that many providers and patients were unaware of the potential for these reactions. They also stated that montelukast should only be used in allergic rhinitis when other medications have proven ineffective. Observational studies that have evaluated a link between montelukast and neuropsychiatric events have mostly found no association. [PMID 19815116, PMID 25683909]
  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - in rare cases, montelukast has been associated with Churg-Strauss syndrome. It is unclear if there is a true causal relationship.
  • Kidney disease - no dose adjustment necessary
  • Liver disease
    • Mild-moderate: no dose adjustment necessary
    • Severe: has not been studied

Zafirlukast (Accolate®)

Dosage forms

Tablet
  • 10 mg
  • 20 mg

Dosing

Asthma
  • 5 - 11 years of age
    • 10 mg twice a day
    • Take 1 hour before or 2 hours after a meal. Food decreases absorption.
  • ≥ 12 years of age and adults
    • 20 mg twice a day
    • Take 1 hour before or 2 hours after a meal. Food decreases absorption.

Generic / Price

- YES/$

Mechanism of action

  • Leukotriene Receptor Antagonist (LTRA) - blocks leukotriene receptors and inhibits leukotriene-induced airway edema, smooth muscle contraction, and other inflammatory actions

FDA-approved Indications

  • Asthma - prevention and prophylaxis in patients 5 years of age and older. Zafirlukast does NOT treat acute bronchospasm.

Side effects



Side effect Zafirlukast Placebo
Headache 12.9% 11.7%
Infection 3.5% 3.4%
Nausea 3.1% 2.0%
Diarrhea 2.8% 2.1%
Generalized pain 1.9% 1.7%

Drug interactions

  • CYP2C9 substrates - zafirlukast is a weak CYP2C9 inhibitor. It may increase levels of CYP2C9 substrates.
  • CYP2C9 inhibitors and inducers - zafirlukast is a CYP2C9 substrate. CYP2C9 inhibitors and inducers may affect zafirlukast levels.
  • Warfarin - zafirlukast may increase levels of warfarin and affect coagulation. Monitor INR closely when combining.
  • Erythromycin - may decrease zafirlukast levels
  • Theophylline - may decrease zafirlukast levels
  • Aspirin - aspirin may increase zafirlukast levels
  • CYP3A4 substrates - in vitro studies have shown zafirlukast to be a CYP3A4 inhibitor

Contraindications / Precautions

  • Liver toxicity - Zafirlukast has been associated with liver toxicity. If signs of liver toxicity occur, zafirlukast should be stopped and a liver enzymes should be checked.
  • Neuropsychiatric events - neuropsychiatric events including insomnia and depression have been reported in some patients
  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - in rare cases, zafirlukast has been associated with Churg-Strauss syndrome. It is unclear if there is a true causal relationship.
  • Liver disease - DO NOT USE
  • Kidney disease - no dose adjustment necessary


Zileuton | Zyflo® | Zyflo CR®

Dosage forms

Tablet (Zyflo®)
  • 600 mg
Tablet, extended-release (Zyflo CR®)
  • 600 mg

Dosing - Zyflo®

Asthma (≥ 12 years old and adults)
  • 600 mg four times a day
  • May take without regard to food

Dosing - Zyflo CR®

Asthma (≥ 12 years old and adults)
  • Two 600 mg tablets (1200 mg) twice a day
  • Take within one hour after morning and evening meal. Food increases absorption.

Generic / Price

  • Zyflo - NO/$$$$
  • Zyflo CR - YES/$$$$

Lab monitoring

  • Check serum ALT before treatment begins, once a month for the first 3 months, every 2-3 months for the remainder of the first year, and periodically thereafter.

Other

Zyflo CR®
  • Food increases absorption. Take on full stomach
  • Do not crush, cut, or chew tablets

Mechanism of action

  • 5-lipoxygenase inhibitor - blocks leukotriene formation and inhibits leukotriene-induced airway edema, smooth muscle contraction, and other inflammatory actions

FDA-approved indications

  • Asthma - prevention and prophylaxis in patients 12 years of age and older. Zafirlukast does NOT treat acute bronchospasm.

Side effects



Side effect Zileuton Placebo
Headache 24.6% 24%
Upset stomach 8.2% 2.9%
Pain (unspecified) 7.8% 5.3%
Nausea 5.5% 3.7%
Liver enzyme elevations (3X ULN) 4.6% 1.1%
Abdominal pain 4.6% 2.4%
Asthenia 3.8% 2.4%
Muscle pain 3.2% 2.9%

Drug interactions

  • CYP1A2 substrates - zileuton is a CYP1A2 moderate inhibitor. It may affect levels of CYP1A2 substrates.
  • CYP3A4 substrates - zileuton is a CYP3A4 weak inhibitor. It may affect levels of CYP3A4 substrates.
  • Theophylline - zileuton may increase theophylline levels. When adding zileuton to theophylline, the theophylline dose should be halved. Similarly, when adding theophylline to zileuton, use a lower dose of theophylline.
  • Propranolol - zileuton may increase propranolol levels. Use caution when combined.
  • Warfarin - zileuton may increase levels of warfarin and affect coagulation. Monitor INR closely when combining.

Contraindications / Precautions

  • Liver disease - DO NOT USE
  • Liver toxicity - zileuton has been associated with liver toxicity. Check serum ALT before treatment begins, once a month for the first 3 months, every 2-3 months for the remainder of the first year, and periodically thereafter. In trials, 4.6% of zileuton-treated patients developed ALT elevations ≥ 3X ULN compared to 1.1% of control patients. If symptoms of liver dysfunction (e.g. right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, or “flu-like” symptoms) develop or if ALT levels greater than 5X ULN occur, zileuton should be discontinued. In trials, ALT levels returned to <2X ULN in an average of 32 days in patients who discontinued zileuton due to ALT elevations.
  • Neuropsychiatric events - neuropsychiatric events including sleep disorders and behavior changes have been reported in some patients
  • Kidney disease - no dose adjustment necessary


Pricing legend
  • $ = 0 - $50
  • $$ = $51 - $100
  • $$$ = $101 - $150
  • $$$$ = > $151
  • Pricing based on one month of therapy at standard dosing in an adult
  • Pricing based on information from GoodRX.com®
  • Pricing may vary by region and availability