LEUKOTRIENE MODIFIERS










Montelukast (Singulair®)

Dosage form
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)

Precautions / Contraindications
  • Phenylketonuria - 4 and 5 mg chewable tablets contain phenylalanine
  • Neuropsychiatric events - neuropsychiatric events including agitation, aggressive behavior, memory problems, depression, hallucinations, etc. have been reported in some patients
  • 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 form
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

Precautions / Contraindications
  • 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 form
Zyflo® tablet
  • 600 mg
Zyflo CR® extended-release tablet
  • 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.

Precautions / Contraindications
  • 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



Asthma studies

ICS vs ICS/LABA vs ICS/LTRA in Children with Uncontrolled Asthma, NEJM (2010) [PubMed abstract]
  • Design: Randomized, crossover trial (N=182 | length = 16 weeks on each regimen) in children with uncontrolled asthma on Fluticasone 100 twice daily
  • Treatment: Fluticasone 250 twice daily vs Salmeterol/Fluticasone 50/100 twice daily vs Fluticasone 100 twice daily + Montelukast 5 - 10 mg once daily
  • Primary outcome: The primary outcome was the differential response to each of the three step-up therapies on the basis of fixed threshold criteria for the following three asthma-control measures: the need for treatment with oral prednisone for acute asthma exacerbations, the number of asthma control days, and the FEV1.
  • Results:
    • Salmeterol/Fluticasone was more likely to be the best response when compared to Fluticasone (p-value=0.002) and Fluticasone + Montelukast (p-value=0.004)
    • There was no significant difference between Fluticasone and Fluticasone + Montelukast
    • White race predicted a better response to Salmeterol/Fluticasone
    • Black patients were least likely to have a best response to Fluticasone + Montelukast
  • Findings: Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy.

LABA vs LTRA Added to ICS in Uncontrolled Asthma, BMJ (2003) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=1490 | length = 52 weeks) in patients with uncontrolled asthma
  • Treatment: Fluticasone 100 mcg twice daily + Montelukast 10 mg once daily or Salmeterol 50 mcg twice daily
  • Primary outcome: The primary endpoint was the percentage of patients with at least one asthma exacerbation. Asthma exacerbation was defined as worsening asthma requiring an unscheduled visit to a doctor, emergency department, or hospital or treatment with oral, intravenous, or intramuscular corticosteroids
  • Results:
    • Primary outcome: Montelukast - 20.1%, Salmeterol - 19.1% (diff 1%, 95%CI [-3.1% to 5%])
    • The Salmeterol group had a significantly greater increase in FEV₁ than the Montelukast group (p-value<0.001)
  • Findings: The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol



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