Can montelukast be given with Inhaled Corticosteroids (ICS) + Long-Acting Beta Agonists (LABA) in patients with asthma or Chronic Obstructive Pulmonary Disease (COPD)?

Can Montelukast Be Given with ICS + LABA?

Yes, montelukast can be added to ICS + LABA therapy in asthma patients, but it is explicitly listed as an alternative (not preferred) option in current guidelines, and the FDA issued a Boxed Warning for montelukast in March 2020 requiring careful neuropsychiatric monitoring. 1, 2

Guideline-Based Positioning

For Adults and Adolescents ≥12 Years

Montelukast as add-on therapy to ICS + LABA is positioned at Step 4-5 care as an alternative option, not preferred therapy. 1 The 2020 NAEPP guidelines explicitly state:

• Step 4 (medium-dose ICS-LABA): Daily medium-dose ICS + LTRA is listed as an alternative option 1
• Step 5 (medium-high dose ICS-LABA): Daily medium-dose ICS + LTRA is an alternative 1

Critical caveat: The guidelines note that "LTRAs including montelukast were not considered for this update, and/or have an increased risk of adverse consequences and need for monitoring that make their use less desirable" due to the FDA Boxed Warning issued in March 2020. 1

For Children 5-11 Years

Montelukast can be added to ICS + LABA but remains an alternative option:

• Step 4: Daily medium-dose ICS + LTRA or Theophylline is listed as alternative to high-dose ICS-LABA 1
• Step 5: Daily high-dose ICS + LTRA is an alternative option 1

For Children 0-4 Years

Montelukast is listed as an alternative at multiple steps when combined with ICS, though LABA use is limited in this age group:

• Step 3: Daily medium-dose ICS + montelukast 1
• Step 4: Daily high-dose ICS + montelukast 1

Evidence Supporting Triple Therapy

Efficacy Data

Research demonstrates that adding montelukast to ICS + LABA provides measurable clinical benefits, though the magnitude is modest:

• A 6-month open-label study of 1,681 patients adding montelukast to ICS or ICS+LABA showed significant improvements in ACT scores (14.6 to 19.4, p<0.0001), mini-AQLQ scores (4.0 to 5.3, p<0.0001), and FEV1 (2.46 to 2.60L, p<0.0001) 3

• A comparative study showed montelukast added to ICS/LABA significantly decreased FeNO (p<0.05) and improved airflow obstruction (p<0.05), with changes in FeNO correlating with FEV1 improvements (r=-0.71, p<0.001) 4

• An 8-week RCT demonstrated inhaled montelukast plus mometasone was significantly more effective than mometasone alone in improving FEV1 (0.22L vs 0.17L, p=0.033), daytime symptoms (p=0.005), nighttime symptoms (p=0.015), and asthma control days (p=0.004) 5

Why Not Preferred?

The 2007 EPR-3 guidelines established that for patients ≥12 years requiring Step 3+ care, LABA is the preferred adjunctive therapy to combine with ICS over leukotriene modifiers. 1 This preference persists in the 2020 guidelines, which position ICS-LABA combinations as preferred over ICS + LTRA at equivalent steps. 1

Mandatory Safety Monitoring

FDA Boxed Warning Requirements

The FDA issued a Boxed Warning for montelukast in March 2020, requiring neuropsychiatric surveillance at every clinical encounter. 1, 2 Monitor for:

• Unusual behavioral changes
• Mood disturbances and depression
• Anxiety and agitation
• Aggressive behavior
• Suicidal ideation 2

Discontinue montelukast immediately if any neuropsychiatric symptoms develop. 2

Hepatic Monitoring

Monitor liver enzymes periodically during long-term therapy, and instruct patients to discontinue and contact their physician if signs of liver dysfunction develop. 2

Clinical Algorithm for Decision-Making

When to Consider Adding Montelukast to ICS + LABA:

1. Patient already on medium-to-high dose ICS + LABA with inadequate control (Step 4-5 care) 1
2. Patient has specific phenotypes where montelukast shows particular efficacy:
   • Exercise-induced bronchoconstriction 1, 6, 7
   • Aspirin-sensitive asthma 1, 6, 7
   • Allergic rhinitis comorbidity 7
   • Viral-induced wheezing 7
3. Patient cannot tolerate or refuses biologics (which would be considered at Step 5-6) 1
4. Patient has documented aspirin sensitivity and is already on ICS/LABA 6

When NOT to Add Montelukast:

1. Patient has history of neuropsychiatric disorders (relative contraindication given FDA Boxed Warning) 2
2. Asthma control can be achieved by optimizing ICS + LABA dosing (step up ICS dose or verify adherence/technique first) 1
3. Patient is candidate for biologic therapy (anti-IgE, anti-IL5, etc.) at Step 5-6 1
4. Patient requires Step 3 care only (where ICS-LABA alone is preferred over adding third agent) 1

Reassessment Timeline

Reassess asthma control every 2-6 weeks after adding montelukast. 2 If no clear benefit is observed within 4-6 weeks despite satisfactory technique and adherence, discontinue montelukast and consider alternative therapies or diagnoses. 1, 2

If asthma remains well-controlled for ≥3 consecutive months, consider stepping down therapy to find the minimum effective regimen. 2

Common Pitfalls to Avoid

• Never use montelukast for acute asthma exacerbations (it has no role in acute management) 2
• Never increase montelukast dose beyond recommended amounts (exhibits flat dose-response curve with maximum efficacy at standard dosing) 2
• Never overlook continued neuropsychiatric monitoring even in stable patients (symptoms can emerge at any time during therapy) 2
• Never use montelukast as monotherapy when ICS therapy is appropriate and feasible 2
• Never assume triple therapy (ICS + LABA + montelukast) is superior to optimizing ICS + LABA dosing first 1