Beyond ICS-LABA: When to Add Tiotropium, and How to Weigh Montelukast After the Boxed Warning

A clinical brief for referring providers — part 3 of a 4-part asthma pharmacotherapy series.

Test your knowledge

The FDA boxed warning added to montelukast in March 2020 is for which class of adverse events? a) Cardiovascular b) Hepatic c) Serious neuropsychiatric events

(Answer at the bottom — it changed prescribing across every subgroup.)

The add-ons

Parts 1 and 2 covered the backbone: low-dose inhaled corticosteroid (ICS), and the single-inhaler maintenance-and-reliever strategy. Now, the two add-ons that come up once ICS plus a long-acting beta2 agonist (LABA) isn't enough — a long-acting muscarinic antagonist (LAMA), and a leukotriene receptor antagonist (LTRA).

LAMA — tiotropium

Tiotropium (Spiriva Respimat) is the only LAMA FDA-approved for asthma. Added to ICS, it improved lung function (forced expiratory volume in 1 second [FEV1] peak +180 mL, trough +130 mL) and reduced exacerbations requiring systemic corticosteroids (relative risk [RR] 0.67; 95% CI 0.48–0.92) versus ICS alone, on high-strength evidence (Anderson et al., Cochrane 2015).

Where it fits in the ladder (NAEPP 2020)

LABA is the preferred first add-on to ICS. The guideline conditionally recommends against adding LAMA to ICS instead of adding LABA.

If a LABA is not being used, adding LAMA to ICS is a conditional option over continuing same-dose ICS alone.

Step 5: add LAMA to ICS-LABA — triple therapy. Adding LAMA on top of ICS-LABA improved control and quality of life (exacerbation rate unchanged).

Montelukast — the LTRA, and the warning that reshaped its use

Montelukast is an oral tablet — useful for adherence in patients who can't or won't use inhalers — but it is an alternative, not preferred, controller: similar symptom control to ICS at Step 2 with less exacerbation reduction, and a weaker add-on than LABA or LAMA at Steps 4–5.

In March 2020 the FDA added a boxed warning for serious neuropsychiatric events — agitation, aggression, depression, sleep disturbances, and suicidal thoughts and behavior, among others (FDA; Clarridge et al., 2021). The asthma indication was not removed, but the FDA directs prescribers to weigh benefit and risk case by case, discuss it with patients and caregivers, and monitor for behavioral changes; for allergic rhinitis, use is now reserved for patients who don't respond to or can't tolerate other therapies. Following the warning, montelukast prescribing fell significantly across every age and severity subgroup (Shanmugam et al., JAMA Network Open 2026).

The practical read

Montelukast still has a place — but it's a shared-decision conversation now, not a reflex, and patients need to know what to watch for and to report changes rather than quietly stopping.

Next in this series: severe asthma and the biologics — the CHEST 2026 framework for choosing, and switching, targeted therapy.

The answer

c) Serious neuropsychiatric events — including agitation, aggression, depression, sleep disturbances, and suicidal thoughts and behavior. The asthma indication stands, but prescribing is now a documented benefit-risk decision, and allergic-rhinitis use is restricted to those who fail or can't tolerate alternatives (FDA; Clarridge et al., 2021).