Why is maintenance-and-reliever therapy (MART) with budesonide‑formoterol not indicated for children younger than 6 years?

Why MART is Not Indicated Under 6 Years Old

MART (maintenance-and-reliever therapy) with budesonide-formoterol is not indicated for children under 6 years of age primarily due to lack of adequate safety and efficacy data in this population, combined with practical delivery device limitations and the uncertain nature of asthma diagnosis in young children.

Evidence Base and Regulatory Considerations

The fundamental issue is insufficient clinical trial data in young children. The FDA approval for budesonide-formoterol specifically states that "the safety and effectiveness of budesonide and formoterol fumarate dihydrate in asthma patients less than 6 years of age have not been established" 1. This reflects the reality that most MART clinical trials enrolled patients aged 12 years and older 2, 3.

Key Developmental and Physiological Barriers

Device delivery challenges represent a major practical limitation 4:

• Children under 4 years typically cannot generate sufficient peak inspiratory flows for dry powder inhalers (DPIs)
• Most require nebulizers or metered-dose inhalers (MDIs) with valved holding chambers and face masks
• Face mask delivery with low tidal volumes results in significantly reduced aerosol delivery to the lungs
• Young children often cannot cooperate adequately with inhaler technique

Diagnostic uncertainty complicates treatment decisions in this age group 5:

• Viral respiratory infections are the most common cause of wheezing in young children
• Most children who wheeze with viral infections experience remission by age 6, likely due to growing airway size
• Not all wheeze and cough are caused by asthma—caution is needed to avoid inappropriate, prolonged therapy
• Inability to obtain reproducible spirometric measurements makes objective assessment of treatment response difficult

Regulatory Framework and Available Evidence

The FDA's pediatric regulations 4 allow extrapolation of efficacy from older children and adults when supplemented with safety and pharmacokinetic data in younger age groups. However, this extrapolation has not been adequately performed for MART in children under 6 years.

What IS Approved for Young Children

For children under 6 years with asthma, the following have FDA approval 5, 6:

• Budesonide nebulizer solution: Ages 1-8 years
• Fluticasone DPI: Ages 4 years and older
• Salmeterol DPI (LABA alone): Ages 4 years and older
• Montelukast: Ages 2-6 years (chewable tablets); ages 1-5 years (granules)

Notably, combination ICS/LABA products have limited data even for ages 4-5 years 6. Only one study of salmeterol added to ICS included patients as young as 4 years, and the lower age limit for most combination therapy studies is 6 years.

MART-Specific Considerations

MART requires formoterol specifically because of its rapid onset of action 7. The MART strategy depends on patients using the same ICS/formoterol inhaler for both maintenance and quick relief, with the rapid bronchodilation being essential for symptom relief. However:

• GINA guidelines explicitly do not recommend SMART for children 5-11 years old 7
• GINA does not recommend ICS/formoterol as reliever therapy in those younger than 12 years 7
• The 2020 NAEPP guidelines recommend MART for ages 5-11 years at steps 3-4, but this represents the lower age limit based on available evidence 7, 8

Clinical Trial Evidence Gap

Research confirms this evidence gap 2, 9:

• "There is no evidence for the use of single inhaler fixed combinations of inhaled corticosteroids + long-acting β2-agonists in children (<12 years of age)" 2
• Most SMART trials were conducted in adults and adolescents aged ≥12 years 3
• The Cochrane review on MART noted "no trials included children younger than age 12" 9

Alternative Approaches for Young Children

For children under 6 years requiring step-up therapy beyond low-dose ICS 5:

1. Increase ICS dose: Some data show dose-dependent improvements in children 4 years and younger
2. Add leukotriene receptor antagonist (montelukast) as alternative adjunctive therapy
3. Consider adding LABA to medium-dose ICS before increasing to high-dose ICS (to minimize potential side effects), though data are limited with small numbers of 4-year-olds showing improvement in impairment but not risk domain

Critical caveat: Treatment in young children is often a therapeutic trial—if no clear beneficial response occurs within 4-6 weeks with satisfactory technique and adherence, treatment should be stopped and alternative diagnoses considered 5.

Safety Monitoring Concerns

Young children may be at greater risk for systemic effects from high-dose ICS 6, including growth suppression 1. The growth of pediatric patients receiving ICS should be monitored, and each patient should be titrated to the lowest effective dose 1. The flexibility of MART dosing has not been studied for safety in this vulnerable population.