# Stepwise Pharmacotherapy for Adults and Adolescents — GINA 2024

## Fundamental Principle

All adults and adolescents with asthma should receive ICS-containing treatment. SABA-only treatment is no longer recommended for any step of asthma management. As-needed ICS-formoterol in Steps 1-2 of Track 1 reduced the risk of severe exacerbations by 60-64% compared with as-needed SABA alone.

## Two-Track Approach

GINA 2024 provides two treatment tracks for adults and adolescents (>=12 years):

- **Track 1 (Preferred):** Reliever is as-needed low-dose ICS-formoterol at all steps
- **Track 2 (Alternative):** Reliever is as-needed SABA; a separate ICS must be taken whenever SABA is used

Track 1 is preferred because ICS-formoterol as reliever reduces the risk of severe exacerbations compared with using SABA as reliever, with similar symptom control.

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## Track 1 (Preferred) — ICS-Formoterol as Reliever

### Step 1 — Infrequent Symptoms

- **Controller:** None
- **Reliever:** As-needed low-dose ICS-formoterol (e.g., budesonide-formoterol 200/6 mcg, 1 inhalation as needed)
- **Indication:** Symptoms fewer than twice per month

### Step 2 — Symptoms Twice or More Per Month but Less Than Daily

- **Controller:** None (as-needed ICS-formoterol also serves as controller)
- **Reliever:** As-needed low-dose ICS-formoterol (e.g., budesonide-formoterol 200/6 mcg, 1 inhalation as needed)
- **Indication:** Symptoms >=2 times/month but not daily
- **Note:** Alternatively, daily low-dose ICS controller can be added if patient prefers regular controller

### Step 3 — Symptoms Most Days, or Waking Due to Asthma Once or More Per Week

- **Controller:** Low-dose ICS-formoterol maintenance (e.g., budesonide-formoterol 200/6 mcg, 1 inhalation once or twice daily)
- **Reliever:** As-needed low-dose ICS-formoterol (same inhaler as maintenance)
- **Regimen name:** Maintenance And Reliever Therapy (MART)
- **Indication:** Symptoms most days, or waking with asthma >=1 time/week, or any exacerbation risk factors

### Step 4 — Daily Symptoms, or Waking Due to Asthma Once or More Per Week, and Low Lung Function

- **Controller:** Medium-dose ICS-formoterol maintenance (e.g., budesonide-formoterol 400/12 mcg, 1 inhalation twice daily)
- **Reliever:** As-needed low-dose ICS-formoterol (same inhaler)
- **Regimen name:** MART with medium-dose ICS-formoterol
- **Consider add-on:** LAMA (e.g., tiotropium soft-mist inhaler 5 mcg once daily)
- **Indication:** Symptoms not controlled on Step 3, with daily symptoms, night waking >=1/week, and/or low lung function

### Step 5 — Severe Asthma / Referral for Phenotypic Assessment

- **Controller:** High-dose ICS-formoterol MART, OR add-on LAMA, OR guided by phenotyping
- **Reliever:** As-needed low-dose ICS-formoterol
- **Add-on therapies (guided by phenotype):**
  - Anti-IgE (omalizumab)
  - Anti-IL5/IL5R (mepolizumab, benralizumab, reslizumab)
  - Anti-IL4R (dupilumab)
  - Anti-TSLP (tezepelumab)
  - Low-dose OCS (only if other options exhausted, consider side effects)
- **Indication:** Uncontrolled on Step 4 despite good adherence and inhaler technique; refer to specialist

---

## Track 2 (Alternative) — SABA as Reliever

### Step 1

- **Controller:** Take low-dose ICS whenever SABA is taken (concomitant or combination inhaler)
- **Reliever:** As-needed SABA (e.g., salbutamol 100 mcg, 1-2 puffs as needed)
- **Indication:** Symptoms fewer than twice per month

### Step 2

- **Controller:** Daily low-dose ICS (e.g., budesonide 200-400 mcg/day, OR fluticasone propionate 100-250 mcg/day, OR beclomethasone 200-500 mcg/day)
- **Reliever:** As-needed SABA
- **Indication:** Symptoms >=2 times/month but not daily

### Step 3

- **Controller:** Low-dose ICS-LABA maintenance (e.g., fluticasone propionate/salmeterol 100/50 mcg 1 inhalation BID, OR budesonide/formoterol 200/6 mcg 1 inhalation BID)
- **Reliever:** As-needed SABA
- **Alternative:** Medium-dose ICS
- **Indication:** Symptoms most days, or waking with asthma >=1 time/week

### Step 4

- **Controller:** Medium/high-dose ICS-LABA (e.g., fluticasone propionate/salmeterol 250/50 mcg 1 inhalation BID, OR budesonide/formoterol 400/12 mcg 1 inhalation BID)
- **Reliever:** As-needed SABA
- **Consider add-on:** LAMA (tiotropium 5 mcg once daily)
- **Indication:** Not controlled on Step 3

### Step 5

- Same as Track 1 Step 5: refer for phenotypic assessment and add-on biologic therapy

---

## Stepping Up and Stepping Down

### Stepping Up
- Before stepping up, confirm the diagnosis, check and correct inhaler technique, verify adherence, and address modifiable risk factors and comorbidities (rhinitis, GERD, obesity, obstructive sleep apnea, anxiety/depression)
- Consider a short-term step-up (1-2 weeks) for viral infections or allergen exposure
- Sustained step-up: if asthma remains uncontrolled after 2-3 months of current step

### Stepping Down
- Consider stepping down when asthma has been well controlled for at least 3 months
- Reduce ICS dose by approximately 25-50% at 3-month intervals
- Never completely withdraw ICS in adults or adolescents with asthma
- Continue to monitor symptoms and lung function after step-down
- The preferred approach in Track 1 is to step down to as-needed ICS-formoterol alone (Steps 1-2)

## Key ICS-Formoterol Doses for MART (Track 1)

| Step | ICS-Formoterol Maintenance Dose | Maximum Reliever Dose |
| :--- | :--- | :--- |
| Steps 1-2 | No maintenance (reliever only) | Budesonide-formoterol: total max 48 mcg formoterol/day |
| Step 3 | Budesonide-formoterol 200/6 mcg, 1 inhalation once or twice daily | As above |
| Step 4 | Budesonide-formoterol 200/6 mcg, 2 inhalations twice daily | As above |
| Step 5 | High-dose ICS-formoterol or add biologic | As above |

Note: The maximum recommended total formoterol dose from both maintenance and reliever use is 48 mcg/day (12 actuations of budesonide-formoterol 200/6 mcg).

## Inhaler Technique and Adherence

- Check inhaler technique at every visit. Up to 80% of patients use their inhaler incorrectly.
- Use a physical demonstration of the correct technique, not just verbal instruction.
- Poor adherence is the most common reason for uncontrolled asthma. Ask about adherence in a non-judgmental way.
- Simplify the regimen where possible; single-inhaler MART reduces the number of devices and complexity.
