Exacerbation Study (MANDALA)

AIRSUPRA® (albuterol/budesonide) Inhalation Aerosol is a combination of albuterol, a beta2-adrenergic agonist and budesonide, a corticosteroid, and is indicated for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients with asthma 18 years of age and older.1

MANDALA

Study Design1-4

Phase III, randomized, double-blind, multicenter, variable length exacerbation study (≥24 weeks duration) that evaluated the efficacy and safety of as-needed albuterol/budesonide versus as-needed albuterol in patients with moderate to severe asthma.

Clinical Trials MANDALA Graphic

Primary Endpoint

  • Time to first severe exacerbation

Key Secondary Endpoints

  • Annualized rate of severe exacerbations

  • Annualized total systemic corticosteroid dose

Post Hoc Analysis

Patient Population (N=3040)

  • ≥12 years old

  • Symptomatic moderate to severe asthma

  • Receiving ICS maintenance throughout the trial with or without other controllers

Inclusion/Exclusion Criteria

While patients 12 to 17 years old were included in MANDALA, AIRSUPRA is not approved in this age group; therefore, efficacy results are only presented for adults ≥18 years of age. Since albuterol/budesonide 180/80 mcg is not an approved dose, this website will not include results for this arm of the study.

Adult Efficacy Population (n=2940)1,4

MANDALA Key Demographics Chart
MANDALA Key Demographics Chart
MANDALA Key Clinical Parameters Chart
MANDALA Key Clinical Parameters Chart

*Patients continued to receive their maintenance medications during the study.

†Taken with or without LTRA, LAMA, or theophylline.

Primary Endpoint: Time to First Severe Exacerbation1‡

Mandala Severe Exacerbation Graph
Mandala Severe Exacerbation Graph
zoom-cta

Data shown are for patients ≥18 years old.1 Data are from the pre-planned on-treatment efficacy analysis and included data collected while on randomized treatment prior to treatment discontinuation or change in maintenance therapy.2

‡Curve truncated when <1% of patient population remained at risk.

Albuterol/budesonide 180/160 mcg demonstrated a significant

28 Percentage Reduction In Exacerbation

reduction in risk of severe exacerbation vs albuterol (HR, 0.72; 95% CI: 0.60, 0.86; P<0.001)

Data shown are for patients ≥18 years old.1 Data are from the pre-planned on-treatment efficacy analysis and included data collected while on randomized treatment prior to treatment discontinuation or change in maintenance therapy.2

‡Curve truncated when <1% of patient population remained at risk.

Key Secondary Endpoints

Annualized Severe Exacerbation Rate1§

MANDALA Annualized Severe Exacerbation Rate Graph
MANDALA Annualized Severe Exacerbation Rate Graph

Annualized Systemic Corticosteroid Dose1,5‖

MANDALA Annualized Systemic Corticosteroid Dose Graph
MANDALA Annualized Systemic Corticosteroid Dose Graph

20% of adults on AIRSUPRA 180/160 mcg and 26% of adults on albuterol 180 mcg received SCS due to asthma.1

There was a significant reduction in the annualized rate of severe exacerbations and a significant difference in the annualized total SCS dose with as-needed albuterol/budesonide 180/160 mcg vs albuterol.1

Data shown are for patients ≥18 years old.1 Data are from the pre-planned on-treatment efficacy analysis and included data collected while on randomized treatment prior to treatment discontinuation or change in maintenance therapy.2

§There were 324 severe exacerbations in the albuterol/budesonide 180/160 mcg group and 403 in the albuterol group.1

‖Mean annualized doses of SCS were rounded to the nearest whole number in the AIRSUPRA Prescribing Information1; prednisone equivalent.2

Safety in the Overall MANDALA Population

Summary of adverse reactions reported in ≥1% of patients1

Safety Summary Adverse Reactions Chart in MANDALA
Safety Summary Adverse Reactions Chart in MANDALA

Data shown for albuterol/budesonide 180/160 mcg and albuterol 180 mcg are for patients ≥12 years old. AIRSUPRA is not approved for patients 12 to 17 years of age.

Oral candidiasis also includes those reactions reported under the preferred term oropharyngeal candidiasis.

Oral candidiasis also includes those reactions reported under the preferred term oropharyngeal candidiasis.

MANDALA Post Hoc Analysis6#

This post hoc analysis assessed the occurrence of asthma deterioration and the progression to a severe asthma exacerbation in patients receiving as-needed albuterol/budesonide (n=979) or as-needed albuterol (n=980).

Asthma Deterioration and Severe Exacerbation

Asthma Deterioration

≥1 of the following for ≥2 consecutive days:

  • PEF decline ≥20% from baseline

  • Study medication use >4 inhalations/day and ≥2x baseline

  • Symptom score**
    Night-time score > baseline and ≥2, OR Daytime score > baseline and =3

Severe Asthma Exacerbation

An asthma worsening leading to ≥1 of the following:

  • ≥3-day course of SCS or corresponding single injectable dose

  • Emergency room or urgent care visit due to asthma that required SCS

  • Hospitalization due to asthma

  • Death due to asthma

#Patients were ≥18 years old.

**Asthma symptom score is assessed on a 4-point scale from 0 to 3, with higher values indicating more severe asthma symptoms.

Progression From Asthma Deterioration to Severe Exacerbation

Severe Asthma Exacerbation Icon

Asthma deterioration was experienced by 725 (74.1%) patients receiving albuterol/budesonide 180/160 mcg and 780 (79.6%) receiving albuterol 180 mcg

Asthma Deterioration Icon

For 45 (6.2%) patients on albuterol/budesonide and 79 (10.1%) patients on albuterol, the asthma deterioration progressed to a severe exacerbation within 21 days

Cumulative Probability Severe Exacerbation Graph
Cumulative Probability Severe Exacerbation Graph
zoom-cta

††This graph illustrates the risk of progression from asthma deterioration to severe exacerbation within the subsequent 21 days.

‡‡Data are presented for the comparison of albuterol/budesonide 180/160 mcg (FDA-approved dose) vs albuterol 180 mcg only for patients ≥18 years of age.

Limitations6

This is a post hoc analysis from the MANDALA study. Data should be interpreted with caution and the ability to draw conclusions is limited.

  • Time-to-event analyses are based on subgroups of patients who experienced asthma deterioration after randomization; this criterion may be influenced by treatment assignment
  • Data are from patients who remain highly adherent (median, 85.1% of study days) to their ICS-containing maintenance; results may differ for patients whose maintenance regimens and/or adherence differ
  • Other indicators of asthma deterioration not captured in the definition here may exist

MANDALA results publication: Albuterol–budesonide fixed-dose combination rescue inhaler for asthma

New England Journal of Medicine, 2022

Access Article 

MANDALA analysis publication: Asthma deteriorations and severe exacerbations

The Journal of Allergy and Clinical Immunology: In Practice, 2024

Access Article 

Learn more about
AIRSUPRA

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AstraZeneca recommends use of AIRSUPRA only in accordance with its approved Prescribing Information.1

Specialist Perspective

Reframing Rescue Therapy

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Primary Care Perspective

Shifting to ICS Rescue Therapy

 ICS Rescue Therapy Video
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See an overview of the burden of asthma, the role of inflammation in exacerbations, and a potential treatment option.

Rethinking Asthma Rescue

Challenges in asthma care

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Exacerbation study for a rescue therapy (mild asthma)

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Lung function study for a rescue therapy

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Additional resources and learning

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CI, confidence interval; FDA, Food and Drug Administration; FEV1, forced expiratory volume in 1 second; GINA, Global Initiative for Asthma; HR, hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; PEF, peak expiratory flow; RR, rate ratio; SCS, systemic corticosteroid.

References:

1. AIRSUPRA® (albuterol/budesonide) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2025. 2. Papi A, Chipps BE, Beasley R, et al. Albuterol-budesonide fixed-dose combination rescue inhaler for asthma. N Engl J Med. 2022;386(22):2071-2083. doi:10.1056/NEJMoa2203163. 3. Chipps BE, Albers FC, Reilly L, et al. Efficacy and safety of as-needed albuterol/budesonide versus albuterol in adults and children aged ≥4 years with moderate-to-severe asthma: rationale and design of the randomised, double-blind, active-controlled MANDALA study. BMJ Open Respir Res. 2021;8(1):e001077. doi:10.1136/bmjresp-2021-001077. 4. Data on File, REF-174347, AstraZeneca Pharmaceuticals LP. 5. Data on File, REF-197604, AstraZeneca Pharmaceuticals LP. 6. Chipps BE, Papi A, Beasley R, et al. Albuterol-budesonide rescue reduces progression from asthma deterioration to severe exacerbation. J Allergy Clin Immunol Pract. 2024;12(10):2847-2851. doi:10.1016/j.jaip.2024.06.037.

 

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Important Information for the Healthcare Professional

This study discusses some information about AIRSUPRA® (albuterol 90 mcg/budesonide 80 mcg) that is not contained in or consistent with the FDA-approved Prescribing Information.

AstraZeneca and Avillion executed a Co-Development Agreement to advance AIRSUPRA through a global clinical development program for the treatment of asthma: AstraZeneca manufactures and markets AIRSUPRA while Avillion was the clinical trial Sponsor and provided funding for MANDALA. Some authors may have a financial interest in either AIRSUPRA or AstraZeneca/Avillion and/or may have received compensation from AstraZeneca/Avillion in connection with this study or other engagements. AstraZeneca recommends use of AIRSUPRA only in accordance with its approved Prescribing Information. In connection with the discussions contained in the reprint, please note:

  • The study evaluated efficacy and safety for patients ≥4 years old. Only patients ≥12 years old received the approved dosage of AIRSUPRA (albuterol/budesonide 180/160 mcg). While patients <18 years old were included in MANDALA, AIRSUPRA is not approved for this age group.
  • The study assessed an albuterol/budesonide MDI 180/80 mcg as needed arm. This is not an approved dose.
  • This prespecified exploratory analysis from MANDALA evaluated asthma deterioration and the effect of as-needed albuterol/budesonide on progression from deterioration to a severe exacerbation.
  • A post hoc analysis evaluated albuterol/budesonide 180/160 mcg in patients ≥18 years old (FDA-approved population).
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MANDALA: Select Inclusion and Exclusion Criteria1,3

Key Inclusion Criteria:

  • Symptomatic patients with moderate-to-severe asthma

  • At least one year since asthma diagnosis

  • ≥1 severe asthma exacerbation in previous year

  • Asthma maintenance therapy* for ≥3 months, with stable dosing for ≥4 weeks prior to screening

  • Prebronchodilator FEV1 ≥40 to <90% of predicted normal (for patients aged 12 to <18 years old, ≥60%) and confirmed reversibility to albuterol

Key Exclusion Criteria:

  • COPD or other significant lung disease

  • SCS within 6 weeks prior to screening

  • Chronic OCS use (≥3 weeks within 3 months prior to screening)

  • Biologic treatment within 3 months or 5 half-lives of screening

While patients 12 to 17 years old were included in MANDALA, AIRSUPRA is not approved in this age group; therefore, efficacy results are only presented for adults ≥18 years of age

*Medium- to high-dose ICS or low- to high-dose ICS-LABA with or without additional controller.

COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting ß2-agonist; OCS, oral corticosteroid; SCS, systemic corticosteroid.

Severe Exacerbation

In the MANDALA trial, a severe exacerbation was defined as1:

  • Worsening or onset of asthma symptoms that required systemic corticosteroid (SCS) for ≥3 days

  • An emergency department (ED) visit that led to the use of SCS for ≥3 days

  • An inpatient hospitalization for ≥24 hours due to asthma

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You are about to leave RethinkingAsthmaRescue.com
Important Information for the Healthcare Professional

This study discusses some information about AIRSUPRA® (albuterol 90 mcg/budesonide 80 mcg) that is not contained in or consistent with the FDA-approved Prescribing Information.

AstraZeneca and Avillion executed a Co-Development Agreement to advance AIRSUPRA through a global clinical development program for the treatment of asthma: AstraZeneca manufactures and markets AIRSUPRA while Avillion was the clinical trial Sponsor and provided funding for MANDALA. Some authors may have a financial interest in either AIRSUPRA or AstraZeneca/Avillion and/or may have received compensation from AstraZeneca/Avillion in connection with this study or other engagements. AstraZeneca recommends use of AIRSUPRA only in accordance with its approved Prescribing Information. In connection with the discussions contained in the reprint, please note:

  • The study evaluated efficacy and safety for patients ≥4 years old. Only patients ≥12 years old received the approved dosage of AIRSUPRA (albuterol/budesonide 180/160 mcg). While patients <18 years old were included in MANDALA, AIRSUPRA is not approved for this age group.
  • The study assessed an albuterol/budesonide MDI 180/80 mcg as needed arm. This is not an approved dose.
  • The primary efficacy analysis in MANDALA was a pre-planned on-treatment analysis, which included data collected while on randomized treatment prior to treatment discontinuation or change in maintenance therapy.
  • The results of a prespecified intention-to-treat analysis were also included in the MANDALA publication and included all data, regardless of a change in maintenance therapy or treatment discontinuation.
  • Adverse events occurring in at least 2% of patients in any trial group were reported in the study. The most common adverse events were nasopharyngitis, headache, and upper respiratory tract infections.
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You are about to leave RethinkingAsthmaRescue.com
Important Information for the Healthcare Professional

This study discusses some information about AIRSUPRA® (albuterol 90 mcg/budesonide 80 mcg) that is not contained in or consistent with the FDA-approved Prescribing Information.

AstraZeneca and Avillion executed a Co-Development Agreement to advance AIRSUPRA through a global clinical development program for the treatment of asthma: AstraZeneca manufactures and markets AIRSUPRA while Avillion was the clinical trial Sponsor and provided funding for MANDALA. Some authors may have a financial interest in either AIRSUPRA or AstraZeneca/Avillion and/or may have received compensation from AstraZeneca/Avillion in connection with this study or other engagements. AstraZeneca recommends use of AIRSUPRA only in accordance with its approved Prescribing Information. In connection with the discussions contained in the reprint, please note:

  • The study evaluated efficacy and safety for patients ≥4 years old. Only patients ≥12 years old received the approved dosage of AIRSUPRA (albuterol/budesonide 180/160 mcg). While patients <18 years old were included in MANDALA, AIRSUPRA is not approved for this age group.
  • The study assessed an albuterol/budesonide MDI 180/80 mcg as needed arm. This is not an approved dose.
  • This prespecified exploratory analysis from MANDALA evaluated asthma deterioration and the effect of as-needed albuterol/budesonide on progression from deterioration to a severe exacerbation.
  • A post hoc analysis evaluated albuterol/budesonide 180/160 mcg in patients ≥18 years old (FDA-approved population).
Continue
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Cumulative Probability Severe Exacerbation Graph

IMPORTANT SAFETY INFORMATION

  • Contraindications: Hypersensitivity to albuterol, budesonide, or to any of the excipients

  • Deterioration of Asthma: Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient continues to experience symptoms after using AIRSUPRA or requires more doses of AIRSUPRA than usual, it may be a marker of destabilization of asthma and requires evaluation of the patient and their treatment regimen

  • Paradoxical Bronchospasm: AIRSUPRA can produce paradoxical bronchospasm, which may be life threatening. Discontinue AIRSUPRA immediately and institute alternative therapy if paradoxical bronchospasm occurs. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister

  • Cardiovascular Effects: AIRSUPRA, like other drugs containing beta2-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by pulse rate, blood pressure, and/or other symptoms. If such effects occur, AIRSUPRA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST-segment depression. Therefore, AIRSUPRA, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension

  • Do Not Exceed Recommended Dose: Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs

  • Hypersensitivity Reactions, Including Anaphylaxis: Can occur after administration of albuterol sulfate and budesonide, components of AIRSUPRA, as demonstrated by cases of anaphylaxis, angioedema, bronchospasm, oropharyngeal edema, rash, and urticaria. Discontinue AIRSUPRA if such reactions occur

  • Risk of Sympathomimetic Amines with Certain Coexisting Conditions: AIRSUPRA, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines

  • Hypokalemia: Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients. The decrease in serum potassium is usually transient, not requiring supplementation

  • Immunosuppression and Risk of Infections: Due to possible immunosuppression from the use of inhaled corticosteroids (ICS), potential worsening of infections could occur. Use with caution. A more serious or fatal course of chickenpox or measles can occur in susceptible patients

  • Oropharyngeal Candidiasis: Has occurred in patients treated with ICS agents. Monitor patients periodically. Advise patients to rinse his/her mouth with water, if available, without swallowing after inhalation

  • Hypercorticism and Adrenal Suppression: May occur with very high doses in susceptible individuals. If such changes occur, consider appropriate therapy

  • Reduction in Bone Mineral Density: Decreases in bone mineral density have been observed with long-term administration of ICS. For patients at high risk for decreased bone mineral density, assess initially and periodically thereafter

  • Glaucoma and Cataracts: Have been reported following the long-term administration of ICS, including budesonide, a component of AIRSUPRA

  • Effects on Growth: Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of AIRSUPRA have not been established in pediatric patients, and AIRSUPRA is not indicated for use in this population

  • Most common adverse reactions (incidence ≥ 1%) are headache, oral candidiasis, cough, and dysphonia

  • Drug Interactions: AIRSUPRA should be administered with caution to patients being treated with:

  • Strong cytochrome P450 3A4 inhibitors (may cause systemic corticosteroid effects)

  • Short-acting bronchodilators (concomitant use of additional beta-agonists with AIRSUPRA should be used judiciously to prevent beta-agonist overdose)

  • Beta-blockers (may block pulmonary effects of beta-agonists and produce severe bronchospasm)

  • Diuretics or non-potassium-sparing diuretics (may potentiate hypokalemia or ECG changes). Consider monitoring potassium levels

  • Digoxin (may decrease serum digoxin levels). Consider monitoring digoxin levels

  • Monoamine oxidase inhibitors (MAOI) or tricyclic antidepressants (Use AIRSUPRA with extreme caution; may potentiate effect of albuterol on the cardiovascular system)

  • Use AIRSUPRA with caution in patients with hepatic impairment, as budesonide systemic exposure may increase. Monitor patients with hepatic disease

INDICATION

AIRSUPRA is a combination of albuterol, a beta2-adrenergic agonist and budesonide, a corticosteroid, indicated for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients with asthma 18 years of age and older.

Please see full Prescribing Information, including Patient Information.

You may report side effects related to AstraZeneca products.

This product information is intended for US healthcare professionals only.

IMPORTANT SAFETY INFORMATION