Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

initial treatment step 1: asthma symptoms 1-2 days per week or less and no risk factors for exacerbations

1st line – low-dose inhaled corticosteroid plus formoterol as needed

Back
ACUTE
|
initial treatment step 1: asthma symptoms 1-2 days per week or less and no risk factors for exacerbations
1st line – 

low-dose inhaled corticosteroid plus formoterol as needed

Inhaled corticosteroid (ICS)-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made.[52] The GINA track 1 (preferred) approach is to start on as-needed low-dose ICS plus formoterol (ICS-formoterol).[52]

In GINA track 1, the decision to start steps 1-2 (i.e., as-needed low-dose ICS-formoterol) instead of step 3 (i.e., low-dose ICS-formoterol as MART) is determined by the absence of risk factors for exacerbation. These include daily symptoms, current smoking, low lung function, a recent severe exacerbation or history of life-threatening exacerbation, impaired perception of severity, severe airway hyperresponsiveness, or current exposure to an allergic trigger.[52] 

Patient response should be reviewed 2-3 months after starting treatment, or earlier if clinically indicated, and should include checks of both treatment adherence and inhaler technique. Decisions made about further treatment changes should then follow the stepwise approach to ongoing management.[52]

Primary options

budesonide/formoterol inhaled: consult specialist for guidance on as-needed dose

2nd line – low-dose inhaled corticosteroid plus short-acting beta agonist as needed

Back
ACUTE
|
initial treatment step 1: asthma symptoms 1-2 days per week or less and no risk factors for exacerbations
2nd line – 

low-dose inhaled corticosteroid plus short-acting beta agonist as needed

Inhaled corticosteroid (ICS)-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made.[52]

The GINA track 2 (alternative) approach is to start on low-dose ICS whenever a short-acting beta agonist (SABA) is taken, as either separate or combined inhalers.[52] Consider the likelihood of adherence to maintenance therapy before prescribing a SABA as a reliever. When choosing between steps 1 and 2 (track 2), taking an ICS whenever a SABA is taken is preferred over daily ICS plus as-needed SABA (track 2, step 2) to ensure that patients with infrequent symptoms receive an ICS dose.[52]

Patient response should be reviewed 2-3 months after starting treatment, or earlier if clinically indicated, and should include checks of both treatment adherence and inhaler technique. Decisions made about further treatment changes should then follow the stepwise approach to ongoing management.[52]

​For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

beclomethasone dipropionate inhaled: 80-240 micrograms/day

or

budesonide inhaled: 180-600 micrograms/day

or

ciclesonide inhaled: 80-160 micrograms/day

or

fluticasone propionate inhaled: 88-264 micrograms/day

or

mometasone inhaled: 200 micrograms/day

-- AND --

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

or

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

initial treatment step 2: asthma symptoms less than 3-5 days per week and normal (or mildly reduced) lung function

1st line – low-dose inhaled corticosteroid plus formoterol as needed

Back
ACUTE
|
initial treatment step 2: asthma symptoms less than 3-5 days per week and normal (or mildly reduced) lung function
1st line – 

low-dose inhaled corticosteroid plus formoterol as needed

Inhaled corticosteroid (ICS)-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made.[52]

The GINA track 1 (preferred) approach is to start on as-needed low-dose ICS-formoterol.[52]

In GINA track 1, the decision to start steps 1-2 (i.e., as-needed low-dose ICS-formoterol) instead of step 3 (i.e., low-dose ICS-formoterol as MART) is determined by the absence of risk factors for exacerbation. These include daily symptoms, current smoking, low lung function, a recent severe exacerbation or history of life-threatening exacerbation, impaired perception of severity, severe airway hyperresponsiveness, or current exposure to an allergic trigger.[52] 

Patient response should be reviewed 2-3 months after starting treatment, or earlier if clinically indicated, and should include checks of both treatment adherence and inhaler technique. Decisions made about further treatment changes should then follow the stepwise approach to ongoing management.[52]  

Primary options

budesonide/formoterol inhaled: consult specialist for guidance on as-needed dose

2nd line – low-dose inhaled corticosteroid

Back
ACUTE
|
initial treatment step 2: asthma symptoms less than 3-5 days per week and normal (or mildly reduced) lung function
2nd line – 

low-dose inhaled corticosteroid

Inhaled corticosteroid (ICS)-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made.[52]

The GINA track 2 (alternative) approach is to start on daily low-dose ICS.[52]​ Consider the likelihood of adherence to maintenance therapy before prescribing a SABA as a reliever. When choosing between steps 1 and 2 (track 2), taking an ICS whenever a SABA is taken is preferred over daily ICS plus as-needed SABA (track 2, step 2) to ensure that patients with infrequent symptoms receive an ICS dose.[52]

Patient response should be reviewed 2-3 months after starting treatment, or earlier if clinically indicated, and should include checks of both treatment adherence and inhaler technique. Decisions made about further treatment changes should then follow the stepwise approach to ongoing management.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

beclomethasone dipropionate inhaled: 80-240 micrograms/day

OR

budesonide inhaled: 180-600 micrograms/day

OR

ciclesonide inhaled: 80-160 micrograms/day

OR

fluticasone propionate inhaled: 88-264 micrograms/day

OR

mometasone inhaled: 200 micrograms/day

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ACUTE
|
initial treatment step 2: asthma symptoms less than 3-5 days per week and normal (or mildly reduced) lung function
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

Note that the track 2 options tend to increase treatment complexity, requiring more inhalers. Consider the likelihood of adherence to maintenance therapy before prescribing a short-acting beta agonist as a reliever.

For patients using metered-dose inhalers, spacer devices improve drug delivery.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

initial treatment step 3: asthma symptoms most days (e.g., 4-5 days per week or more), or waking due to asthma once a week or more, low lung function, and risk factors for exacerbations

1st line – low-dose inhaled corticosteroid plus formoterol as maintenance therapy and low-dose inhaled corticosteroid plus formoterol as reliever therapy

Back
ACUTE
|
initial treatment step 3: asthma symptoms most days (e.g., 4-5 days per week or more), or waking due to asthma once a week or more, low lung function, and risk factors for exacerbations
1st line – 

low-dose inhaled corticosteroid plus formoterol as maintenance therapy and low-dose inhaled corticosteroid plus formoterol as reliever therapy

Inhaled corticosteroid (ICS)-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made.[52]

The GINA track 1 (preferred) approach is to start on daily low-dose ICS low-dose ICS-formoterol as maintenance and reliever therapy (MART).[52] In this regimen, the patient takes a regular fixed dose of the MART inhaler, plus uses the same inhaler as an as-needed reliever (maximum recommended formoterol dose of 72 micrograms/day).

In GINA track 1, the decision to start step 3 (i.e., low-dose ICS-formoterol as MART) instead of steps 1-2 (i.e., as-needed low-dose ICS-formoterol) is determined by the presence of risk factors for exacerbation. These include daily symptoms, current smoking, low lung function, a recent severe exacerbation or history of life-threatening exacerbation, impaired perception of severity, severe airway hyperresponsiveness, or current exposure to an allergic trigger.[52] 

Patient response should be reviewed 2-3 months after starting treatment, or earlier if clinically indicated, and should include checks of both treatment adherence and inhaler technique. Decisions made about further treatment changes should then follow the stepwise approach to ongoing management.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]​​

Other combination formulations may be available; consult a local drug formulary for more options.

Primary options

budesonide/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

2nd line – low-dose inhaled corticosteroid plus long-acting beta agonist

Back
ACUTE
|
initial treatment step 3: asthma symptoms most days (e.g., 4-5 days per week or more), or waking due to asthma once a week or more, low lung function, and risk factors for exacerbations
2nd line – 

low-dose inhaled corticosteroid plus long-acting beta agonist

Inhaled corticosteroid (ICS)-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made.[52] A GINA track 2 (alternative) approach is to start on daily low-dose ICS plus a long-acting beta agonist (ICS-LABA).[52]

Patient response should be reviewed 2-3 months after starting treatment, or earlier if clinically indicated, and should include checks of both treatment adherence and inhaler technique. Decisions made about further treatment changes should then follow the stepwise approach to ongoing management.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

A Cochrane review comparing regular ICS-formoterol with ICS-salmeterol found both combinations to have a similar safety profile in patients with chronic asthma.[101]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

budesonide/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

mometasone/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone propionate/salmeterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone furoate/vilanterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ACUTE
|
initial treatment step 3: asthma symptoms most days (e.g., 4-5 days per week or more), or waking due to asthma once a week or more, low lung function, and risk factors for exacerbations
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

Note that the track 2 options tend to increase treatment complexity, requiring more inhalers. Consider the likelihood of adherence to maintenance therapy before prescribing a short-acting beta agonist as a reliever.

For patients using metered-dose inhalers, spacer devices improve drug delivery.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

2nd line – medium-dose inhaled corticosteroid

Back
ACUTE
|
initial treatment step 3: asthma symptoms most days (e.g., 4-5 days per week or more), or waking due to asthma once a week or more, low lung function, and risk factors for exacerbations
2nd line – 

medium-dose inhaled corticosteroid

Inhaled corticosteroid (ICS)-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made.[52] A GINA track 2 (alternative) approach is to start on daily medium-dose ICS.[52]

Patient response should be reviewed 2-3 months after starting treatment, or earlier if clinically indicated, and should include checks of both treatment adherence and inhaler technique. Decisions made about further treatment changes should then follow the stepwise approach to ongoing management.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

beclomethasone dipropionate inhaled: >240-480 micrograms/day

OR

budesonide inhaled: >600-1200 micrograms/day

OR

ciclesonide inhaled: >160-320 micrograms/day

OR

fluticasone propionate inhaled: >264-440 micrograms/day

OR

mometasone inhaled: 400 micrograms/day

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ACUTE
|
initial treatment step 3: asthma symptoms most days (e.g., 4-5 days per week or more), or waking due to asthma once a week or more, low lung function, and risk factors for exacerbations
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

Note that the track 2 options tend to increase treatment complexity, requiring more inhalers. Consider the likelihood of adherence to maintenance therapy before prescribing a short-acting beta agonist as a reliever. 

For patients using metered-dose inhalers, spacer devices improve delivery of the drug.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

initial treatment step 4: daily asthma symptoms, waking at night once a week or more, and low lung function

1st line – medium-dose inhaled corticosteroid plus formoterol as maintenance therapy and low-dose inhaled corticosteroid plus formoterol as reliever therapy

Back
ACUTE
|
initial treatment step 4: daily asthma symptoms, waking at night once a week or more, and low lung function
1st line – 

medium-dose inhaled corticosteroid plus formoterol as maintenance therapy and low-dose inhaled corticosteroid plus formoterol as reliever therapy

In an urgent care setting or where a patient presents with an acute exacerbation, please refer to guidance for managing Acute asthma exacerbation in adults.

Inhaled corticosteroid (ICS)-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made.[52] The GINA track 1 (preferred) approach is to start on daily medium-dose ICS-formoterol as maintenance and reliever therapy (MART), using the same inhaler for both maintenance and reliever doses.

The maintenance dose is increased by increasing the number of inhalations (e.g., 2 inhalations twice daily), but the reliever is still low-dose ICS-formoterol (1 inhalation). The maximum recommended formoterol dose is 72 micrograms/day.

This is equivalent to step 4 in the GINA stepwise approach to ongoing management.[52] 

Patient response should be reviewed 2-3 months after starting treatment, or earlier if clinically indicated, and should include checks of both treatment adherence and inhaler technique. Decisions made about further treatment changes should then follow the stepwise approach to ongoing management.[52] 

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]   

Other combination formulations may be available; consult a local drug formulary for more options.

Primary options

budesonide/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

Consider – short-course oral corticosteroid

Back
ACUTE
|
initial treatment step 4: daily asthma symptoms, waking at night once a week or more, and low lung function
Consider – 

short-course oral corticosteroid

Treatment recommended for SOME patients in selected patient group

Patients whose initial presentation is with severely uncontrolled asthma may need a short course of oral corticosteroids.[52]

Primary options

prednisone: 40-50 mg orally once daily for 5-7 days

2nd line – medium- or high-dose inhaled corticosteroid plus long-acting beta agonist

Back
ACUTE
|
initial treatment step 4: daily asthma symptoms, waking at night once a week or more, and low lung function
2nd line – 

medium- or high-dose inhaled corticosteroid plus long-acting beta agonist

In an urgent care setting or where a patient presents with an acute exacerbation, please refer to guidance for managing Acute asthma exacerbation in adults.

Inhaled corticosteroid (ICS)-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made.[52]​ A GINA track 2 (alternative) approach is to start on daily medium- or high-dose ICS plus long-acting beta agonist (ICS-LABA).[52]

Patient response should be reviewed 2-3 months after starting treatment, or earlier if clinically indicated, and should include checks of both treatment adherence and inhaler technique. Decisions made about further treatment changes should then follow the stepwise approach to ongoing management.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

budesonide/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

mometasone/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone propionate/salmeterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone furoate/vilanterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

Consider – short-course oral corticosteroid

Back
ACUTE
|
initial treatment step 4: daily asthma symptoms, waking at night once a week or more, and low lung function
Consider – 

short-course oral corticosteroid

Treatment recommended for SOME patients in selected patient group

Patients whose initial presentation is with severely uncontrolled asthma may need a short course of oral corticosteroids.[52]

Primary options

prednisone: 40-50 mg orally once daily for 5-7 days

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ACUTE
|
initial treatment step 4: daily asthma symptoms, waking at night once a week or more, and low lung function
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

Note that the track 2 options tend to increase treatment complexity, requiring more inhalers. Consider the likelihood of adherence to maintenance therapy before prescribing a short-acting beta agonist as a reliever.

For patients using metered-dose inhalers, spacer devices improve delivery of the drug.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

2nd line – high-dose inhaled corticosteroid

Back
ACUTE
|
initial treatment step 4: daily asthma symptoms, waking at night once a week or more, and low lung function
2nd line – 

high-dose inhaled corticosteroid

In an urgent care setting or where a patient presents with an acute exacerbation, please refer to guidance for managing Acute asthma exacerbation in adults.

Inhaled corticosteroid (ICS)-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made.[52] A GINA track 2 (alternative) approach recommended is to start on high-dose ICS therapy.[52]

Patient response should be reviewed 2-3 months after starting treatment, or earlier if clinically indicated, and should include checks of both treatment adherence and inhaler technique. Decisions made about further treatment changes should then follow the stepwise approach to ongoing management.[52]  

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]   

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

beclomethasone dipropionate inhaled: >480 micrograms/day

OR

budesonide inhaled: >1200 micrograms/day

OR

ciclesonide inhaled: >320 micrograms/day

OR

fluticasone propionate inhaled: >440 micrograms/day

OR

mometasone inhaled: >400 micrograms/day

Consider – short-course oral corticosteroid

Back
ACUTE
|
initial treatment step 4: daily asthma symptoms, waking at night once a week or more, and low lung function
Consider – 

short-course oral corticosteroid

Treatment recommended for SOME patients in selected patient group

Patients whose initial presentation is with severely uncontrolled asthma may need a short course of oral corticosteroids.[52]

Primary options

prednisone: 40-50 mg orally once daily for 5-7 days

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ACUTE
|
initial treatment step 4: daily asthma symptoms, waking at night once a week or more, and low lung function
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

Note that the track 2 options tend to increase treatment complexity, requiring more inhalers. Consider the likelihood of adherence to maintenance therapy before prescribing a short-acting beta agonist as a reliever.

For patients using metered-dose inhalers, spacer devices improve delivery of the drug.[52] 

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

ONGOING

ongoing treatment step 1: patients using short-acting beta agonist (SABA) alone or with newly diagnosed asthma, with normal (or mildly reduced) lung function

1st line – low-dose inhaled corticosteroid plus formoterol as needed

Back
ONGOING
|
ongoing treatment step 1: patients using short-acting beta agonist (SABA) alone or with newly diagnosed asthma, with normal (or mildly reduced) lung function
1st line – 

low-dose inhaled corticosteroid plus formoterol as needed

A low-dose inhaled corticosteroid (ICS) with the long-acting beta agonist (LABA) formoterol (ICS-formoterol) used on an as-needed basis, for relief of symptoms and before exercise if needed, is the preferred controller treatment at step 1 (GINA track 1).[52] This is based on evidence that showed that low-dose ICS-formoterol as needed is superior to as-needed short-acting beta agonist (SABA) use alone for prevention of asthma exacerbations.[83][84][85][86][87]​​ In addition, even modest over-use of SABA increases the risk of severe exacerbations and asthma-related death, and adding any ICS significantly reduces this risk.[52][88][93]​​ High SABA use is associated with a significant increase in exacerbations and asthma-related healthcare utilization.[94][95]​​ Patient populations most at risk for SABA over-reliance include older adults, smokers, and patients with low income.[95] The Global Policy Steering Group on Improving Asthma Outcomes recommends a patient reassessment if ≥3 SABA inhalers are used in 1 year.[96]

Although formoterol is a LABA, it has a fast onset of action and so can be used as a reliever treatment.[167]

In GINA track 1, the decision to start steps 1-2 (i.e., as-needed low-dose ICS-formoterol) instead of step 3 (i.e., low-dose ICS-formoterol as MART) is determined by the absence of risk factors for exacerbation. These include daily symptoms, current smoking, low lung function, a recent severe exacerbation or history of life-threatening exacerbation, impaired perception of severity, severe airway hyperresponsiveness, or current exposure to an allergic trigger.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

So far, all evidence for as-needed ICS-formoterol in mild asthma is with budesonide/formoterol.[52]

The recommended maximum daily usage of as-needed budesonide/formoterol corresponds to a total of 72 micrograms formoterol. However, in randomized controlled trials in mild asthma, such high usage was rarely seen, with average use around 3-4 doses per week.[52][83][84][97]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Primary options

budesonide/formoterol inhaled: consult specialist for guidance on as-needed dose

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 1: patients using short-acting beta agonist (SABA) alone or with newly diagnosed asthma, with normal (or mildly reduced) lung function
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast. Monitor for neuropsychiatric symptoms during treatment, and discontinue immediately if symptoms occur.[71]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

2nd line – low-dose inhaled corticosteroid plus short-acting beta agonist as needed

Back
ONGOING
|
ongoing treatment step 1: patients using short-acting beta agonist (SABA) alone or with newly diagnosed asthma, with normal (or mildly reduced) lung function
2nd line – 

low-dose inhaled corticosteroid plus short-acting beta agonist as needed

Another option recommended by GINA for step 1 treatment is a low-dose inhaled corticosteroid (ICS) taken whenever a short-acting beta agonist is taken (track 2). This can include combination anti-inflammatory relievers.

The evidence for using an ICS and SABA at step 1 is indirect, being taken from small studies with separate or combination ICS and SABA inhalers in patients eligible for step 2 treatment.[89][90][91][92]​ Consider the likelihood of adherence to maintenance therapy before prescribing a SABA as a reliever. When choosing between steps 1 and 2 (track 2), taking an ICS whenever a SABA is taken is preferred over daily ICS plus as-needed SABA (track 2, step 2) to ensure that patients with infrequent symptoms receive an ICS dose.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

beclomethasone dipropionate inhaled: 80-240 micrograms/day

or

budesonide inhaled: 180-600 micrograms/day

or

ciclesonide inhaled: 80-160 micrograms/day

or

fluticasone propionate inhaled: 88-264 micrograms/day

or

mometasone inhaled: 200 micrograms/day

-- AND --

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

or

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

or

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 1: patients using short-acting beta agonist (SABA) alone or with newly diagnosed asthma, with normal (or mildly reduced) lung function
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

ongoing treatment step 2: asthma not controlled on step 1 treatment

1st line – low-dose inhaled corticosteroid plus formoterol as needed

Back
ONGOING
|
ongoing treatment step 2: asthma not controlled on step 1 treatment
1st line – 

low-dose inhaled corticosteroid plus formoterol as needed

Inhaled low-dose corticosteroid (ICS)-formoterol on an as-needed basis for relief of symptoms and before exercise, if needed, is GINA's preferred option at step 2 (track 1). This regimen decreases glucocorticoid exposure at the expense of some degree of symptom control, but is noninferior to low-dose ICS maintenance therapy in terms of prevention of exacerbation.[52][97]​ 

So far, all evidence for as-needed ICS-formoterol in mild asthma is with budesonide/formoterol.[52]

The recommended maximum daily usage of as-needed budesonide/formoterol corresponds to a total of 72 micrograms formoterol. However, in randomized controlled trials in mild asthma, such high usage was rarely seen, with average use around 3-4 doses per week.[52][83][84][97]

In GINA track 1, the decision to start steps 1-2 (i.e., as-needed low-dose ICS-formoterol) instead of step 3 (i.e., low-dose ICS-formoterol as MART) is determined by the absence of risk factors for exacerbation. These include daily symptoms, current smoking, low lung function, a recent severe exacerbation or history of life-threatening exacerbation, impaired perception of severity, severe airway hyperresponsiveness, or current exposure to an allergic trigger.[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Primary options

budesonide/formoterol inhaled: consult specialist for guidance on as-needed dose

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 2: asthma not controlled on step 1 treatment
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59] 

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59] 

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52] 

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast. Monitor for neuropsychiatric symptoms during treatment, and discontinue immediately if symptoms occur.[71] 

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]​ 

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

2nd line – low-dose inhaled corticosteroid

Back
ONGOING
|
ongoing treatment step 2: asthma not controlled on step 1 treatment
2nd line – 

low-dose inhaled corticosteroid

A regular, daily low-dose inhaled corticosteroid (ICS) plus as-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) is an alternative option at step 2 (track 2).[1][52]​​​​

There is a large body of evidence from randomized controlled trials and observational studies that severe exacerbations, hospitalizations, and mortality are reduced with daily low-dose ICS. However, adherence with maintenance ICS in patients with mild asthma is very low.[52]​ Consider the likelihood of adherence to maintenance therapy before prescribing a SABA as a reliever. When choosing between steps 1 and 2 (track 2), taking an ICS whenever a SABA is taken is preferred over daily ICS plus as-needed SABA (track 2, step 2) to ensure that patients with infrequent symptoms receive an ICS dose.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

beclomethasone dipropionate inhaled: 80-240 micrograms/day

OR

budesonide inhaled: 180-600 micrograms/day

OR

ciclesonide inhaled: 80-160 micrograms/day

OR

fluticasone propionate inhaled: 88-264 micrograms/day

OR

mometasone inhaled: 200 micrograms/day

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ONGOING
|
ongoing treatment step 2: asthma not controlled on step 1 treatment
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

The use of ICS-SABA for as-needed therapy is based on studies with separate or combination ICS and SABA inhalers that showed no difference in exacerbation rates compared with daily ICS.[89][90][91][92]

For patients using metered-dose inhalers, spacer devices improve delivery of the drug.[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 2: asthma not controlled on step 1 treatment
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

2nd line – low-dose inhaled corticosteroid plus short-acting beta agonist as needed

Back
ONGOING
|
ongoing treatment step 2: asthma not controlled on step 1 treatment
2nd line – 

low-dose inhaled corticosteroid plus short-acting beta agonist as needed

Low-dose inhaled corticosteroid (ICS) taken whenever a short-acting beta agonist (SABA) is taken is another option at step 2 (track 2).[52][62]​ The ICS and SABA can be given in single or combination inhalers. This is based on studies with separate or combination ICS and SABA inhalers, showing no difference in exacerbations compared with daily ICS.[89][90][91][92]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

beclomethasone dipropionate inhaled: 80-240 micrograms/day

or

budesonide inhaled: 180-600 micrograms/day

or

ciclesonide inhaled: 80-160 micrograms/day

or

fluticasone propionate inhaled: 88-264 micrograms/day

or

mometasone inhaled: 200 micrograms/day

-- AND --

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

or

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

or

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 2: asthma not controlled on step 1 treatment
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast. Monitor for neuropsychiatric symptoms during treatment, and discontinue immediately if symptoms occur.[71]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

2nd line – leukotriene receptor antagonist

Back
ONGOING
|
ongoing treatment step 2: asthma not controlled on step 1 treatment
2nd line – 

leukotriene receptor antagonist

Leukotriene receptor antagonists (LTRAs) are less effective than inhaled corticosteroids (ICS), but may be appropriate as an alternative initial controller treatment in patients who are unable or unwilling to use ICS, patients who experience adverse effects from ICS, or patients with concomitant allergic rhinitis.[52][99]

Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71] These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.​[52]

Primary options

montelukast: 10 mg orally once daily

OR

zafirlukast: 20 mg orally twice daily

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ONGOING
|
ongoing treatment step 2: asthma not controlled on step 1 treatment
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

The use of ICS-SABA for as-needed therapy is based on studies with separate or combination ICS and SABA inhalers that showed no difference in exacerbation rates compared with daily ICS.[89][90][91][92]

For patients using metered-dose inhalers, spacer devices improve delivery of the drug.[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 2: asthma not controlled on step 1 treatment
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations

1st line – low-dose inhaled corticosteroid plus formoterol as maintenance therapy and low-dose inhaled corticosteroid plus formoterol as reliever therapy

Back
ONGOING
|
ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations
1st line – 

low-dose inhaled corticosteroid plus formoterol as maintenance therapy and low-dose inhaled corticosteroid plus formoterol as reliever therapy

GINA’s preferred option at step 3 is low-dose inhaled corticosteroid (ICS)-formoterol as maintenance therapy and low-dose ICS-formoterol as reliever therapy (track 1).[52] In the maintenance and reliever therapy (MART) regimen, the patient takes a regular fixed dose, plus uses the same inhaler as an as-needed reliever.[52]​​​

ICS-formoterol as MART is GINA's preferred option at step 3 because this treatment reduces exacerbations and provides similar levels of asthma control at relatively low doses of ICS compared with either regular, fixed-dose ICS-long-acting beta agonist plus short-acting beta agonist (SABA) as needed or a higher dose of ICS plus SABA as needed.[102][103][104][105][106][107][108]

In GINA track 1, the decision to start step 3 (i.e., low-dose ICS-formoterol as MART) instead of steps 1-2 (i.e., as-needed low-dose ICS-formoterol) is determined by the presence of risk factors for exacerbation. These include daily symptoms, current smoking, low lung function, a recent severe exacerbation or history of life-threatening exacerbation, impaired perception of severity, severe airway hyperresponsiveness, or current exposure to an allergic trigger.[52]

MART regimens are the recommended option at step 3 in the 2020 US guidelines.[62] 

For patients taking ICS-formoterol as MART, the maximum recommended dose of formoterol in a single day is 72 micrograms metered dose (equivalent to 54 micrograms delivered dose) for budesonide/formoterol.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Other combination formulations may be available; consult a local drug formulary for more options.

Primary options

budesonide/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

Consider – leukotriene receptor antagonist

Back
ONGOING
|
ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations
Consider – 

leukotriene receptor antagonist

Treatment recommended for SOME patients in selected patient group

Add-on leukotriene receptor antagonist (LTRA) is an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. 

Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Primary options

montelukast: 10 mg orally once daily

OR

zafirlukast: 20 mg orally twice daily

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

2nd line – low-dose inhaled corticosteroid plus long-acting beta agonist

Back
ONGOING
|
ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations
2nd line – 

low-dose inhaled corticosteroid plus long-acting beta agonist

The main alternative to inhaled corticosteroid (ICS)-formoterol as maintenance and reliever therapy in GINA guidance is low-dose ICS plus long-acting beta agonist (LABA) as regular treatment with as-needed short-acting beta agonist (SABA) or as-needed ICS-SABA as a reliever (track 2). Adding a LABA to ICS in a combination inhaler leads to improved symptoms and lung function, and a reduced risk of exacerbations.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

In traditional ICS plus LABA treatment, the drugs are prescribed as a fixed-dose combination inhaler.[52]

A Cochrane review comparing regular ICS-formoterol with ICS-salmeterol found both combinations to have a similar safety profile in patients with chronic asthma.[101]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

budesonide/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

mometasone/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone propionate/salmeterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone furoate/vilanterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ONGOING
|
ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

The evidence for including as-needed ICS-SABA comes from a multinational, phase 3, double-blind, randomized trial evaluating the efficacy and safety of albuterol/budesonide, compared to albuterol alone, used as rescue medication in patients with uncontrolled moderate-to-severe asthma receiving ICS-containing maintenance therapies that remained unchanged throughout the study (step 3 therapy).[110] This showed that the risk of severe asthma exacerbation was significantly lower with as-needed use of the fixed-dose albuterol/budesonide combination than with as-needed albuterol alone.[110] Note that this track 2 option can be considerably more complex than the track 1 option, typically requiring multiple inhalers.

For patients using metered-dose inhalers, spacer devices improve delivery of the drug.[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

Consider – leukotriene receptor antagonist

Back
ONGOING
|
ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations
Consider – 

leukotriene receptor antagonist

Treatment recommended for SOME patients in selected patient group

Add-on leukotriene receptor antagonist (LTRA) is an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. 

Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Primary options

montelukast: 10 mg orally once daily

OR

zafirlukast: 20 mg orally twice daily

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

2nd line – medium-dose inhaled corticosteroid

Back
ONGOING
|
ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations
2nd line – 

medium-dose inhaled corticosteroid

Increasing the inhaled corticosteroid (ICS) to a medium dose is another second-line option (track 2), but this is less efficacious than adding a long-acting beta agonist to low-dose ICS.[52]

For patients using metered-dose inhalers, spacer devices improve delivery of the drug and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

beclomethasone dipropionate inhaled: >240-480 micrograms/day

OR

budesonide inhaled: >600-1200 micrograms/day

OR

ciclesonide inhaled: >160-320 micrograms/day

OR

fluticasone propionate inhaled: >264-440 micrograms/day

OR

mometasone inhaled: 400 micrograms/day

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ONGOING
|
ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

Much of the evidence for including as-needed ICS-SABA comes from a multinational, phase 3, double-blind, randomized trial evaluating the efficacy and safety of albuterol/budesonide, compared to albuterol alone, used as rescue medication in patients with uncontrolled moderate-to-severe asthma receiving ICS-containing maintenance therapies that remained unchanged throughout the study (step 3 therapy).[110] This showed that the risk of severe asthma exacerbation was significantly lower with as-needed use of the fixed-dose albuterol/budesonide combination than with as-needed albuterol alone.[110] Note that this track 2 option can be considerably more complex than the track 1 option, typically requiring multiple inhalers.

For patients using metered-dose inhalers, spacer devices improve delivery of the drug.[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

Consider – leukotriene receptor antagonist

Back
ONGOING
|
ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations
Consider – 

leukotriene receptor antagonist

Treatment recommended for SOME patients in selected patient group

Add-on leukotriene receptor antagonist (LTRA) is an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. 

Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Primary options

montelukast: 10 mg orally once daily

OR

zafirlukast: 20 mg orally twice daily

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbations
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

ongoing treatment step 4: asthma not controlled on step 3 treatment

1st line – medium-dose inhaled corticosteroid plus formoterol as maintenance therapy and low-dose inhaled corticosteroid plus formoterol as reliever therapy

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
1st line – 

medium-dose inhaled corticosteroid plus formoterol as maintenance therapy and low-dose inhaled corticosteroid plus formoterol as reliever therapy

Medium-dose inhaled corticosteroid (ICS)-formoterol as maintenance therapy and low-dose ICS-formoterol as reliever therapy is GINA’s preferred option at step 4 (track 1).[52] For adults and adolescents with asthma, combination ICS-formoterol as maintenance and reliever therapy (MART) is better at reducing exacerbations than the same dose of maintenance ICS-long-acting beta agonist or high doses of ICS.[106] For the MART regimen, the same inhaler should be used for both maintenance and reliever doses. The maintenance dose can be increased by increasing the number of inhalations, but the reliever is still low-dose ICS-formoterol.[52]

MART regimens are the recommended option at step 4 in the 2020 US guidelines.[62] 

For patients taking ICS-formoterol as MART, the maximum recommended dose of formoterol in a single day is 72 micrograms metered dose (equivalent to 54 micrograms delivered dose) for budesonide/formoterol.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Other combination formulations may be available; consult a local drug formulary for more options.

Primary options

budesonide/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

Consider – leukotriene receptor antagonist

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

leukotriene receptor antagonist

Treatment recommended for SOME patients in selected patient group

Add-on leukotriene receptor antagonist (LTRA) is an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. 

Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Primary options

montelukast: 10 mg orally once daily

OR

zafirlukast: 20 mg orally twice daily

Consider – long-acting muscarinic antagonist

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

long-acting muscarinic antagonist

Treatment recommended for SOME patients in selected patient group

Long-acting muscarinic antagonists (LAMAs), such as tiotropium, glycopyrrolate, or umeclidinium, may be used as an add-on therapy if asthma is persistently uncontrolled despite medium- or high-dose inhaled corticosteroid (ICS)-long-acting beta agonist (LABA).[52] At step 4, there is insufficient evidence to support ICS plus LAMA over ICS plus LABA.[62][112]​​ Adding LAMAs to medium- or high-dose ICS-LABA modestly improves lung function and time to severe exacerbations requiring an oral corticosteroid.[112][113][114][115][116][117]​​ A systematic review and meta-analysis found beneficial effects of ICS-LABA-LAMA on exacerbations and asthma control compared to ICS-LABA, but no significant differences in quality of life or mortality.[115]​ Benefit is seen primarily in patients with a history of exacerbations in the previous year.[118]

LAMAs may be given as a separate inhaler, or in a combination ("triple") inhaler that contain ICS, LABA, and LAMA. Availability of the inhalers varies by country.[52] Combination inhalers are not detailed here - consult your local drug formulary for details on available inhalers and doses.

Primary options

tiotropium inhaled: 2.5 micrograms inhaled once daily

OR

umeclidinium inhaled: 62.5 micrograms inhaled once daily

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

2nd line – medium-dose inhaled corticosteroid plus long-acting beta agonist

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
2nd line – 

medium-dose inhaled corticosteroid plus long-acting beta agonist

For patients taking daily low-dose inhaled corticosteroid (ICS) plus long-acting beta agonist (LABA) with as-needed short-acting beta agonist (SABA) or as-needed ICS-SABA at step 3 (track 2), then a step-up option for track 2 is an increase to daily medium-dose ICS plus LABA with as-needed SABA or as-needed ICS-SABA at step 4.[52][111]

In traditional ICS plus LABA treatment, the drugs are prescribed as a fixed-dose combination inhaler.[52]​​​

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

A Cochrane review comparing regular ICS-formoterol with ICS-salmeterol found both combinations to have a similar safety profile in patients with chronic asthma.[101]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

budesonide/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

mometasone/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone propionate/salmeterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone furoate/vilanterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

The evidence for including as-needed ICS-SABA comes from a multinational, phase 3, double-blind, randomized trial evaluating the efficacy and safety of albuterol/budesonide, compared to albuterol alone, in a sub-population of patients taking maintenance medium-dose ICS-LABA or high-dose ICS (step 4 therapy).[110] This showed that there was a significant decrease in risk of severe exacerbations with as-needed high-dose ICS-SABA compared with as-needed SABA.[110] Note that this track 2 option can be considerably more complex than the track 1 option, typically requiring multiple inhalers.

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

For patients using metered-dose inhalers, spacer devices improve delivery of the drug.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

Consider – leukotriene receptor antagonist

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

leukotriene receptor antagonist

Treatment recommended for SOME patients in selected patient group

Add-on leukotriene receptor antagonist (LTRA) is an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. 

Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Primary options

montelukast: 10 mg orally once daily

OR

zafirlukast: 20 mg orally twice daily

Consider – long-acting muscarinic antagonist

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

long-acting muscarinic antagonist

Treatment recommended for SOME patients in selected patient group

Long-acting muscarinic antagonists (LAMAs), such as tiotropium, glycopyrrolate, or umeclidinium, may be used as an add-on therapy if asthma is persistently uncontrolled despite medium- or high-dose inhaled corticosteroid (ICS)-long-acting beta agonist (LABA).[52] At step 4, there is insufficient evidence to support ICS plus LAMA over ICS plus LABA.[62][112]​​ Adding LAMAs to medium- or high-dose ICS-LABA modestly improves lung function and time to severe exacerbations requiring an oral corticosteroid.[112][113][114][115][116][117]​​ A systematic review and meta-analysis found beneficial effects of ICS-LABA-LAMA on exacerbations and asthma control compared to ICS-LABA, but no significant differences in quality of life or mortality.[115]​ Benefit is seen primarily in patients with a history of exacerbations in the previous year.[118]

LAMAs may be given as a separate inhaler, or in a combination ("triple") inhaler that contain ICS, LABA, and LAMA. Availability of the inhalers varies by country.[52] Combination inhalers are not detailed here - consult your local drug formulary for details on available inhalers and doses.

Primary options

tiotropium inhaled: 2.5 micrograms inhaled once daily

OR

umeclidinium inhaled: 62.5 micrograms inhaled once daily

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

2nd line – high-dose inhaled corticosteroid plus long-acting beta agonist

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
2nd line – 

high-dose inhaled corticosteroid plus long-acting beta agonist

Increasing to high-dose inhaled corticosteroid plus long-acting beta agonist (ICS-LABA) is an option at step 4 (track 2), but clinicians and patients should consider the potential increase in adverse effects relating to ICS.[52] The increased dose of ICS rarely provides substantial extra benefit compared with a medium dose, and the risk of adverse effects is increased. Systemic adverse effects relating to long-term, high-dose ICS include easy bruising, an increased risk of osteoporosis, cataracts, glaucoma, and adrenal suppression. Local adverse effects of ICS include oropharyngeal candidiasis (oral thrush) and dysphonia.[52]

A suitable ICS-LABA combination formulation inhaler should be used whenever possible. However, if the high dose of ICS is not achievable with the combination formulation (in order to not go above the maximum LABA dose), a separate ICS inhaler can be added to the combination formulation to achieve the necessary ICS dose.

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

A Cochrane review comparing regular ICS-formoterol with ICS-salmeterol found both combinations to have a similar safety profile in patients with chronic asthma.[101]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

budesonide/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

mometasone/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone propionate/salmeterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone furoate/vilanterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

The evidence for including as-needed ICS-SABA comes from a multinational, phase 3, double-blind, randomized trial evaluating the efficacy and safety of albuterol/budesonide, compared to albuterol alone, in a sub-population of patients taking maintenance medium-dose ICS-LABA or high-dose ICS (step 4 therapy).[110] This showed that there was a significantly decreased risk of severe exacerbations with high-dose as-needed ICS-SABA compared with as-needed SABA.[110] 

Note that this track 2 option can be considerably more complex than the track 1 option, typically requiring multiple inhalers.[110]

For patients using metered-dose inhalers, spacer devices improve delivery of the drug.[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

Consider – leukotriene receptor antagonist

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

leukotriene receptor antagonist

Treatment recommended for SOME patients in selected patient group

Add-on leukotriene receptor antagonist (LTRA) is an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. 

Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Primary options

montelukast: 10 mg orally once daily

OR

zafirlukast: 20 mg orally twice daily

Consider – long-acting muscarinic antagonist

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

long-acting muscarinic antagonist

Treatment recommended for SOME patients in selected patient group

Long-acting muscarinic antagonists (LAMAs), such as tiotropium, glycopyrrolate, or umeclidinium, may be used as an add-on therapy if asthma is persistently uncontrolled despite medium- or high-dose inhaled corticosteroid (ICS)-long-acting beta agonist (LABA).[52] At step 4, there is insufficient evidence to support ICS plus LAMA over ICS plus LABA.[62][112]​​ Adding LAMAs to medium- or high-dose ICS-LABA modestly improves lung function and time to severe exacerbations requiring an oral corticosteroid.[112][113][114][115][116][117]​​ A systematic review and meta-analysis found beneficial effects of ICS-LABA-LAMA on exacerbations and asthma control compared to ICS-LABA, but no significant differences in quality of life or mortality.[115]​ Benefit is seen primarily in patients with a history of exacerbations in the previous year.[118]

LAMAs may be given as a separate inhaler, or in a combination ("triple") inhaler that contain ICS, LABA, and LAMA. Availability of the inhalers varies by country.[52] Combination inhalers are not detailed here - consult your local drug formulary for details on available inhalers and doses.

Primary options

tiotropium inhaled: 2.5 micrograms inhaled once daily

OR

umeclidinium inhaled: 62.5 micrograms inhaled once daily

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

2nd line – high-dose inhaled corticosteroid

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
2nd line – 

high-dose inhaled corticosteroid

Increasing the inhaled corticosteroid (ICS) to a high dose is another second-line option (track 2), but this is less efficacious than adding a long-acting beta agonist to medium-dose ICS.[52]

The increased dose of ICS rarely provides substantial extra benefit compared with a medium dose, and the risk of adverse effects is increased. Systemic adverse effects relating to long-term, high-dose ICS include easy bruising, an increased risk of osteoporosis, cataracts, glaucoma, and adrenal suppression.[52]

For patients using metered-dose inhalers, spacer devices improve delivery of the drug and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52] 

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

beclomethasone dipropionate inhaled: >480 micrograms/day

OR

budesonide inhaled: >1200 micrograms/day

OR

ciclesonide inhaled: >320 micrograms/day

OR

fluticasone propionate inhaled: >440 micrograms/day

OR

mometasone inhaled: >400 micrograms/day

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

The evidence for including as-needed ICS-SABA comes from a multinational, phase 3, double-blind, randomized trial evaluating the efficacy and safety of albuterol/budesonide, compared to albuterol alone, in a sub-population of patients taking maintenance medium-dose ICS-LABA or high-dose ICS (step 4 therapy).[110] This showed that there was no significant increase in time to first severe exacerbation with as-needed ICS-SABA compared with as-needed SABA.[110] Note that this track 2 option can be considerably more complex than the track 1 option, typically requiring multiple inhalers.

For patients using metered-dose inhalers, spacer devices improve delivery of the drug.[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

Consider – leukotriene receptor antagonist

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

leukotriene receptor antagonist

Treatment recommended for SOME patients in selected patient group

Add-on leukotriene receptor antagonist (LTRA) is an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. 

Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Primary options

montelukast: 10 mg orally once daily

OR

zafirlukast: 20 mg orally twice daily

Consider – long-acting muscarinic antagonist

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

long-acting muscarinic antagonist

Treatment recommended for SOME patients in selected patient group

Long-acting muscarinic antagonists (LAMAs), such as tiotropium, glycopyrrolate, or umeclidinium, may be used as an add-on therapy if asthma is persistently uncontrolled despite medium- or high-dose inhaled corticosteroid (ICS)-long-acting beta agonist (LABA).[52] At step 4, there is insufficient evidence to support ICS plus LAMA over ICS plus LABA.[62][112]​​ Adding LAMAs to medium- or high-dose ICS-LABA modestly improves lung function and time to severe exacerbations requiring an oral corticosteroid.[112][113][114][115][116][117]​​ A systematic review and meta-analysis found beneficial effects of ICS-LABA-LAMA on exacerbations and asthma control compared to ICS-LABA, but no significant differences in quality of life or mortality.[115]​ Benefit is seen primarily in patients with a history of exacerbations in the previous year.[118]

LAMAs may be given as a separate inhaler, or in a combination ("triple") inhaler that contain ICS, LABA, and LAMA. Availability of the inhalers varies by country.[52] Combination inhalers are not detailed here - consult your local drug formulary for details on available inhalers and doses.

Primary options

tiotropium inhaled: 2.5 micrograms inhaled once daily

OR

umeclidinium inhaled: 62.5 micrograms inhaled once daily

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 4: asthma not controlled on step 3 treatment
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist

1st line – consider high-dose inhaled corticosteroid plus formoterol as maintenance therapy and low-dose inhaled corticosteroid plus formoterol as reliever therapy

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
1st line – 

consider high-dose inhaled corticosteroid plus formoterol as maintenance therapy and low-dose inhaled corticosteroid plus formoterol as reliever therapy

If a patient with asthma has persistent symptoms or exacerbations despite taking step 4 treatment with good adherence and correct inhaler technique, and after trialing or considering other step 4 controller options, then they should be referred to a specialist in severe asthma (track 1 or track 2).[52] GINA has released a separate pocket guide on difficult-to-treat and severe asthma. GINA: diagnosis and management of difficult-to-treat and severe asthma Opens in new window

Following specialist assessment and optimization of existing treatment, high-dose inhaled corticosteroid (ICS)-formoterol as maintenance therapy and low-dose ICS-formoterol as reliever therapy may be considered on a trial basis at step 5 (GINA track 1).[52]

For the maintenance and reliever therapy (MART) regimen, the same inhaler should be used for both maintenance and reliever doses. The maintenance dose can be increased by increasing the number of inhalations, but the reliever is still low-dose ICS-formoterol.[52]

For patients taking ICS-formoterol as MART, the maximum recommended dose of formoterol in a single day is 72 micrograms metered dose (equivalent to 54 micrograms delivered dose) for budesonide/formoterol.[52] 

Other combination formulations may be available; consult a local drug formulary for more options.

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Primary options

budesonide/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

Consider – leukotriene receptor antagonist

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

leukotriene receptor antagonist

Treatment recommended for SOME patients in selected patient group

Add-on leukotriene receptor antagonist (LTRA) is an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. 

Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Primary options

montelukast: 10 mg orally once daily

OR

zafirlukast: 20 mg orally twice daily

Consider – long-acting muscarinic antagonist

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

long-acting muscarinic antagonist

Treatment recommended for SOME patients in selected patient group

Long-acting muscarinic antagonists (LAMAs), such as tiotropium, glycopyrrolate, or umeclidinium, may be used as an add-on therapy if asthma is persistently uncontrolled despite medium- or high-dose inhaled corticosteroid (ICS)-long-acting beta agonist (LABA).[52] Adding LAMAs to medium- or high-dose ICS-LABA modestly improves lung function and time to severe exacerbations requiring an oral corticosteroid.[112][113][114][115][116][117]​​ A systematic review and meta-analysis found beneficial effects of ICS-LABA-LAMA on exacerbations and asthma control compared to ICS-LABA, but no significant differences in quality of life or mortality.[115]​ Benefit is seen primarily in patients with a history of exacerbations in the previous year.[118]

LAMAs may be given as a separate inhaler, or in a combination ("triple") inhaler that contain ICS, LABA, and LAMA. Availability of the inhalers varies by country.[52] Combination inhalers are not detailed here - consult your local drug formulary for details on available inhalers and doses.

Primary options

tiotropium inhaled: 2.5 micrograms inhaled once daily

OR

umeclidinium inhaled: 62.5 micrograms inhaled once daily

Consider – biologic agent

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

biologic agent

Treatment recommended for SOME patients in selected patient group

Omalizumab can be considered at step 5 in patients with moderate or severe allergic asthma that is uncontrolled on step 4-5 treatment.[52]​​[126][127][128][168]

Mepolizumab, reslizumab, or benralizumab can be considered for patients with severe eosinophilic asthma that is uncontrolled on step 4-5 treatment.[52][129][130]​ Reslizumab must be given intravenously and is approved for use in adults ≥18 years of age only.

Dupilumab can be considered for patients with moderate-to-severe eosinophilic/type 2 asthma, or patients requiring treatment with maintenance oral corticosteroids.[52][131][153]​ Tezepelumab can be considered for patients with severe asthma as an add-on maintenance treatment.[52][132][133]

Some biologics are suitable for self-administration at home after appropriate training.[156]

Primary options

omalizumab: dose depends on baseline serum IgE level and patient weight; consult specialist for guidance on dose

OR

mepolizumab: 100 mg subcutaneously every 4 weeks

OR

reslizumab: 3 mg/kg intravenous infusion every 4 weeks

OR

benralizumab: 30 mg subcutaneously every 4 weeks for the first 3 doses, followed by 30 mg every 8 weeks thereafter

OR

dupilumab: 400 mg subcutaneously initially, followed by 200 mg every other week; or 600 mg subcutaneously initially, followed by 300 mg every other week

More

OR

tezepelumab: 210 mg subcutaneously every 4 weeks

Consider – bronchial thermoplasty

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

bronchial thermoplasty

Treatment recommended for SOME patients in selected patient group

Bronchial thermoplasty is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle.

This procedure is a potential option at step 5 in patients ages ≥18 years when the patient's asthma remains uncontrolled despite optimized pharmacologic therapy and referral to a specialist.[52]​​​

Consider – azithromycin

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

azithromycin

Treatment recommended for SOME patients in selected patient group

Azithromycin is included in the GINA guideline as an alternative add-on therapy (off-label) for patients ages 18 years and older with severe asthma (i.e., after referral at step 5).[52][119]​ A Cochrane review of macrolides (including azithromycin) for the management of chronic asthma found macrolides superior to placebo in reducing severe exacerbations and improving symptoms.[120] However, more robust clinical trial evidence is needed for definite conclusions to be drawn, and concerns remain over the potential for selection of resistant infections and frequency of adverse effects, especially gastrointestinal upset.[52][120][121]

In addition, a cohort study including almost 8 million antibiotic exposures showed an association between outpatient azithromycin use and an increased risk of cardiovascular death and noncardiovascular death.[122] Before starting add-on azithromycin, the patient’s sputum should be checked for atypical mycobacteria, their EKG should be assessed for long QTc interval and re-checked a month after starting treatment, and the risk of antimicrobial resistance should be considered.[52] A baseline audiogram should also be performed to allow monitoring of the effect of azithromycin on hearing function.

Primary options

azithromycin: 500 mg orally three times weekly

Consider – low-dose oral corticosteroid

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

low-dose oral corticosteroid

Treatment recommended for SOME patients in selected patient group

Should only be considered if the patient has poor control of symptoms and/or frequent exacerbations despite correct inhaler technique and good adherence with step 5 treatments, having excluded contributory factors, and having tried other add-on treatments, including biologic agents.[52] Results from a systematic review and meta-analysis suggested that patients with increased markers of type 2 inflammation (i.e., high blood eosinophils and fractional exhaled nitric oxide values) are most responsive to oral corticosteroid therapy.[123]

As oral corticosteroids often lead to substantial adverse effects, patients need to be counseled about and monitored for potential adverse effects, especially if treatment is expected to last 3 months or more.[124] Some patients may need therapy for prevention of osteoporosis.[52]

Primary options

prednisone: ≤7.5 mg orally once daily

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

2nd line – consider high-dose inhaled corticosteroid plus long-acting beta agonist

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
2nd line – 

consider high-dose inhaled corticosteroid plus long-acting beta agonist

If a patient with asthma has persistent symptoms or exacerbations despite taking step 4 treatment with good adherence and correct inhaler technique, and after trialing or considering other step 4 controller options, then they should be referred to a specialist in severe asthma (track 1 or track 2).[52] GINA has released a separate pocket guide on difficult-to-treat and severe asthma. GINA: diagnosis and management of difficult-to-treat and severe asthma Opens in new window

Following specialist assessment and optimization of existing treatment, high-dose inhaled corticosteroid (ICS) plus long-acting beta agonist (LABA) may be considered at step 5 (GINA track 2). However, the increased dose of ICS rarely provides substantial extra benefit compared with a medium dose, and the risk of adverse effects is increased, including adrenal suppression. A high dose should only be used on a trial basis for 3 to 6 months while good asthma control is not attained with medium-dose ICS plus LABA and/or a third controller (e.g., leukotriene receptor antagonist or sustained-release theophylline). The patient must also take a short-acting beta agonist (SABA) as needed.[52]

For patients using metered-dose inhalers, spacer devices improve drug delivery and, for ICS, reduce the risk of local adverse effects (e.g., dysphonia and oral candidiasis).[52]

If the patient has symptoms that persist and/or exacerbations despite high-dose ICS or ICS plus LABA, then their treatment may be adjusted based on eosinophilia (>3%) in induced sputum (sputum-guided treatment). However, only a limited number of centers have facilities to analyze induced sputum routinely.[52]

A suitable ICS-LABA combination formulation inhaler should be used whenever possible. However, if the high dose of ICS is not achievable with the combination formulation (in order to not go above the maximum LABA dose), a separate ICS inhaler can be added to the combination formulation to achieve the necessary ICS dose.

A Cochrane review comparing regular ICS-formoterol with ICS-salmeterol found both combinations to have a similar safety profile in patients with chronic asthma.[101]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Examples of suitable drug regimens are given here; however, consult a local drug formulary for more options.

Primary options

budesonide/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

mometasone/formoterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone propionate/salmeterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

OR

fluticasone furoate/vilanterol inhaled: dose depends on brand and formulation; consult product literature for guidance on dose

Consider – short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) as needed

Treatment recommended for SOME patients in selected patient group

As-needed short-acting beta agonist (or inhaled corticosteroid-short-acting beta agonist) should also be prescribed.[52]

The evidence for including as-needed ICS-SABA comes from a multinational, phase 3, double-blind, randomized trial evaluating the efficacy and safety of albuterol/budesonide, compared to albuterol alone, in a sub-population of patients taking maintenance medium-dose ICS-LABA or high-dose ICS (step 4 therapy).[110] This showed that there was no significant increase in time to first severe exacerbation with as-needed ICS-SABA compared with as-needed SABA.[110] Note that this track 2 option can be considerably more complex than the track 1 option, typically requiring multiple inhalers.

For patients using metered-dose inhalers, spacer devices improve delivery of the drug.[52]

Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

Primary options

albuterol inhaled: 90-180 micrograms every 4-6 hours when required

OR

levalbuterol inhaled: 45-90 micrograms every 4-6 hours when required

OR

albuterol/budesonide inhaled: 180 micrograms (albuterol)/160 micrograms (budesonide) when required, maximum 12 inhalations/day

Consider – leukotriene receptor antagonist

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

leukotriene receptor antagonist

Treatment recommended for SOME patients in selected patient group

Add-on leukotriene receptor antagonist (LTRA) is an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect.

Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Primary options

montelukast: 10 mg orally once daily

OR

zafirlukast: 20 mg orally twice daily

Consider – long-acting muscarinic antagonist

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

long-acting muscarinic antagonist

Treatment recommended for SOME patients in selected patient group

Long-acting muscarinic antagonists (LAMAs), such as tiotropium, glycopyrrolate, or umeclidinium, may be used as an add-on therapy if asthma is persistently uncontrolled despite medium- or high-dose inhaled corticosteroid (ICS)-long-acting beta agonist (LABA).[52] Adding LAMAs to medium- or high-dose ICS-LABA modestly improves lung function and time to severe exacerbations requiring an oral corticosteroid.[112][113][114][115][116][117]​​ A systematic review and meta-analysis found beneficial effects of ICS-LABA-LAMA on exacerbations and asthma control compared to ICS-LABA, but no significant differences in quality of life or mortality.[115]​ Benefit is seen primarily in patients with a history of exacerbations in the previous year.[118]

LAMAs may be given as a separate inhaler, or in a combination ("triple") inhaler that contain ICS, LABA, and LAMA. Availability of the inhalers varies by country.[52] Combination inhalers are not detailed here - consult your local drug formulary for details on available inhalers and doses.

Primary options

tiotropium inhaled: 2.5 micrograms inhaled once daily

OR

umeclidinium inhaled: 62.5 micrograms inhaled once daily

Consider – biologic agent

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

biologic agent

Treatment recommended for SOME patients in selected patient group

Omalizumab can be considered at step 5 in patients with moderate or severe allergic asthma that is uncontrolled on step 4-5 treatment.[52]​​[126][127][128][168]​​

Mepolizumab, reslizumab, or benralizumab can be considered for patients with severe eosinophilic asthma that is uncontrolled on step 4-5 treatment.[52][129][130]​ Reslizumab must be given intravenously and is approved for use in adults ≥18 years of age only.

Dupilumab can be considered for patients with moderate-to-severe eosinophilic/type 2 asthma, or patients requiring treatment with maintenance oral corticosteroids.[52][131][153]​ Tezepelumab can be considered for patients with severe asthma as an add-on maintenance treatment.[52][132][133]

Some biologics are suitable for self-administration at home after appropriate training.[156]

Primary options

omalizumab: dose depends on baseline serum IgE level and patient weight; consult specialist for guidance on dose

OR

mepolizumab: 100 mg subcutaneously every 4 weeks

OR

reslizumab: 3 mg/kg intravenous infusion every 4 weeks

OR

benralizumab: 30 mg subcutaneously every 4 weeks for the first 3 doses, followed by 30 mg every 8 weeks thereafter

OR

dupilumab: 400 mg subcutaneously initially, followed by 200 mg every other week; or 600 mg subcutaneously initially, followed by 300 mg every other week

More

OR

tezepelumab: 210 mg subcutaneously every 4 weeks

Consider – bronchial thermoplasty

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

bronchial thermoplasty

Treatment recommended for SOME patients in selected patient group

Bronchial thermoplasty is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle.

This procedure is a potential option at step 5 in patients ages ≥18 years when the patient's asthma remains uncontrolled despite optimized pharmacologic therapy and referral to a specialist.[52]​​​

Consider – azithromycin

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

azithromycin

Treatment recommended for SOME patients in selected patient group

Azithromycin is included in the GINA guideline as an alternative add-on therapy (off-label) for patients ages 18 years and older with severe asthma (i.e., after referral at step 5).[52][119]​ A Cochrane review of macrolides (including azithromycin) for the management of chronic asthma found macrolides superior to placebo in reducing severe exacerbations and improving symptoms.[120] However, more robust clinical trial evidence is needed for definite conclusions to be drawn, and concerns remain over the potential for selection of resistant infections and frequency of adverse effects, especially gastrointestinal upset.[52][120][121]

In addition, a cohort study including almost 8 million antibiotic exposures showed an association between outpatient azithromycin use and an increased risk of cardiovascular death and noncardiovascular death.[122] Before starting add-on azithromycin, the patient’s sputum should be checked for atypical mycobacteria, their EKG should be assessed for long QTc interval and re-checked a month after starting treatment, and the risk of antimicrobial resistance should be considered.[52] A baseline audiogram should also be performed to allow monitoring of the effect of azithromycin on hearing function.

Primary options

azithromycin: 500 mg orally three times weekly

Consider – low-dose oral corticosteroid

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

low-dose oral corticosteroid

Treatment recommended for SOME patients in selected patient group

Should only be considered if the patient has poor control of symptoms and/or frequent exacerbations despite correct inhaler technique and good adherence with step 5 treatments, having excluded contributory factors, and having tried other add-on treatments, including biologic agents.[52] Results from a systematic review and meta-analysis suggested that patients with increased markers of type 2 inflammation (i.e., high blood eosinophils and fractional exhaled nitric oxide values) are most responsive to oral corticosteroid therapy.[123]

As oral corticosteroids often lead to substantial adverse effects, patients need to be counseled about and monitored for potential adverse effects, especially if treatment is expected to last 3 months or more.[124] Some patients may need therapy for prevention of osteoporosis.[52]

Primary options

prednisone: ≤7.5 mg orally once daily

Consider – management of exercise-induced bronchoconstriction

Back
ONGOING
|
ongoing treatment step 5: asthma not controlled on step 4 treatment and patient reviewed by specialist
Consider – 

management of exercise-induced bronchoconstriction

Treatment recommended for SOME patients in selected patient group

The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) 5-20 minutes before exercise and, for patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA), and/or a leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

In a 6-week study in patients with mild asthma, low-dose budesonide/formoterol, taken as needed for symptoms and before exercise, was noninferior compared with daily ICS plus SABA as needed for reducing exercise-induced bronchoconstriction.[81] This suggests that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise. However, more studies are needed here.[52]

LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction - these include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma, requiring stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

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