Types
There are five combination inhalers approved by the U.S. Food and Drug Administration (FDA) for treating asthma:
Advair HFA, a combination of the steroid fluticasone and the LABA salmeterol (approved in 2000) Advair Diskus, a combination of the steroid fluticasone and the LABA salmeterol in dry powder form (approved in 2000) Symbicort, a combination of the steroid budesonide and the LABA formoterol (approved in 2006) Dulera, a combination of the steroid mometasone and the LABA formoterol (approved in 2010) Breo Ellipta, a combination of the steroid fluticasone and the LABA vilanterol (approved in 2015)
Generic forms of Advair, known by the brand names AirDuo Respiclick, Wixela Inhub, and others, also are available. Symbicort generics (including the branded generic Breyna, approved in 2022) are also commonly sold as a budesonide/formoterol inhaler.
Uses
Combination inhalers are used to control asthma symptoms and ward off asthma attacks. They do double duty by each targeting a specific aspect of the physiological events that comprise an asthma attack:
Corticosteroids, also known as steroids, mimic the hormone cortisol which the body naturally produces to control inflammation. When used on a daily basis, corticosteroids help control the inflammation that contributes to airway hyperresponsiveness. LABAs are classified as bronchodilators, meaning they help open (dilate) the airways of the lungs—i. e. , the bronchi and bronchioles. Although their mechanism of action is similar to that of rescue inhalers, they are longer-lasting and, when taken daily, are effective in preventing bronchospasms and the narrowing of airways.
Other Approved and Off-Label Uses
Symbicort and Breo also are approved for the daily treatment of chronic obstructive pulmonary disease (COPD). Advair Diskus, the dry powder form of the drug, is approved for COPD as well, although its aerosolized form, Advair HFA, is not.
Studies have shown that salmeterol, the LABA used in Advair HFA, increases the risk of pneumonia in people with COPD. Though Advair Diskus also contains salmeterol, the dose is far smaller and is considered safer for ongoing use.
Some healthcare providers prescribe Dulera off-label to people with COPD, although its safety and effectiveness for this purpose have not yet been established.
Before Taking
You are a candidate for a combination asthma inhaler if a rescue inhaler alone fails to control your asthma, meaning you:
Must use your rescue inhaler more than twice a week Awaken at night with asthma symptoms more than twice a month Have to refill your rescue inhaler prescription more than twice a week
That is not to suggest a combination inhaler is a one-size-fits-all-solution. A 2015 study in the Annals of the American Thoracic Society argued that inhaled steroids were just as effective in controlling asthma symptoms as combined steroid/LABA therapy and allowed for adjustments in doses when needed.
Other studies contend that, because of their convenience, people are more likely to use them as prescribed, effectively improving health outcomes in people with asthma. Moreover, combination inhalers require a smaller dose of steroids to achieve the same benefits in control as single steroid inhalers.
A 2013 review in the Cochrane Database of Systematic Reviews concluded that people who used combination inhalers were less likely to be hospitalized or need emergency room visits than those who used two different inhalers and were less likely to need stronger oral steroids in the future.
Precautions and Contrainidications
The only absolute contraindication for the use of a combination inhaler is a known allergy to any active or inactive ingredient used in the inhaler. This includes an allergy to milk, as milk powder is a central inactive ingredient in both Advair Diskus and Breo Ellipta.
LABAs are known to affect blood pressure, blood sugar, heart rate, thyroid hormone production, and the firing of brain cells. These effects are tempered somewhat by inhaled corticosteroids, allowing LABAs to be delivered at smaller doses.
There also is evidence the long-term use of inhaled corticosteroids can affect the eyes as well as impair the body’s ability to fight infections.
Because of these concerns, combination asthma inhalers should be used with caution in people with the following health conditions:
Cardiac arrhythmia Cataracts Coronary artery disease Diabetes Epilepsy Glaucoma Hyperthyroidism Uncontrolled high blood pressure
People with any of these conditions should be routinely monitored to identify changes in their health status while on combination inhalers. In some cases, treatment may need to be stopped if symptoms worsen.
All combination asthma inhalers should be used with caution during pregnancy, as animal studies have suggested a potential for fetal harm, but no well-controlled studies in humans are available.
Although there is no evidence of an increased risk of birth defects in pregnancy registries, it is still important to speak with your healthcare provider to weigh the benefits and risks of treatment if you are pregnant, breastfeeding, or planning to get pregnant.
Dosage
The combination asthma inhalers currently approved by the FDA can be categorized by their delivery system:
Advair HFA, Dulera, and Symbicort are meter-dose inhalers (MDIs) that deliver the medications using an aerosolized propellent. Advair Diskus and Breo Ellipta are dry powder inhalers (DPIs) that deliver a dose of the medication in powder form that you simply inhale through the mouthpiece.
The recommended dose can vary by age. As a general rule, smaller doses are prescribed when first starting treatment and increased only if the drug fails to provide adequate control of symptoms.
Have your healthcare provider fully explain the benefits and limitations of each option to determine which inhaler is best suited to your needs.
How to Take and Store
MDIs and DPIs have pros and cons. MDIs deliver accurate doses and are easy to use, but require hand-breath coordination. DPIs don’t have buttons or require hand-breath coordination, but they can deliver varying doses based on how forcefully you inhale the medication.
Learning how to use a device properly can help you reap the optimal benefits.
To use an MDI like Advair HFA, Dulera, or Symbicort:
Remove the cap on the mouthpiece. Prime the inhaler if you have not used it recently by shaking the canister for five seconds and spraying it away from your face in a short burst. Repeat once. If the inhaler does not need priming (i. e. , you have used it recently), simply shake well for five seconds. Exhale fully to empty the lungs. Put the mouthpiece into your mouth and wrap your lips tightly to create a seal. Simultaneously press the inhaler button while taking a deep breath. Hold your breath for 10 seconds. Gently exhale. Repeat steps 3 through 7 to deliver your second dose. Replace the cap until you hear a click. Rinse your mouth with water to clear medication residue. Do not swallow.
MDIs need to be cleaned once weekly by wiping the mouthpiece with a dampened tissue and cleaning the aerosol opening with a dry cotton swab. Do not submerge the canister in water.
To use a DPI like Advair Diskus or Breo Ellipta:
Open the mouthpiece cover. Do not shake the inhaler. Push the loading lever until you hear a click. This delivers the prescribed dose of medication. Exhale fully. Place your lips around the mouthpiece to form a tight seal. Breathe in quickly only through your mouth to inhale the medication. Hold your breath for 10 seconds. Gently exhale. Repeat steps 2 to 7 if you are using Advair Diskus. You do not need to repeat these if you are using Breo Ellipta. Clean the mouthpiece, if needed, with a dry tissue. (DPIs do not need routine cleaning. )Slide the mouthpiece cover completely to close the device. Rinse your mouth with water and spit. Do not swallow.
MDIs and DPIs can be stored safely at room temperature, ideally between 68 degrees F and 77 degrees F. Do not store MDIs near heat or an open flame as this can cause bursting. Keep out of reach of children or pets.
Do not use an inhaler or any medication past its expiration date.
Side Effects
As with any medication, combination asthma inhalers can cause side effects. Many of these are relatively mild and will gradually resolve as your body adapts to treatment. Let your healthcare provider know if any side effect is severe, persists, or worsens.
Common
Common side effects are largely the same between the different inhalant formulations. Those affecting 2% or more of users include:
Stuffy or runny nose Sneezing Headache Sore throat Hoarseness Cough Sinus pain Dizziness Flu-like symptoms Nausea or vomiting Upper respiratory infection Oral thrush (candidiasis)
Of the various drug formulations, Dulera has the fewest side effects (primarily stuffy or runny nose, sneezing, headache, and sinus pain).
The risk of oral thrush can be reduced by using a spacer with a MDI. Because DPIs such as Advair Diskus and Breo Ellipta cannot accommodate a spacer, you can reduce your risk of thrush by rinsing your mouth thoroughly with water after every use.
Severe
An uncommon but serious side effect of combination asthma inhalers is paradoxical bronchospasm, a condition in which symptoms of asthma worsen rather than improve. LABAs are responsible for this effect, although the exact cause of the reaction is poorly understood.
Paradoxical bronchospasms appear to affect people with severe airway inflammation who use an inhalant for the first time.
Anaphylaxis, a potentially life-threatening, whole-body allergy, is a rare occurrence with combination asthma inhalers, but cases have been reported in people who have used Advair Diskus or Breo Ellita due to an underlying milk allergy.
Call 911 or seek emergency care if you experience the following after using a combination asthma inhaler:
Sudden severe rash or hivesShortness of breathWheezingDizzinessIrregular heartbeatSwelling of the face, tongue, or lipsA feeling of impending doom
If left untreated, anaphylaxis can lead to shock, coma, asphyxiation, cardiac or respiratory failure, and death.
Warnings and Interactions
Corticosteroids are known to affect bone density, but this appears to be less a risk with inhaled corticosteroids than with oral corticosteroids. Still, young children should be monitored as the long-term use of a combination inhaler may impair growth. The risks appear greatest among toddlers with severe persistent asthma.
There are a number of common drugs and drug classes known to interact with combination asthma inhalers.
Corticosteroids and LABAs are both metabolized by a liver enzyme called cytochrome P450 (CYP450) and can interact with other drugs that use the same enzyme for metabolization. This competition can slow the rate at which a drug is cleared from the body. This may either increase the concentration of a drug (along with its side effects) or decrease the concentration of a drug (and reduce its efficacy).
Among the drugs of greatest concern are:
Antibiotics like clarithromycin, telithromycin, and troleandomycin Antifungals like ketoconazole, itraconazole, and voriconazole Atypical antidepressants like Serzone (nefazodone) HIV drugs like Kaletra (ritonavir/lopinavir), Crixivan (indinavir), and Invirase (saquinavir)
LABAs on their own can interact with four classes of drugs in different ways. These include:
Beta-blockers like Lopressor (metoprolol) or Sectral (acebutolol) may block the effect of the combination inhaler and even trigger bronchospasms. Monoamine oxidase inhibitor (MAOI) antidepressants like Parnate (tranylcypromine) may trigger heart rhythm problems. Non-potassium-sparing diuretics like hydrochlorothiazide may lead to low potassium (hypokalemia) and trigger cardiac irregularities. Tricyclic antidepressants like Elavil (amitriptyline) can also cause heart rhythm disturbances if used with a LABA.
To avoid drug interactions, let your healthcare provider know about any drug you are taking, be it prescription, over-the-counter, herbal, or recreational.
Black Box Warning
Until late 2017, the FDA issued a black box warning for all corticosteroid/LABA inhalers, advising consumers that the drugs were associated with an increased risk of asthma-related deaths. The advisement was based on studies in which 13 deaths were reported among 13,176 LABA users over a 28-week study period.
On December 20, 2017, the FDA reversed the order when it was shown that the risk of death occurred when LABAs were used on their own (in monotherapy). Current research has shown that the combined use of a LABA and corticosteroid poses no such harm.
Although the black box warning has been stripped from the packaging of combination asthma inhalers, it remains on all single-ingredient LABA medications.
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