What to Know About Combination Asthma Inhalers

Medications for Daily Use When Rescue Inhalers Are Not Enough

Combination asthma inhalers are important tools for the long-term control of asthma symptoms. They combine two different inhaled medications—a corticosteroid and a long-acting beta-agonist (LABA)—which together can ease airway hyperresponsiveness that can lead to an asthma attack.

There are five such inhalers approved by the U.S. Food and Drug Administration (FDA) for the treatment of asthma: Advair HFA, Advair Diskus, Breo Ellipta, Dulera, and Symbicort. Each has its advantages, drawbacks, and limitations.

Uses

The combination inhalers approved by the FDA for the treatment of asthma are (by date of approval):

  • 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 (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, are now available. Symbicort generics, commonly sold as a budesonide/formoterol inhaler, are also available.

How They Work

The two drug classes used in combination inhalers have different mechanisms of action that contribute to the long-term control of asthma symptoms:

  • Corticosteroids, also known as steroids, mimic the hormone cortisol which the body uses 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 that 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 are also approved for the daily treatment of chronic obstructive pulmonary disease (COPD). Advair Diskus, the dry powder form of the drug, is also approved for COPD treatment, though 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.

Dulera is not yet approved for COPD treatment, although its application is pending. Although some doctors prescribe Dulera off-label to patients with COPD, its safety and effectiveness for this purpose have not yet been established.

Before Taking

You are a candidate for a combination asthma inhaler if you are unable to control your asthma symptoms with a rescue inhaler alone. Generally speaking, your asthma is not being well controlled if:

  • You use your rescue inhaler more than twice weekly.
  • You awaken at night with asthma symptoms more than twice monthly.
  • You have to refill your rescue inhaler prescription more than twice weekly.

In the past, inhaled corticosteroids were the first drugs used as controller medications if a rescue inhaler failed to provide adequate control of asthma symptoms. Today, instead of waiting to add a LABA to the treatment plan, many health authorities—including the Global Initiative for Asthma (GINA)—endorse the combined use of an inhaled corticosteroid and an inhaled LABA from the start.

That is not to suggest that 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, combinations inhalers are more likely to increase drug adherence rates and, in turn, improve 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 to the use of 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 the use of inhaled corticosteroids, allowing LABAs to be delivered at smaller doses.

There is also evidence that 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:

People with any of the conditions should be routinely monitored to identify any 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 are classified as Pregnancy Category C drugs, meaning that 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 doctor 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 only increased if the drug fails to provide adequate control of symptoms.

Recommended Dosages
Drug Formulations in micrograms (mg) Approved for Recommended Dose
Advair HFA •45 mcg fluticasone/230 mcg salmeterol
•150 mcg fluticasone/230 mcg salmeterol
•230 mcg fluticasone/230 mcg salmeterol
Adult and children 12 and over 2 inhalations twice daily, 12 hours apart
Advair Diskus 100 mcg fluticasone/50 mcg salmeterol
250 mcg fluticasone/50 mcg salmeterol
500 mcg fluticasone/50 mcg salmeterol
Adults and children 4 and over 2 inhalations twice daily, 12 hours apart
Breo Ellipta •100 mcg fluticasone/25 mcg vilanterol
•200 mcg fluticasone/25 mcg vilanterol
Adults 18 and over 1 inhalation daily
Dulera 100 mcg mometasone/5 mcg formeterol
200 mcg mometasone/5 mcg formeterol
Adult and children 12 and over  2 inhalations twice daily, 12 hours apart
Symbicort 80 mcg budesonide/4.5 mcg formeterol (children)
160 mcg budesonide/4.5 mcg formeterol (adults)
Adult and children 6 and over 2 inhalations twice daily, 12 hours apart

There is no one combination asthma inhaler that is inherently "better" than the others. Some may be more appropriate based on age, while cost, delivery system, and dosing requirements (once-daily vs. twice-daily) may also factor into the decision.

Speak to your doctor to fully understand the benefits and limitations of each option and why some may be better suited for you than others.

How to Take and Store

MDIs and DPIs have their pros and cons. MDIs deliver accurate doses and are easy-to-use, but they 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:

  1. Remove the cap on the mouthpiece.
  2. 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 this one more time. If the inhaler does not need priming (i.e., you have used it recently), simply shake well for five seconds.
  3. Exhale fully to empty the lungs.
  4. Put the mouthpiece into your mouth and wrap your lips tightly to create a seal.
  5. Simultaneously press the inhaler button while taking a deep breath.
  6. Hold your breath for 10 seconds.
  7. Gently exhale.
  8. Repeat steps 3 through 7 to deliver your second dose.
  9. Replace the cap until you hear a click.
  10. 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:

  1. Open the mouthpiece cover. Do not shake the inhaler.
  2. Push the loading lever until you hear a click. This delivers the prescribed dose of medication.
  3. Exhale fully.
  4. Place your lips around the mouthpiece to form a tight seal.
  5. Breathe in quickly only through your mouth to inhale the medication.
  6. Hold your breath for 10 seconds.
  7. Gently exhale.
  8. Repeat steps 2 to 7 if you are using Advair Diskus. You do not need to repeat these if you are using Breo Ellipta.
  9. Clean the mouthpiece, if needed, with a dry tissue. (DPIs do not need routine cleaning.)
  10. Slide the mouthpiece cover completely to close the device.
  11. Rinse your mouth with water and spit. Do not swallow.

Both MDIs and DPIs have built-in dose counters that tell you how many doses are left after each inhalation. Be sure to refill your prescription when the counter gets down to "20" (or "10" for Breo Ellipta).

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 are relatively mild and will gradually resolve as your body adapts to treatment. Let your doctor 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 MDIs. Because DPIs like Advair Diskus and Breo Ellipta cannot accommodate a spacer, the only way to reduce your risk of thrush is by rinsing your mouth thoroughly with water after every use.

Severe

An uncommon but serious side effect of combination asthma inhalers is paradoxical bronchospasm in which symptoms of asthma worsen rather than improve. LABAs are the agents 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.

The sudden onset of shortness of breath, wheezing, chest pain, and cough after the use of a combination asthma inhaler should always be regarded as a medical emergency. People who experience paradoxical bronchospasm should not be rechallenged with the same drug.

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 hives
  • Shortness of breath
  • Wheezing
  • Dizziness
  • Irregular heartbeat
  • Swelling of the face, tongue, or lips
  • A 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 of 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 by 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 doctor know about any drug you are taking, be it prescription, over-the-counter, herbal, or recreational.

Black Box Warning

Until late-2017, the FDA had 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 early 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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Article Sources
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  1. GlaxoSmithKline. Advair HFA (fluticasone propionate and salmeterol inhalation aerosol), for oral inhalation use. Updated February 2020.

  2. GlaxoSmithKline. Advair Diskus 100/50 (fluticasone propionate 100 mcg and salmeterol 50 mcg inhalation powder), Advair Diskus 250/50 (fluticasone propionate 250 mcg and salmeterol 50 mcg inhalation powder), Advair Diskus 500/50 (fluticasone propionate 500 mcg and salmeterol 50 mcg inhalation powder). Updated January 2019.

  3. AstraZeneca. Symbicort (budesonide and formoterol fumarate dihydrate) Inhalation Aerosol, for oral inhalation use. Updated January 2017.

  4. Merck & Co. Dulera (mometasone furoate and formoterol fumarate dihydrate) inhalation aerosol, for oral inhalation use. Updated June 2017.

  5. GlaxoSmithKline. Breo Ellipta (fluticasone furoate and vilanterol inhalation powder), for oral inhalation use. Update January 2019.

  6. Teva Pharmaceutical. AirDuo Respiclick (fluticasone propionate and salmeterol) inhalation powder 55 mcg/14 mcg, AirDuo Respiclick(fluticasone propionate and salmeterol) inhalation powder 113 mcg/14 mcg, AirDuo Respiclick (fluticasone propionate and salmeterol) inhalation powder 232 mcg/14 mcg. Updated January 2017.

  7. Mylan. Wixela Inhub (fluticasone propionate and salmeterol inhalation powder), for oral inhalation use. Updated January 2019.

  8. Yang HH, Lai CC, Wang YH, et al. Severe exacerbation and pneumonia in COPD patients treated with fixed combinations of inhaled corticosteroid and long-acting beta2 agonist. Int J Chron Obstruct Pulmon Dis. 2017;12:2477-85. doi:10.2147/COPD.S139035

  9. Tang W, Sun L, Fizgerald JM. A paradigm shift in the treatment of mild asthma?. J Thorac Dis. 2018;10(10):5655-8. doi:10.21037/jtd.2018.09.127

  10. Israel E, Roche N, Martin RJ, et al. Increased dose of inhaled corticosteroid versus add-on long-acting β-agonist for step-up therapy in asthma. Ann Am Thorac Soc. 2015;12(6):798-806. doi:10.1513/AnnalsATS.201412-580OC

  11. Kew KM, Karner C, Mindus SM, Ferrara G. Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children. Cochrane Database Syst Rev. 2013;12:CD009019. doi:10.1002/14651858.CD009019.pub2

  12. Robles J, Motheral L. Hypersensitivity reaction after inhalation of a lactose-containing dry powder inhaler. J Pediatr Pharmacol Ther. 2014;19(3):206-11. doi:10.5863/1551-6776-19.3.206

  13. Shroff S, Thomas RK, D'Souza G, Nithyanandan S. The effect of inhaled steroids on the intraocular pressure. Digit J Ophthalmol. 2018;24(3):6-9. doi:10.5693/djo.01.2018.04.001

  14. Billington CK, Penn RB, Hall IP. β Agonists. Handb Exp Pharmacol. 2017;237:23-40. doi:10.1007/164_2016_64

  15. Magee JS, Pittman LM, Jette-Kelly LA. Paradoxical bronchoconstriction with short-acting beta agonistAm J Case Rep. 2018;19:1204-7. doi:10.12659/AJCR.910888

  16. Philip J. The effects of inhaled corticosteroids on growth in children. Open Respir Med J. 2014;8:66-73. doi:10.2174/1874306401408010066

  17. Ajimura CM, Jagan N, Morrow LE, Malesker MA. Drug interactions with oral inhaled medications. J Pharm Technol. 2018 Dec;34(6):273-80. doi:10.1177/8755122518788809

  18. Hasford J, Virchow JC. Excess mortality in patients with asthma on long-acting beta2-agonists. Eur Respir J. 2006;28(5):900-2. doi: 10.1183/09031936.00085606

  19. U.S. Food and Drug Administration. FDA drug safety communication: FDA review finds no significant increase in risk of serious asthma outcomes with long-acting beta agonists (LABAs) used in combination with inhaled corticosteroids (ICS). December 20, 2017.