Is The Albuterol Inhaler Obsolete?

For decades, the mainstay of asthma treatment has been a daily maintenance steroid inhaler coupled with an as-needed albuterol rescue inhaler. New evidence suggests that there are better options than albuterol and that it may be time to retire the albuterol inhaler for asthma.

 

The metered-dose inhaler was invented in 1955, when 13-year-old Susie Maison asked her father why she had to take her asthma medication in a squeeze bottle and why it could not be put into a can, like hairspray. Her father was the president of Riker Laboratories (now 3M) and thought that his daughter was onto something. Within a year, Riker released the Medihaler-epi and Medihaler-iso, containing the β-agonists, epinephrine and isoprenaline, respectively. These gave way to the β-agonist inhalers that I prescribed in the 1980’s: Alupent (metaproterenol), Maxair (pirbuterol), Brethaire (terbutaline), Tornalate (bitolterol), Proventil (albuterol), and Ventolin (albuterol). With the international agreement to eliminate inhalers containing chlorofluorocarbons, all of these except albuterol were taken off the market by 2010.  And so, for the past 12 years, albuterol (also known as salbutamol outside of the United States) has been the sole short-acting β-agonist available in the United States.

Why use albuterol in asthma, anyway?

Asthma is an obstructive lung disease where the airways of the lungs become narrowed. This narrowing is caused by a combination of bronchospasm and inflammation. Bronchospasm is caused by contraction of the smooth muscles that line the airways and can be relieved by β-agonists, such as albuterol. Inflammation is caused by a group of biochemicals that cause white blood cells such as neutrophils, eosinophils, and lymphocytes in the airways to become activated resulting in swelling of the airway walls and secretion of mucus into the airways. Inflammation can be relieved by corticosteroids.

β-agonists can relieve the bronchospasm component of airway narrowing almost immediately but steroids take hours or days to relieve airway inflammation. Albuterol and other β-agonists only relieve bronchoconstriction and have no effect on inflammation. Albuterol’s duration of action is 3 – 6 hours. Therefore, in an asthma flare, β-agonists alone can provide partial short-term improvement in airway narrowing but will not relieve the underlying inflammation. For decades, asthma treatment has required albuterol and steroids to be given separately. Albuterol and other β-agonists are most commonly given by inhalation, either via a metered-dose inhaler or by a nebulizer. Steroids can be given via metered-dose inhalers on a scheduled basis for prevention of asthma flares. Steroids can also be given by pills (such as prednisone) or by intravenous infusions (such as methylprednisolone) once a patient’s asthma flares up.

The argument against inhalers containing only albuterol

This month, the MANDALA study was published in the New England Journal of Medicine that indicates that a combination of albuterol plus the corticosteroid budesonide in a single inhaler is better for relieving asthma symptoms than an albuterol-only inhaler. In this randomized double-blind study, 3,132 subjects with moderate to severe asthma at 295 different centers worldwide (including the U.S.) were given a rescue inhaler containing only albuterol or were given a rescue inhaler containing both albuterol and budesonide. Those subjects who received the albuterol + budesonide inhaler had 26% fewer severe asthma flares than those who received albuterol alone. The implication of the study is that when a person’s asthma flares up, treating both inflammation and bronchospasm is more effective than treating bronchospasm alone.

This reinforces the asthma treatment guidelines recommended by GINA (the Global Initiative for Asthma). GINA began as a collaborative effort of the U.S. National Institutes of Health and the World Health Organization and over the past 29 years, it has become the gold standard for asthma treatment recommendations. The 2022 GINA Report recommends that the first line asthma reliever treatment should initially be a combined formoterol (a long-acting β-agonist) + steroid inhaler and if this is not available, then the second line is to use two inhalers: an albuterol (a short-acting β-agonist) inhaler plus a separate steroid inhaler simultaneously. The formoterol + steroid inhaler is thus preferred over the albuterol only inhaler as a reliever medication.

The U.S. National Institutes of Health’s National Asthma Education and Prevention Program (NAEPP) updated their asthma treatment guidelines in 2020 and made similar recommendation for the use of a formoterol + inhaled corticosteroid combination inhaler for use as both a maintenance and a reliever inhaler in patients with moderate or severe asthma.

Formoterol is a long-acting β-agonist and is the ingredient in the inhaler, Foradil. It is also an ingredient in the combination inhalers Symbicort (formoterol + budesonide) and Dulera (formoterol + mometasone). Budesonide and mometasone are both inhaled corticosteroids. In 2003, the FDA required that all inhalers containing both long-acting β-agonists + inhaled corticosteroids (such as Symbicort and Dulera) include black box warnings in their package inserts. These warnings stated that long-acting beta agonists have been linked to increased death and that Symbicort, Dulera, and all other combined long-acting β-agonist + corticosteroid inhalers should only be used in patients with severe asthma not controlled by an inhaled corticosteroid alone. The black box warnings further specified that these combination inhalers should be discontinued as soon as possible once asthma is controlled. The black box warnings originated because of the SMART trial (Salmeterol Multicenter Asthma Research Trial) published in 2006. In this study, asthmatics were treated with salmeterol (a long-acting β-agonist) or placebo as a sole maintenance inhaler for asthma and the results indicated increased death in patients receiving salmeterol. An important criticism of this study is that patients were not treated with an inhaled steroid, just the inhaled salmeterol. The implication is that subjects in the SMART trial were only treated for bronchospasm and their airway inflammation was left untreated. Nevertheless, due to the SMART trial, the FDA required the black box warning of risk of death for any inhaler containing a long-acting beta agonist, including those in which the long-acting β-agonist is combined with an inhaled corticosteroid. In 2017, the FDA removed the black box warning on these combination inhalers after further studies showed that the combination inhalers were not associated with increased death (unlike the single agent long-acting β-agonist inhalers).

However, the previously required black box warnings have left an indelible imprint on American physician prescribing practices. Despite the removal of these warnings 5 years ago, many physicians remain hesitant to adopt the GINA guidelines recommending that combination long=acting β-agonist + inhaled corticosteroid inhalers be used as rescue inhalers. Furthermore, the use of inhalers such as Symbicort and Dulera as rescue inhalers is still considered off-label in the United States.

To make matters worse, the asthma management strategy of using a formoterol + inhaled corticosteroid combination inhaler as both a maintenance and a reliever inhaler has been referred to by the National Asthma Education and Prevention Program and others as “SMART” (Single Maintenance And Reliever Therapy). This unfortunate use of the term “SMART” to promote the use of a combination inhaler containing a long-acting β-agonist in asthma has been confused by many clinicians with the SMART study published in 2006 that condemned the use of long-acting β-agonists in asthma and resulted in the previous black box warnings. As a consequence, when many physicians hear about “SMART” asthma therapy, they think that this means “…don’t use long-acting β-agonists for asthma”.

The net result is that American physicians are considerably behind the rest of the world when it comes to using formoterol + corticosteroid inhalers as asthma reliever inhalers and instead continue to rely on albuterol-only inhalers. The graph below from the U.S. FDA shows that formoterol (diamonds) has a similar onset of action as albuterol (triangles) but has a longer effect than albuterol.

The pharmaceutical company, AstraZeneca, is now developing the combination albuterol + budesonide inhaler used in the MANDALA study that is currently only known as PT027. A new drug application was filed with the FDA last month for PT027 so we will likely see it commercially available in the United States in the near future. There is reason to hope that the albuterol + corticosteroid inhaler will be better accepted by American physicians as a rescue inhaler than the formoterol + corticosteroid inhalers.

Is this the end of albuterol?

I think the answer to that question is a pretty solid “No”. Albuterol will continue to be used in COPD and the probable high cost of the combination albuterol + budesonide inhaler will be a barrier to widespread replacement of albuterol-only inhalers in patients with asthma.

What about COPD? Albuterol-only inhalers will continue to be used in another obstructive lung disease, COPD. There is a general reluctance to use inhaled steroids in patients with COPD where, unlike asthma, inhaled steroids increase the risk of pneumonia in most COPD patients. Therefore, albuterol-only inhalers will likely continue to be used as reliever inhalers in patients with COPD.

What about mild asthma? The MANDALA study only looked at patients with moderate to severe asthma. There is a very large population of patients with asthma for whom albuterol-only inhalers seem to work well. This includes patients with exercise-induced asthma and asthma that is only triggered when a person inhales something that they are allergic to (such as cat antigens). These asthma patients were not included in the MANDALA study and so we do not know if the combination albuterol + budesonide inhaler works better than an albuterol-only inhaler for them. As a consequence, it is likely that AstraZeneca will only seek FDA approval for PT027 in those patients with moderate or severe asthma and not in those with mild asthma.

What about cost to patients? Once PT027 is approved by the FDA, it will likely be expensive. A generic albuterol inhaler costs about $30 whereas brand name albuterol is about $75 per inhaler. PT027 will probably be priced closer to brand name combination long-acting β-agonists + corticosteroid inhalers. These typically cost about $300 – $400 per inhaler (a generic formoterol + budesonide inhaler costs about $200 per inhaler). Price alone will make albuterol preferred by those asthmatics without prescription medication insurance. Even for those with insurance, high co-pays and high deductibles may preclude widespread adoption of PT027 as the asthma reliever inhaler of choice.

What about employers? Most employers leave the decision about which drugs will be covered by employee health insurance up to the commercial insurance companies. However, employers may want to pressure insurance companies to include PT027 on their health insurance formularies if the 26% reduction in severe asthma flares using PT027 is confirmed. Currently, asthma exacerbations result in a loss of 8.7 million work days and 5.3 million school days every year in the United States. The total cost of these missed work and school days is $3 billion per year. If the 26% reduction in severe asthma flares translates to a 26% reduction in missed work days and missed school days from asthma, then it may be cheaper overall for employers to include PT027 on their insurance formulary, even if they have to pay higher insurance premiums.

What about hospitals? Hospital formularies typically carry albuterol inhalers and for medical-legal reasons, there will continue to be hesitancy for hospitals to adopt the GINA recommendations of a combination formoterol + inhaled corticosteroid reliever inhaler for hospitalized asthma patients as long as this use is considered off-label by the FDA. Presumably, since it contains a short-acting β-agonist, PT027 will get an FDA approved indication as a reliever inhaler, making it more palatable for hospital pharmacies to replace albuterol on their formularies. However, the cost of PT027 (compared to albuterol-only inhalers) may be a barrier for widespread hospital use.

The bottom line is that for those people with moderate to severe asthma who are either wealthy or have superb prescription medication insurance, albuterol inhalers will likely become obsolete. For everyone else with asthma and for those with COPD, albuterol inhalers will be preferred.

June 28, 2022