The Surprising Reintroduction of Primatene Mist in the United States

In November 2018, the U.S. Food and Drug Administration (FDA) approved Primatene Mist (Amphastar Pharmaceuticals, Inc.), an epinephrine metered-dose inhaler (MDI), for the treatment of mild intermittent asthma in patients ages 12 years and older. This hydrofluoroalkane-based MDI replaces a chlorofluorocarbon (CFC)-based MDI previously marketed with the same name and is the result of a New Drug Application (NDA). It is the only FDA-approved over-the-counter (OTC) inhaler for the treatment of asthma in the United States. The medical and public health communities strongly oppose OTC sale of Primatene Mist. Several leading U.S. health societies (1–5), including the American Thoracic Society (ATS) (6), have published statements of alarm regarding FDA approval.

Epinephrine MDI Policy History

Early MDIs used CFC propellants, which were found to contribute to ozone-layer depletion. The United States joined the Montreal Protocol (1989) and passed an amendment to the U.S. Clean Air Act (1990) to reduce CFC use by the year 2000. To avoid impacting human health, the Montreal Protocol allowed “essential use protections,” so that some medications, like MDIs, would remain available until alternatives could be developed. Although albuterol manufacturers released non-CFC MDIs in 1996 (7), epinephrine MDI manufacturers continued using CFC propellants. However, mounting safety concerns surrounding OTC epinephrine MDI were not factored into this protection status. Despite American Medical Association and American College of Chest Physicians statements published in 1999 and 2000, reexamination of essential use protections was delayed until 2006. In a series of FDA hearings, physicians and medical organizations cited both safety concerns with epinephrine and asthma guideline recommendations for albuterol (8). Essential use status was eventually revoked; however, manufacturers were provided additional time (through 2011) to develop a non-CFC replacement. After December 31, 2011, with no non-CFC replacement, epinephrine MDI was removed from shelves.

In July 2012, Dr. Monica Kraft, ATS President, provided Congressional testimony against future restoration of epinephrine MDI, echoing the views of many medical organizations: “It is my strongly held view and the view of the American Thoracic Society that returning epinephrine inhaler to the U.S. market would be ill advised. . . . Epinephrine is NOT one of the medications that are considered safe for the treatment of asthma” (9).

Amphastar Pharmaceuticals, Inc. submitted its first NDA for a hydrofluoroalkane epinephrine MDI in 2014. The FDA hosted a public call for input and held a joint meeting of the Pulmonary Allergy and Nonprescription Drug Advisory Committees (10), where physicians and patients cited safety concerns about epinephrine MDI use in asthma. The proposed MDI design lacked an easily interpretable dose counter, and, for this reason, the joint panel determined that device safety had not been established (vote 17 to 7) and the risk/benefit profile was unfavorable (18 to 6), and thus recommended against approval (10).

In 2018, Amphastar submitted the NDA for the current version of Primatene Mist, addressing the comments made in the prior NDA rejection. In contrast with 2014, the FDA did not hold a public comment period, convene a panel meeting, or solicit input from medical societies. The FDA claims to have met with patient advocacy groups and physicians, although details are not publicly available. Despite decades of safety concerns, prior FDA approval for epinephrine MDI, originally granted in 1956, provided sufficient historical precedent to compel present approval once the dose counter concerns had been addressed (11). The ATS has declared “great concern” regarding lack of public input in the recent FDA decision (6).

Clinical Concerns with Epinephrine MDI

Albuterol, a selective, short-acting β₂ agonist (SABA) that relaxes small airway smooth muscle and relieves bronchoconstriction, was discovered in 1966, entered the commercial market in the UK in 1969, and was followed by widespread global use. It was approved by the FDA for the U.S. market in 1981, and has remained the mainstay of temporary asthma relief in the U.S. and worldwide. It was previously recommended as monotherapy for individuals with mild intermittent asthma. The 2019 Global Initiative for Asthma guidelines have upended this paradigm and support the addition of as-needed inhaled corticosteroids (ICSs) for all patients with mild asthma to mitigate exacerbation risk. Preferred reliever therapy for patients of all asthma severity levels is now off-label low-dose budesonide-formoterol (a steroid and long-acting β₂-agonist with relatively quick onset) (12). Albuterol is the only short-acting β₂-agonist available in the United States and remains an option in these and other asthma guidelines (12, 13).

Inhaled epinephrine, a sympathomimetic catecholamine and nonselective α- and β-receptor agonist, is intentionally absent from all current asthma guidelines. The National Asthma Education and Prevention Program guidelines specifically recommend against epinephrine (13). However, in 2006, an estimated 3 million Americans used the previous epinephrine MDI product, and 1 million of these used it as monotherapy for asthma (14).

Limitations of Clinical Utility

Epinephrine use in asthma predates modern medicine and guidelines-based asthma care. The first inhaled epinephrine products were approved before albuterol was developed (15). Few head-to-head appraisals between inhaled epinephrine and its rational comparator (albuterol) exist; however, these data largely show albuterol to be more effective than epinephrine, with superior bronchial protection to methacholine challenge (16) and a longer bronchodilator effect (17).

Safety Concerns

Mechanisms of misuse and adverse events from the previous epinephrine MDI are well documented (18). Systemic α- and β-receptor stimulation may exacerbate symptoms of cardiac origin that can mimic asthma (wheeze, cough, dyspnea), with serious consequences. Patients may self-medicate with improper therapy, delaying effective care. For patients with asthma, overuse of bronchodilators has been associated with increased morbidity, adverse events, and asthma fatality (19–21). Although epinephrine MDI can be safe for occasional use in adults with intermittent asthma and no complicating comorbidities, albuterol has greater clinical effectiveness. The FDA required a label warning limiting use to mild asthma (11, 22). However, this is inadequate, as it is easily ignored and patients may underestimate their disease.

Access to Care and Health Equity

Advocates for epinephrine MDI argue that OTC availability provides access to a life-saving medication that is affordable, convenient, and a safety net for medically marginalized and underinsured populations. The price point of the current epinephrine MDI (around $30) is comparable with the recently approved generic albuterol MDI (Ventolin, $36); however, financial and time costs of seeking an asthma provider for the prescription will remain. Furthermore, with Global Initiative for Asthma guidelines now recommending ICS for all patients with asthma (12), provision of a short-acting bronchodilator alone provides inferior care. Easing access to substandard medication has the potential to deepen care disparities.

Next Steps

One proposed mitigation strategy is behind-the-counter sales of epinephrine MDI, which would require patients to interact with pharmacists. Behind-the-counter sales are not under FDA oversight, so pharmacy retailers would have to do this voluntarily. ATS initiated a joint letter to major retailers with 11 other medical societies, urging them to implement this approach. Another possible solution, though controversial, is OTC albuterol (23). However, any OTC asthma therapy increases convenience at the expense of professional evaluation and safety and provides an opportunity to bypass ICSs, now recommended for use with all levels of asthma severity (12). ATS has previously opposed OTC asthma inhalers (24), but additional cost–benefit analyses of health access, equity, safety, and outcomes with OTC albuterol are needed in the current landscape.

All clinicians should educate patients with asthma on the risks of epinephrine MDI monotherapy and the preferred use of albuterol or off-label ICS-formoterol. Because epinephrine MDI users may be experiencing care gaps, clinicians should ensure proper diagnosis of asthma; correctly evaluate the patient’s asthma severity and comorbidities; emphasize frequent clinical reassessments; manage medications, including ICSs; and confirm proper inhaler technique. Clinicians can familiarize themselves with prescription assistance programs to help patients afford guideline-based therapy and encourage transition away from epinephrine MDI. Access to asthma care continues to rely on the development of care systems. Nonclinicians and acute care clinicians can refer patients with asthma to primary and specialty care in local clinics. Asthma specialists should partner with front-line groups in building these pathways. Finally, clinicians should report any adverse events to the FDA’s Medwatch program, including cardiovascular events, drug reactions, or excess emergency department visits and hospitalizations related to epinephrine MDIs.

Conclusions

The recent FDA approval of Primatene Mist without public input and despite longstanding concerns with epinephrine MDI has set a dangerous precedent. We are alarmed at the lack of transparency in this decision. With epinephrine MDI now on retailer shelves, asthma providers and organizations must be vigilant. Systemic strategies to improve access to asthma care remain fundamental to reducing unmet needs and asthma disparities.