FDA Looks Ahead to Withdrawal of Nonprescription Epinephrine Inhalers

Kate Traynor

BETHESDA, MD 06 October 2009—With two years remaining until ozone-depleting nonprescription epinephrine inhalers must come off the market, FDA is seeking an effective way to inform those who purchase the products that they need to find an alternative remedy for asthma symptoms.

The agency held a public meeting September 25 in Rockville, Maryland, to discuss with stakeholders several challenges with the phaseout. These include identifying people who purchase the inhalers, telling them about the deadline, and protecting their health as they transition to new treatments for their asthma, officials said.

The decision to eliminate epinephrine metered-dose inhalers (MDIs) complies with national and international laws aimed at reducing ozone depletion, including depletion caused by chlorofluorocarbon (CFC) propellants in MDIs.

CFC-containing prescription MDIs with albuterol were similarly banned from the U.S. market at the end of last year, forcing patients to switch to inhalers that use hydrofluoroalkane (HFA) as a propellant.

There is currently no HFA-containing nonprescription epinephrine MDI on the U.S. market. But Stephen Campbell, senior vice president for regulatory affairs at Amphastar Pharmaceuticals, said the company plans this month to file an application with FDA to sell such a product.

Amphastar's Armstrong Pharmaceuticals division markets the Primatene Mist brand of epinephrine MDIs. Campbell estimated that 2–3 million people each year use the CFC version of Primatene Mist, which is labeled as a remedy "for temporary relief of occasional symptoms of mild asthma" that has been diagnosed by a physician.

He said Amphastar bought the rights to the Primatene brand last year from Wyeth after the company declined to develop a version of the product without a CFC propellant.

"We recognize the importance of having an OTC medicine out there, and we're committed to develop and commercialize a replacement for the CFC inhaler," Campbell said.

In the Federal Register notice announcing the meeting, FDA acknowledged that it knew of "at least one manufacturer" that was planning to develop a nonprescription, CFC-free epinephrine MDI. But the agency cautioned that there is "no assurance that the product will be available by December 31, 2011."

For that reason, the agency stated, patients must plan to use alternative medications, such as prescription albuterol MDIs, to control symptoms of asthma.

Therapeutic options. Epinephrine and albuterol are both short-acting beta₂ agonists that serve as bronchodilators when inhaled. Albuterol is recognized by the National Asthma Education and Prevention Program (NAEPP) as a drug of choice for the rapid relief of acute bronchospasm in asthma.

NAEPP's current guidelines, released in 2007, state that epinephrine should not be used for the treatment of acute bronchospasm because the drug causes excessive cardiac stimulation, especially at high doses.

In 2001, the labeling for Primatene Mist stated that the product "eases breathing for asthma patients by reducing spasms of bronchial muscles." This language is not included in the product's current labeling.

Leslie Hendeles, professor of pharmacy and pediatrics at the University of Florida in Gainesville, said nonprescription epinephrine MDIs are a safe and effective treatment for bronchospasm in some patients.

Hendeles cited data from a report he published in 2005 that compared Primatene Mist and a prescription albuterol MDI in eight young adults with nocturnal asthma. In this small population, he said, epinephrine relieved the airway obstruction almost as well as albuterol and had no cardiostimulatory effects.

"What distinguishes the patients in this study from the patients that end up in the emergency room from an asthma attack is [the study patients] are bronchodilator responsive," Hendeles said.

He explained that bronchodilators relax smooth muscle tissue in the airway during an acute asthma episode but do not eliminate potentially deadly mucosal edema and obstructive occlusions in the lungs.

"It is clearly a medial emergency when a patient has a severe asthma episode that does not respond to bronchodilators," Hendeles said.

Hendeles called inhaled corticosteroids the "cornerstone" of asthma therapy in patients with persistent disease whose treatment goal is to prevent attacks from occurring. He said all patients with asthma symptoms should be evaluated by a health care provider and given access to inhaled corticosteroids.

The NAEPP guidelines describe inhaled corticosteroids as "the most potent and consistently effective long-term control medication for asthma." The guidelines recommend daily use of inhaled corticosteroids or other "long-term control medications" for patients with persistent asthma.

Access to care. Marcus Reidenberg, medical professor at Weill Cornell Medical College in New York, said that patients with asthma are disproportionately poor and lack access to medical care. He said the need to seek a physician and obtain a prescription, whether for albuterol or corticosteroids, may well be a barrier to effective care for such patients.

From a practical standpoint, Reidenberg said, nonprescription epinephrine MDIs are the only treatment, other than emergency-room care, that is available to many poor patients who have asthma.

Campbell said purchasing data indicate that many people who buy Primatene Mist lack medical or prescription-drug coverage, while others with such coverage use the product "as a complement medication" to their usual regimen.

To fill the void left by the loss of CFC-propelled epinephrine MDIs, some meeting attendees suggested that albuterol MDIs be made available as a so-called third category of medications that are dispensed by a pharmacist without a prescription.

In such a case, "a patient could go to a pharmacist who could evaluate and triage that patient, and, if it was deemed safe, to have albuterol and to dispense it," Hendeles said. "It would identify the patient who can safely be treated with an over-the-counter product, but it would also identify a patient who would need a steroid and send him to a health care provider."

"I realize it would take an act of Congress to make that happen," Hendeles said.

Andrea Leonard-Segal, director of FDA's Division of Nonprescription Clinical Evaluation, called the concept of a third drug category "a very complicated issue" and offered her unofficial, personal views on the topic.

"There are a lot of people interested in this third category," she said. "If we ever get it, I doubt that we'll have it by 2011 the end of December."

Background information on the withdrawal of CFC-containing epinephrine MDIs and slides from the September meeting will be available at FDA's website.