An FDA advisory panel has recommended against approving a hydrofluoroalkane (HFA)-propelled replacement for inhaled epinephrine (Primatene Mist) for over-the-counter use in mild intermittent asthma.
The advisory committee was split Wednesday on adequate evidence of efficacy for temporary relief of mild symptoms of intermittent asthma in adults and children ages 12 and over, voting 14-10 in favor.
However, the vote went against adequate evidence of safety (7-17), and the overall vote was against a favorable risk-benefit ratio (6-18).
Action Points
- An FDA advisory panel has recommended against approving a replacement for inhaled epinephrine (Primatene Mist) for over-the-counter use in mild intermittent asthma.
- Note that the FDA doesn't have to follow the recommendations of its advisory committees, but usually does.
Many concerns centered on safety -- particularly clogging of the device, inaccuracy of the dose indicator, lack of data for 12- to 16-year-olds, and questions about whether consumers would be at risk from using the inhaler for self-diagnosed or more serious asthma without seeing a physician.
The reformulation added a dose indicator not included in the prior version, which was .
The FDA doesn't have to follow the recommendations of its advisory committee but usually does.
Many of those voting "Yes" for approval cited the more-than-50-year history of the CFC version of the drug, whereas the "No" votes came with a wide range of concerns cited.
One was that the inhaler used a dose indicator rather than a true integrated dose counter -- which was explained as being due to patent issues at the time of design -- and appeared to have poor performance compared with other metered-dose inhalers.
Malfunctions were reported for 7.2% of the epinephrine HFA inhalers examined across studies overall, which the FDA analysis noted was high compared with the "extremely low" reported malfunction rate in phase III clinical trials with prescription metered dose inhalers.
"Any device malfunctions seen in clinical trials are of concern, particularly for an asthma reliever medication, which may be used in a life-saving rescue situation," the briefing documents noted.
Also, the FDA analysis noted that nearly all of the epinephrine inhalers that qualified for analysis in the safety extension study either undercounted or overcounted administered doses to some extent compared with patient diaries (362 and 602, respectively, of 971).
None were considered by the manufacturer as "true" undercounts by more than 10% that could lead to patients thinking they had medication remaining when there was none, but FDA staff criticized the limited data provided by the manufacturer Armstrong, a subsidiary of Amphastar Pharmaceuticals.
"Little data was provided and these data were hard to analyze," said Jennifer Rodriguez Pippins, MD, MPH, a clinical reviewer for the agency.
Likewise, the behavioral data showing that patients could follow the directions to shake the inhaler to ensure accurate dosing was criticized as being demonstrated only in a few patients in a less-than-realistic laboratory setting.
And the device will clog and underdose if the recommended daily washing is skipped for more than 3 days, a company spokesperson acknowledged, which was noted by FDA staff as a somewhat unique problem among metered dose inhalers.
"It strikes me after sitting on these committees that this one is unique in that the discussion of the active ingredient is almost secondary to the discussion of the device," noted panel chair , of the University of Pennsylvania in Philadelphia.
Another common safety concern was reliance on patients self-identifying their asthma symptoms as mild and intermittent.
"We all know patients dramatically underestimate their asthma severity" compared with objective criteria, panel member , of the University of Texas Medical Branch in Galveston, noted.
He also raised the concern that the National Heart, Lung, and Blood Institute guidelines specifically recommend against epinephrine for the management of acute asthma symptoms.
The American Thoracic Society also recommends against the drug, but at the same time supports the need for over-the-counter asthma medication, Gary Ewart, senior director of government relations for that group, explained during the public comment period.
He agreed with , executive director of the American College of Allergy, Asthma, and Immunology, who called for strong warnings on the package if approved to alert patients to seek healthcare assistance for anything more than occasional use.
Over-the-counter availability doesn't preclude involvement of a physician, noted , of the Consumer Healthcare Products Association (CPHA), who spoke in support of approval during the public comment period. The CPHA is a trade group for makers of over-the-counter products.
But although the proposed label states that the inhaler is to be used for asthma diagnosed by a physician, "we know that patients don't typically follow instructions," said Badrul Chowdhury, MD, PhD, director of the FDA's Division of Pulmonary, Allergy, and Rheumatology Products in the Office of Drug Evaluation II.
Nevertheless, "we run the risk when we put up barriers to providing efficacious care for individuals with high-risk conditions of widening disparities," noted panel member , of California's Stanford University.
Another device-related concern was that the inhaler contains approximately 160 puffs compared with the roughly 20 estimated as necessary to treat mild asthma over the course of a week.
Many of the safety concerns would be mitigated if the inhaler could only put out a limited number of puffs, Calhoun noted.
The cardiac safety evidence was based largely on eight patients in a lab study, with overall safety data from fewer patients than the FDA wanted. None of the studies included children younger than 16.
Despite the long history of the CFC-based epinephrine inhaler, it would be hard to tell if there had been safety problems for an OTC agent, Calhoun added.
Several panel members called for a broader look by the FDA at whether any asthma medications should be OTC.