FDA Panel Votes Against Primatene Reboot Due To Safety Concerns

Concerns about safety prompt an FDA advisory panel to recommend against approving Armstrong Pharmaceutical’s NDA for an OTC emergency asthma inhaler. Concerns about device malfunction and about a potentially inaccurate dose indicator also influence the panel.

Concerns about insufficient safety data and device malfunction led a joint panel of FDA experts Feb. 25 to recommend against OTC use of Armstrong Pharmaceutical Inc.’s reformulated emergency asthma inhaler.

A joint panel of the Nonprescription Drugs and Pulmonary-Allergy Drugs advisory committees voted 18-6 against approving Primatene HFA actuated, or breath-triggered, epinephrine inhalation aerosol.The panel also voted 17-7 that Armstrong did not prove the safety of the product proposed to replace Primatene Mist, a metered-dose inhaler.

Primatene Mist was withdrawn from the market in 2011 due to environmental concerns about the use of the ozone-depleting chlorofluorocarbon as a propellant and not because of safety or efficacy concerns.

The panel members voiced concerns about the small size of Armstrong’s phase III clinical study, a lack of pediatric data in the label comprehension study even though the product is indicated for consumers as young as 12 years, and the lack of an actual use trial to show that consumers would appropriately follow the product’s use and cleaning instructions to avoid the risk of clogs and under- or over-dosing.

Armstrong proposed this packaging in its NDA for Primate HFA.

They also echoed FDA’s concerns about the sponsor’s decision to use a dose indicator that estimates the number of doses in the inhaler rather than a dose counter that accurately tracks doses (Also see "FDA Questions Reformulated Primatene Asthma Spray Reliability" - Pink Sheet, 24 Feb, 2014.).

The risk the dose indicator could become useless if the inhaler is dropped, which is a potential scenario if it is kept in a gym bag, backpack or purse, prompted the committee to suggest additional drop tests to assess safety.

Despite the safety concerns, the panel acknowledged in a vote of 14 to 10 that Armstrong demonstrated the new hydrofluoroalkane propelled 125 mcg per inhalation aerosol device effectively relieved mild symptoms of intermittent asthma, including wheezing, tightness of chest and shortness of breath.

Recommended Safety Improvements

While FDA usually follows advisory panels’ advice, it is not required.

The agency occasionally goes against the recommendation of advisory committees, such as its 2013 approval of the Rx-to-OTC switch of Oxytrol for Women, Merck & Co. Inc.’s overactive bladder treatment, after an expert panel voted 6-5 against the switch (Also see "Oxytrol For Women Gets OTC Green Light As Rare First-In-Class Switch" - Pink Sheet, 28 Jan, 2013.).

If FDA makes Primatene HFA available OTC against the committees’ recommendation, panelists and members of the public advocated that FDA first require changes to the current proposed product to improve safety.

At a minimum, the agency should require Armstrong to rename the product so consumers do not assume it is the same formula and device that was previously marketed OTC as Primatene Mist, said NDAC member Judith Kramer, a professor at Duke University School of Medicine.

Kramer maintained changing the name would prompt consumers to more closely read the packaging and labeling, which would help them understand how and when to use the product, when to seek physician care and the limitations of the dose counter.

FDA also should limit the number of doses in the inhaler to better align with the product’s intended use as an emergency inhaler for intermittent asthmatics, said Tonya Winders, president and CEO of the Allergy & Asthma Network Mothers of Asthmatics.

Winders explained the current 200 actuations per inhaler could encourage chronic use and delay visits to health care providers. She recommended the inhaler have 25 actuations, about a week’s worth of medicine when used according to the label.

Others at the meeting agreed, suggesting a range of doses from 16 to 30.

A representative from the American Thoracic Society also recommended FDA require all metered dose inhalers have an effective dose counter, which is more likely to stop asthmatics from reaching for an empty inhaler during an attack.

FDA also should consider strengthening the warnings on the package and device. A representative from the American College of Allergy, Asthma and Immunology suggested putting a “black box style warning” on the OTC product and ensuring the warning is printed on the device and not only on the package insert, which many consumers throw away when they open the box.

Another option is adding a warning to stop use after one week and see a physician if the condition does not improve, added panel member Christianne Roumie, an assistant professor of internal medicine and pediatrics at the Institute of Medicine and Public Health Vanderbilt University.

Appropriateness Of OTC Status Debated

Some panel members questioned whether asthma is an appropriate indication for an OTC product. FDA officials noted the agency’s push for greater access to drugs that might not traditionally be considered for OTC sale under Nonprescription Drug Safe Use Regulatory Expansion Initiative, which would encourage sponsors to use technology and other innovations to help consumers appropriately select and use products (Also see "Firms Explore First-In-Class Switches With NSURE Still In Limbo" - Pink Sheet, 3 Oct, 2013.).

FDA has suggested rescue medicines, such as inhalers, as candidates for switch under NSURE (Also see "Asthma Drug Petition Opposes OTC Approach, NSURE Paradigm" - Pink Sheet, 24 Jun, 2013.). In addition, agency officials noted several times during this meeting that they are interested in seeing a viable OTC rescue inhaler on the market and are open to ideas for improving product safety.

Concerns about treating asthma OTC carried over to the NDAC meeting Feb. 26, which involved many of the same experts. In part because of these concerns, that panel voted to recommend removing from the monograph a provision allowing OTC products with a handheld rubber bulb nebulizer to disperse two inhaled asthma ingredients. (See related story: (Also see "Panel Votes For Removing Nebulizer, Asthma Ingredients From Monograph" - Pink Sheet, 27 Feb, 2014.).)

Under this provision, Nephron Pharmaceuticals Corp. markets the only OTC asthma inhaler currently sold directly to consumers, Asthmanefrin, which delivers racepinephrine to users. Asthmanefrin already attracted FDA scrutiny and a warning letter, but the agency is hesitant to remove it from market because it is medically necessary.