FDA Reapproves Primatene Mist Inhaler for Asthma Despite Concerns

In November 2018, the Food and Drug Administration (FDA) approved a new version of the metered-dose inhaler PRIMATENE MIST, an over-the-counter form of the bronchodilator drug epinephrine, which causes widening of the airways in the lungs for temporary relief of mild symptoms of intermittent asthma in patients aged 12 or older.[1] Of note, epinephrine also is available in injectable forms under such brand names as ADRENACLICK, AUVI-Q and EPIPEN for treatment of anaphylaxis (sudden severe allergic reactions).

The decision to put Primatene Mist — with a change in its propellant substance that is used to spray the drug out of the inhaler — back on store shelves in the U.S. came after the original version of the drug had been banned in late 2011[2] and after the FDA had rejected the new version of the drug in 2014 and 2016.[3] Major expert professional medical groups have decried the recent approval due to concerns that the over-the-counter inhaler will endanger asthma patients.[4]

About asthma and its standard treatment

Asthma is a complex, chronic inflammatory lung disease characterized by repeated episodes of wheezing, shortness of breath, chest tightness and coughing.[5] The coughing often occurs in the nighttime or early morning. The disease afflicts 25 million Americans.[6] Without proper management, asthma can result in frequent emergency room visits, hospitalizations and death.

Clinical practice guidelines, including those developed by the Global Initiative for Asthma, recommend controlling asthma by avoiding triggers (such as smoking and allergens) that can cause an attack and by taking prescription-only asthma medications.[7] Specifically, short-acting inhaled beta2-agonist bronchodilators, such as albuterol (PROAIR HFA, PROVENTIL-HFA, VENTOLIN HFA and others), are recommended for the quick relief of acute (sudden) worsening of asthma symptoms.

An inhaled anti-inflammatory corticosteroid, such as budesonide (PULMICORT FLEXHALER, PULMICORT RESPULES) or fluticasone (FLOVENT DISKUS, FLOVENT HFA), is now recommended for temporary use as needed at the onset of symptoms in patients with mild asthma and as long-term daily maintenance (controller) treatment for all patients with more severe forms of asthma to reduce the risk of serious exacerbations or flare-ups (episodes of sudden, sustained worsening of respiratory symptoms beyond normal day-to-day variations).[8] For patients who remain symptomatic despite adherence to inhaled corticosteroid treatment, a combination drug composed of inhaled corticosteroids and long-acting beta2-agonists, such as budesonide-formoterol (SYMBICORT) or fluticasone-salmeterol (ADVAIR), is recommended.

Concerns about Primatene Mist

The original version of Primatene Mist was removed from the U.S. market because it contained the propellant chlorofluorocarbon, which depletes the atmosphere’s protective ozone layer and was therefore banned under an international treaty.[9] The new version contains a different propellant, hydrofluoroalkane, that does not affect the ozone layer and is used in prescription inhalers containing other medications, such as albuterol.

The FDA claims that it approved the new Primatene Mist version in order to make a rescue inhaler medication available over the counter for patients with mild asthma who run out of their prescription inhalers and to benefit underserved populations who have no other access to asthma treatment.[10], [11] However, epinephrine, the active ingredient in the Primatene Mist inhaler, is not recommended by any asthma treatment guidelines.[12] Furthermore, use of the drug has never been shown to decrease the rate of clinically important outcomes, such as asthma exacerbations requiring hospitalization.[13]

Importantly, prior to the FDA’s first rejection of the new version of Primatene Mist in 2014, members of the agency’s Nonprescription Drugs and Pulmonary-Allergy Drugs Advisory Committees voted 18 to 6 against approval of the drug. Members voting against approval cited, among other things, safety concerns, consumers’ inability to adequately assess the severity of their asthma and national guidelines recommending against use of the drug.[14] Disturbingly, the FDA subsequently did not hold a public comment period, convene another advisory committee meeting or solicit input from professional medical organizations before its November 2018 approval decision.[15]

A group of seven asthma and chest disease organizations — including the Allergy and Asthma Network and the American Lung Association — issued a joint statement criticizing the FDA’s approval of the new version of Primatene Mist.[16]

The statement highlighted that the inhaler masks asthma symptoms instead of treating the condition. It cautioned that patients may use the inhaler to replace more effective and safer prescription asthma drugs. Such a “do-it-yourself” approach for asthma control can result in delayed treatment of asthma exacerbations, potentially causing long-term lung damage or even death, added the statement.

Notably, Primatene Mist can put patients at risk of excessive stimulation of the cardiovascular system, causing increased blood pressure and heart rate, which increase the risk of heart attack and stroke.[17] These risks are greater in patients with a history of high blood pressure or heart disease and those who take higher doses of the inhaler or use it frequently. Other adverse effects of Primatene Mist include bronchitis, cough, dizziness, jitteriness, painful sensations in the mouth and throat, and tremor.[18]

The FDA-required warnings on the labeling for Primatene Mist include limiting its use to patients with mild asthma and alerting users to see a doctor if certain signs of their asthma become worse after using it. Ironically, the labeling of Primatene Mist advises against using the inhaler unless patients have first asked their doctors whether they have asthma. But since the inhaler is available over the counter, it is certain many patients will self-diagnose asthma and use the drug. Other instructions tell patients with certain conditions (such as those with diabetes, high blood pressure, narrow-angle glaucoma [increased pressure in the eye] and seizures) to ask their doctors before using the inhaler.

What You Can Do

If your doctor determines that you have asthma, work with him or her to develop a treatment plan, including determining the right medications for your condition and when to use these medications. Ask your doctor to show you how to use your inhaler to make sure you are using it correctly and getting the right dose.

Whether your asthma symptoms are mild, moderate or severe, do not use Primatene Mist to control your symptoms. If you are currently taking Primatene Mist, talk to your doctor about switching to a safer and more effective alternative for managing your asthma symptoms.
 

References

[1] Armstrong Pharmaceuticals, Inc. Label: epinephrine (PRIMATENE MIST). November 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205920Orig1s000lbl.pdf. Accessed November 26, 2019.

[2] Food and Drug Administration. FDA statement on approval of OTC Primatene Mist to treat mild asthma. November 8, 2018. https://www.fda.gov/news-events/press-announcements/fda-statement-approval-otc-primatene-mist-treat-mild-asthma. Accessed November 26, 2019.

[3] Food and Drug Administration. Center for Drug Regulation and Research. Summary review for application number 2059200rigls000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/205920Orig1s000SumR.pdf. Accessed November 26, 2019.

[4] Allergy & Asthma Network; American Association for Respiratory Care; American College of Allergy, Asthma & Immunology; et al. FDA decision to approve Primatene Mist endangers asthma patients. November 8, 2018. https://www.asthmaeducators.org/resources/Documents/Letter%20re%20Primatene%20Mist%20AAN%2011-9-18.pdf. Accessed November 26, 2019.

[5] Centers for Disease Control and Prevention. Asthma. October 18, 2019. https://www.cdc.gov/asthma/default.htm. Accessed November 26, 2019.

[6] Centers for Disease Control and Prevention. Most recent national asthma data. May 2019. https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm. Accessed November 26, 2019.

[7] Global Initiative for Asthma. Pocket guide for asthma management and prevention (for adults and children older than 5 years). 2019. https://ginasthma.org/wp-content/uploads/2019/04/GINA-2019-main-Pocket-Guide-wms.pdf. Accessed November 26, 2019.

[8] Ibid.

[9] Food and Drug Administration. FDA statement on approval of OTC Primatene Mist to treat mild asthma. November 8, 2018. https://www.fda.gov/news-events/press-announcements/fda-statement-approval-otc-primatene-mist-treat-mild-asthma. Accessed November 26, 2019.

[10] Ibid.

[11] Food and Drug Administration. Center for Drug Regulation and Research. Summary review for application number 2059200rigls000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/205920Orig1s000SumR.pdf. Accessed November 26, 2019.

[12] Sadreameli SC, Brigham EP, Patel A. The surprising reintroduction of Primatene Mist in the United States. Ann Am Thorac Soc. 2019;16(10):1234-1236.

[13] Food and Drug Administration. Center for Drug Regulation and Research. Summary review for application number 2059200rigls000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/205920Orig1s000SumR.pdf. Accessed November 26, 2019.

[14] Ibid.

[15] Sadreameli SC, Brigham EP, Patel A. The surprising reintroduction of Primatene Mist in the United States. Ann Am Thorac Soc. 2019;16(10):1234-1236.

[16] Allergy & Asthma Network; American Association for Respiratory Care; American College of Allergy, Asthma & Immunology; et al. FDA decision to approve Primatene Mist endangers asthma patients. November 8, 2018. https://www.asthmaeducators.org/resources/Documents/Letter%20re%20Primatene%20Mist%20AAN%2011-9-18.pdf. Accessed November 26, 2019.

[17] Armstrong Pharmaceuticals, Inc. Label: epinephrine (PRIMATENE MIST). November 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205920Orig1s000lbl.pdf. Accessed November 26, 2019.

[18] OTC Primatene Mist returns. Med Lett Drugs Ther. 2019;61(1564):9-10.