FDA Approves the First Epinephrine Nasal Spray for Life-Threatening Allergic Reactions

In August 2024 the Food and Drug Administration (FDA) approved an epinephrine nasal spray (NEFFY) for the emergency treatment of type I (immediate, not specific) allergic reactions, including anaphylaxis.[1] For many decades, epinephrine has been used as an injection under the skin or into the muscle (ADRENACLICK, ADRENALIN, AUVI-Q, EPIPEN, SYMJEPI and generics) or as an intravenous infusion for life-threatening allergic reactions in susceptible individuals, such as reactions triggered by foods, medications or insect stings.[2],[3]

The epinephrine nasal spray, the first of its kind, is for adults and children who weigh 66 pounds or greater. People with certain nasal conditions, such as nasal polyps or a history of nasal surgery, should consult with a clinician to determine whether they should avoid the use of nasal epinephrine and instead opt for injectable forms.

Background on allergic reactions, anaphylaxis and epinephrine

Allergic reactions to food are one of the main triggers of anaphylaxis.[4] It is estimated that 8% of children in the United States have food allergies.[5] A prior episode of anaphylaxis is a key indicator of future risk; for example, an observational study, published in 2017, of 292 anaphylaxis cases in children estimated an annualized recurrence rate of 18%.[6] Asthma also increases the risk of recurrence of anaphylaxis.[7]

Epinephrine stimulates two cell receptor types (alpha- and beta-adrenergic) that should lead to blood flow, heart output, airway and anti-inflammatory effects that counteract the destabilizing allergic response.[8] Epinephrine also is strongly associated with the “fight or flight” physiological responses, including anxiety, restlessness, headaches, heart palpitations and tremors, which are adverse effects that often occur when the drug is used to treat an allergic reaction.

Injection of epinephrine is a cornerstone of immediate anaphylaxis management.[9] Epinephrine injection often involves do-it-yourself delivery options (use-at-home vial and needle-syringe kits, or preloaded autoinjectors) for persons who have no medical training.[10] The nasal spray formulation was developed because some people are not comfortable with or are fearful of administering epinephrine by injection; the new nasal spray design is based on device technology that is widely used to reverse opioid overdose.[11],[12]

The epinephrine nasal spray

The drug device is a nasal spray applicator that delivers a 2-milligram (mg) dose of epinephrine into a nostril with a plunger press.[13] The recommended dosage is one spray administered into one nostril. If symptoms do not improve (or if they worsen) after the initial treatment, a second dose can be administered in the same nostril with another, unused device five minutes after the first dose. At all times, patients who are prescribed the epinephrine nasal spray should have immediate access to two of these devices. A small number of individuals may be allergic to the sulfite used in the epinephrine nasal spray, but that should not deter use.[14]

The GoodRx.com-CVS retail price for generic epinephrine autoinjectors is currently about $308 per pair. For Neffy, the retail price is $840 per pair. Between 2007 and 2016 the price of a two-pack of EpiPens increased more than 500% to $608.[15],[16] Public outrage ensued against the EpiPen’s maker, Mylan Pharmaceuticals, and their CEO, Heather Bresch, the daughter of West Virginia Sen. Joe Manchin. Eventually the company paid a nine-figure fraud settlement to the federal government, and Mylan introduced a generic version of EpiPen. Absent analogous political and legal action, monopoly pricing will likely keep the end-user price of nasal epinephrine especially high for many years into the future.

Epinephrine nasal spray is for adults or children experiencing a life-threatening allergic reaction; note that sometimes these reactions may be triggered by exercise or other stressors. Symptoms can include difficulty breathing; hoarseness; hives or severe itching; swelling of face, lips or mouth; itching or skin redness; stomach cramps or diarrhea; and dizziness or loss of consciousness. In the event that further treatment is required, patients are advised to promptly seek emergency medical assistance after using the nasal spray.[17]

Clinical pharmacology data supporting approval

To approve nasal epinephrine, the FDA relied on clinical pharmacology data from 175 adults and 21 children (8-17 years) weighing at least 66 pounds.[18],[19] Findings from both populations, studied in four trials in adults and one in children, showed that nasal epinephrine was “comparable” to injectable forms for three indicators: blood pressure changes, heart rate changes and blood concentrations of epinephrine.

The adult studies used crossover designs so that data could be collected on each treatment condition for each subject. The adult trials involved 2-mg doses of nasal epinephrine, 60 minutes of follow-up and standard intramuscular injection doses of epinephrine (0.3 mg) using an autoinjector or a needle-syringe product as a comparator. The pediatric trial only studied nasal epinephrine. None of the trials involved an anaphylaxis challenge, but two adult studies, involving 79 subjects, tested the pharmacology of nasal epinephrine after a seasonal allergy was triggered with a lab-created antigen.

Detailed results from each of the five studies show that nasal epinephrine generally, but imperfectly, leads to the same pharmacologic changes seen with epinephrine administered by injection across all the populations and allergic challenges that were studied. For example, blood epinephrine concentrations were markedly higher with autoinjectors in the first 15 minutes after injection, whereas concentrations increased more gradually after use of the nasal spray. Twenty to 60 minutes after dosing, there was substantial overlap between the nasal spray and injection epinephrine concentration curves.

The most common (incidence of at least 2%) adverse effects associated with epinephrine dosing, either by nasal spray or by injection, include headache, nasal and throat discomfort, feeling jittery, fatigue, tremor, abdominal or gum pain, dizziness and nausea. Elderly patients may be at greater risk of adverse reactions.

What You Can Do

If you are at risk of anaphylaxis and carry and are comfortable with your autoinjector or needle-syringe epinephrine product, you should continue that precaution. Keep in mind that these prescription products should be stored at room temperature (68 F to 77 F) most of the time and have an expiration date.[20] If you are considering switching to the epinephrine nasal spray, discuss this decision with your clinician.

Given the limited clinical data available for epinephrine nasal spray, Public Citizen’s Health Research Group has classified the product as Do Not Use for Seven Years.
 

References

[1] Food and Drug Administration. News release: FDA approves first nasal spray for treatment of anaphylaxis. August 9, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-nasal-spray-treatment-anaphylaxis?os=rokuZoazxZMs&ref=app. Accessed September 25, 2024.

[2] ARS Pharmaceuticals Operation Inc. Label: epinephrine nasal spray (NEFFY). August 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/214697s000lbl.pdf. Accessed September 19, 2024.

[3] Tanimoto S, Kaliner M, Lockey RF, et al. Pharmacokinetic and pharmacodynamic comparison of epinephrine, administered intranasally and intramuscularly: an integrated analysis. Ann Allergy Asthma Immunol. 2023;130(4):508-514.e1.

[4] Cleveland Clinic. Anaphylaxis. October 17, 2023. https://my.clevelandclinic.org/health/diseases/8619-anaphylaxis. Accessed September 25, 2024.

[5] Centers for Disease Control and Prevention. Food allergies. August 23, 2022. https://www.cdc.gov/healthyschools/foodallergies/. Accessed September 25, 2024.

[6] O'Keefe A, Clarke A, St Pierre Y, et al. The risk of recurrent anaphylaxis. J Pediatr. 2017;180(January):217-221.

[7] Campbell RL, Kelso JM. Anaphylaxis: emergency treatment. UpToDate. June 24, 2023.

[8] Ibid.

[9] Ibid.

[10] Ellis AK, Casale TB, Kaliner M, et al. Development of Neffy, an epinephrine nasal spray, for severe allergic reactions. Pharmaceutics. 2024;16(6):811.

[11] Opioid overdose antidotes to avoid: High-dose naloxone and namefene nasal sprays. Worst Pills, Best Pills News. September 2024. https://www.worstpills.org/newsletters/view/1618. Access September 25, 2024.

[12] Ellis AK, Casale TB, Kaliner M, et al. Development of Neffy, an epinephrine nasal spray, for severe allergic reactions. Pharmaceutics. 2024;16(6):811.

[13] ARS Pharmaceuticals Operation Inc. Label: epinephrine nasal spray (NEFFY). August 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/214697s000lbl.pdf. Accessed September 25, 2024.

[14] Ibid.

[15] Jalonick MC. Mylan CEO defends EpiPen cost to angry lawmakers. PBS News. September 21, 2016. https://www.pbs.org/newshour/health/mylan-ceo-set-defend-epipen-prices-amid-public-outcry. Accessed September 25, 2024.

[16] Scott D. Can we solve the EpiPen cost crisis? Vox. April 4, 2023. https://www.vox.com/policy/23658275/epipen-cost-price-how-much. Accessed September 25, 2024.

[17] Campbell RL, Kelso JM. Anaphylaxis: emergency treatment. UpToDate. June 24, 2023.

[18] Food and Drug Administration. News release: FDA approves first nasal spray for treatment of anaphylaxis. August 9, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-nasal-spray-treatment-anaphylaxis?os=rokuZoazxZMs&ref=app. Accessed September 23, 2024.

[19] ARS Pharmaceuticals Operation Inc. Label: epinephrine nasal spray (NEFFY). August 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/214697s000lbl.pdf. Accessed September 25, 2024.

[20] ARS Pharmaceuticals Operation Inc. Label: epinephrine nasal spray (NEFFY). August 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/214697s000lbl.pdf. Accessed September 19, 2024.