About the Authors
Emily Gaidos is a class of 2025 PharmD candidate at The Ohio State University in Columbus.
Rachel Chandra, PharmD, MPH, FASHP, is a clinical pharmacist at the Dayton Veterans Affairs Medical Center in Ohio.
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Advancing Anaphylaxis Treatment With Needle-Free Epinephrine Delivery
Key Takeaways
- Food allergies affect 8% of US children, with severe reactions requiring immediate epinephrine treatment.
- Epinephrine nasal spray offers a needle-free alternative, addressing needle phobia and hesitancy in administration.
Intranasal epinephrine spray offers a needle-free option for anaphylaxis treatment.
Allergies remain a growing food safety and public health concern. The CDC Healthy Schools initiative—which works with states, school systems, and communities to promote the well-being of children in schools—estimated that 8% of children in the US were affected by food allergies in 2018, with approximately 2 children on average per classroom having the potential to experience a severe allergic reaction.1
Allergic reaction refers to the immune response and associated adverse effects (AEs) that occur due to contact with an allergen. There is no cure, and avoiding known allergens remains the lone prophylaxis of severe allergic reactions. However, avoidance of all allergens can be incredibly difficult, especially in schools and large group settings. For this reason, the public must be more aware of the need for immediate and appropriate treatment for allergic reactions.
In recent decades, awareness of health care prices has increased. In response, patients are trying to take control of their health.2 Amid epinephrine price controversy, the market was ideally suited for innovative options in allergy management. The novel epinephrine formulation of an epinephrine nasal spray (Neffy; ARS Pharmaceuticals) is the only FDA-approved intranasal spray for the treatment of type 1 allergic reactions.3 However, it remains important to assess where epinephrine nasal spray fits within the available epinephrine options for patients with allergies.
Current State
Most severe type 1 allergic reactions occur in community settings.4 When anaphylaxis occurs, it can be life-threatening, requiring immediate medical attention. Guidelines recommend that patients who experience a severe allergic reaction should go to an emergency department for evaluation, even if the effects have subsided.5
Epinephrine remains the mainstay treatment for severe type 1 allergic reactions due to its rapid onset of action. In the community setting, epinephrine is available in an auto-injector, which allows the safe administration of a single dose of epinephrine intramuscularly (IM). Several epinephrine auto-injectors (see Table 1) are approved for use in the treatment of anaphylaxis, with notable differences in pharmacokinetic (PK) and pharmacodynamic (PD) properties. Parenteral administration of epinephrine has a rapid onset and short duration of action, which is preferable in the emergent treatment of severe allergic reactions.6
A drawback of an injectable formulation is the required use of needles to administer the medication. Image Credit: © Sherry Young - stock.adobe.com
However, the utility of epinephrine auto-injectors is limited by reduced refills, failure to carry, and delayed use. A drawback of an injectable formulation is the required use of needles to administer the medication. Regardless of the increasing prescriptions written for epinephrine auto-injectors, not all patients carry the product regularly.4 Epinephrine nasal spray provides the first significant innovation in epinephrine delivery since the first epinephrine auto-injector, the EpiPen was introduced in 1987 for treating anaphylaxis.
A Novel Formulation
ARS Pharmaceuticals’ novel formulation is the first needle-free epinephrine delivery system to be used in community settings. Epinephrine nasal spray was approved in August 2024 for treating type 1 hypersensitivity reactions and anaphylaxis in adults and children who weigh at least 30 kg. Regardless of PK and PD differences, all approved epinephrine products are considered efficacious.
AE profiles are similar among IM and intranasal epinephrine formulations. Epinephrine nasal spray administration results in hypertensive effects, tachycardia, and tremors, similar to IM epinephrine. As a result of the route of administration, epinephrine nasal spray can additionally cause nasal discomfort, intranasal paresthesia, and rhinorrhea.3
Epinephrine nasal spray 2 mg was designed to have a PK profile within the range of available epinephrine 0.3-mg auto-injectors. In a 6-treatment crossover study comparing epinephrine nasal spray with IM epinephrine, epinephrine nasal spray had a maximum concentration lower than that of EpiPen but higher than manual epinephrine injection. Epinephrine nasal spray had a more pronounced increase in systolic and diastolic blood pressure than EpiPen, confirming epinephrine’s systemic absorption.7
No Needle, No Problem
Trypanophobia, the fear of needles, is common. Patients, especially children, can feel uneasiness with injectables. A meta-analysis discovered that trypanophobia affected a majority of children and 20% to 50% of adolescents studied.10 Irrespective of a noted decrease in fear of needles with increasing age, 20% to 30% of adults reported a persistent fear.10 As anaphylaxis is a quick and severe, life-threatening reaction, there must be limited hesitancy in administering epinephrine. Even a few seconds of hesitancy will delay treatment for a vulnerable patient.
“In some cases, patients [with needle-induced anxiety] would delay or not administer the lifesaving treatment at the onset of symptoms, increasing the risk for a severe reaction or negative outcomes requiring additional emergency medical treatment,” wrote the authors of an epinephrine nasal spray press release.11 Failed or delayed treatment is associated with significant increases in risks of biphasic reactions, hospitalizations, and death, and the primary reason cited is trypanophobia.5 Epinephrine nasal spray utilizes an alkylsaccharide (Intravail; ARS Pharmaceuticals) to enhance mucosal absorption of intranasal products. This excipient temporarily alters mucosal viscosity and membrane fluidity to facilitate the absorption of epinephrine without requiring larger doses of epinephrine.4
Overcoming Provider Concerns
Some providers express concerns over the efficacy and the safety of the epinephrine nasal spray for their patients.12 Providers are willing to prescribe epinephrine nasal spray if patients inquire but will recommend that patients carry an epinephrine auto-injector in case the intranasal option does not work as anticipated.12 One provider reveals that they will “wait for reports to come in about how epinephrine nasal spray performs” before recommending it to patients as a replacement for auto-injectors.12
However, ethical and practical concerns prevent the implementation of a clinical trial comparing epinephrine nasal spray with placebo. To observe efficacy in patients experiencing severe allergic reactions, anaphylaxis would have to be induced in patients with diagnosed hypersensitivities.7 Therefore, trials have primarily focused on PK and PD of epinephrine nasal spray compared with epinephrine auto-injectors.4
Other providers raise concerns over the extra efforts required to ensure patient access to this new medication. In a health care landscape where many medications still require justification to insurance companies, the speed with which epinephrine nasal spray is added to drug formularies remains to be seen. In the interim, providers may have to spend extra time ensuring patient medication claims are approved and accessible.12
ARS Pharmaceuticals notes the company looks to ensure epinephrine nasal spray is accessible to the public, regardless of insurance status. Patient assistance will be available for uninsured patients, and co-pay assistance will be available for those with private insurance.11
The Pharmacist’s Role
In addition to their knowledge about insurance adjudication and navigation, pharmacists are uniquely poised to educate patients and caregivers on epinephrine administration (see Table 2) and the importance of its quick administration. According to ARS Pharmaceuticals, “Epinephrine treatment is only effective if available, readily usable, and administered appropriately.” The unit-dose delivery device should look familiar to the community pharmacist, as it is currently used for naloxone HCl nasal spray (Narcan; Emergent), sumatriptan (Imitrex; GlaxoSmithKline), and midazolam (Nayzilam; UCB).4
Conclusion
Allergies continue to be a public health concern, affecting individuals of all ages. Individuals who have experienced a severe allergic reaction, such as anaphylaxis, are encouraged always to carry epinephrine. Fear of needles, administration hesitancy, and failure to carry epinephrine continue to be barriers to optimal health outcomes in an emergency. As such, epinephrine nasal spray may help patients overcome these barriers by standing apart from epinephrine auto-injectors. PF data validates the comparative efficacy among all epinephrine products, but providers will look to real-world applications to strengthen confidence in the newly approved formulation. Moreover, pharmacists will be a great resource for allergy specialists and patients seeking information on epinephrine nasal spray, the first needle-free epinephrine product available in the US market.
REFERENCES
Food allergies. CDC Healthy Schools. August 23, 2022. Accessed September 12, 2024. https://www.cdc.gov/school-health-conditions/food-allergies/?CDC_AAref_Val=https://www.cdc.gov/healthyschools/foodallergies/index.htm
Lupkin S. A decade marked by outrage over drug prices. NPR. December 31, 2019. Accessed September 12, 2024. https://www.npr.org/sections/health-shots/2019/12/31/792617538/a-decade-marked-by-outrage-over-drug-prices.
Neffy. Prescribing information. ARS Pharmaceuticals; 2024. Accessed September 12, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/214697s000lbl.pdf
Ellis AK, Casale TB, Kaliner M, et al. Development of neffy, an epinephrine nasal spray, for severe allergic reactions. Pharmaceutics. 2024;16(6):811. doi:10.3390/pharmaceutics16060811
NIAID-Sponsored Expert Panel; Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126(suppl 6):S1-S58. doi:10.1016/j.jaci.2010.10.007
Dalal R, Grujic D. Epinephrine. In: StatPearls [Internet]. StatPearls Publishing; January 2024. Accessed September 12, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482160/
Casale TB, Ellis AK, Nowak-Wegrzyn A, Kaliner M, Lowenthal R, Tanimoto S. Pharmacokinetics/pharmacodynamics of epinephrine after single and repeat administration of neffy, EpiPen, and manual intramuscular injection. J Allergy Clin Immunol. 2023;152(6):1587-1596. doi:10.1016/j.jaci.2023.08.007
EpiPen. Prescribing information. Mylan; 2016. Accessed September 12, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019430s061lbl.pdf
Auvi-Q. Prescribing information. Kaleo; 2017. Accessed September 12, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/201739s008s009lbl.pdf
McLenon J, Rogers MAM. The fear of needles: a systematic review and meta-analysis. J Adv Nurs. 2019;75(1):30-42. doi:10.1111/jan.13818
ARS Pharmaceuticals receives FDA approval of neffy (epinephrine nasal spray), the first and only needle-free treatment for type I allergic reactions, including anaphylaxis. ARS Pharmaceuticals. August 9, 2024. Accessed September 12, 2024. https://ir.ars-pharma.com/news-releases/news-release-details/ars-pharmaceuticals-receives-fda-approval-neffyr-epinephrine
Redfearn S. A needle-less alternative to EpiPen has FDA approval. Will doctors prescribe it? NPR. August 23, 2024. Accessed September 12, 2024. https://www.npr.org/sections/shots-health-news/2024/08/23/nx-s1-5086219/needle-less-alternative-epipen-fda-approval
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