Epinephrine Nasal Spray Is Here. Updated Anaphylaxis Guidelines Aren't.

A patient who’s terrified of needles now has a legitimate needle-free option for treating anaphylaxis: epinephrine nasal spray (neffy), approved on August 9, 2024.1 However, if this patient were to ask whether the guidelines favor epinephrine nasal spray, the honest answer is not quite yet.

“Guidelines don't happen overnight,” David B.K. Golden, MD, associate professor of medicine at Johns Hopkins and co-chair of the 2023 practice parameter update in anaphylaxis, told HCPLive. “First of all, they take 1 to 3 years to develop. When something new comes on the market, there's not going to be a guideline for it, and that guideline may not happen for years."

About 3 years ago, in December 2023, an updated anaphylaxis practice parameter was published in the Annals of Allergy, Asthma, & Immunology.2 This update focused on 7 key areas: diagnosis, infants and toddlers, community settings, epinephrine autoinjectors, beta-blockers and ACE inhibitors, mast cell disorders, and perioperative anaphylaxis.

At this time, epinephrine autoinjectors were strongly recommended for high-risk patients. The update advised clinicians to deliver an epinephrine autoinjector at the first sign of expected anaphylaxis, not preemptively before symptoms arrive. Clinicians could choose between Adrenaclick, Auvi-Q, EpiPen, EpiPen Jr, Twinject, Adrenalin, and Symjepi.3

Epinephrine Nasal Spray Outperforms in Patient Preference, Efficacy Data

With the approval of epinephrine nasal spray, clinicians gained another treatment option: 1 delivered without a needle. A randomized crossover study presented at the 2026 American Academy of Allergy, Asthma, & Immunology (AAAAI) annual meeting in Philadelphia, found that 88% of 90 participants preferred the intranasal device over injectable epinephrine.4

Patients preferred the intranasal spray for its needle-free design, ease of use, portability, and the sense that bystanders could administer it more easily in an emergency. Nearly all participants (98%–100%) rated its size, weight, and temperature flexibility favorably.4

Epinephrine nasal spray also works just as quickly as any other epinephrine, taking about 5 minutes to take effect.5,6 A large real-world analysis showed that epinephrine nasal spray performed as effectively as epinephrine injections with success rates of 89.9% and 88.9%, respectively.7

“Pharmacokinetic studies have been done, and these are the studies that look at epinephrine drug levels. Epinephrine drug levels are very similar whether epinephrine is delivered by the nasal route or by the intramuscular route,” Marcus Shaker, MD, from Dartmouth Health, told HCPLive.

Neffy's pharmacokinetic profile fell within the range of the approved injectable products, with a mean peak plasma concentration of 481 pg/mL, which is higher than manual intramuscular epinephrine injection (339 pg/mL) but lower than EpiPen (753 pg/mL). Both single and double doses of epinephrine nasal spray produced greater pharmacodynamic effects than either EpiPen or manual injection.8

Still, epinephrine only helps if it's actually used. In 2023, only 3.2 million of the 20 million patients treated for severe reactions filled an auto-injector prescription, and about half consistently carried one.7

“We know that there have been many reports of incorrect use of auto injectors, often leading to significant injuries,” Golden said. “Every product has potential usability and reliability questions.”

Fill rates for neffy aren't yet available, but ARS Pharmaceuticals reported > 5000 prescriptions written as of May 2025, about 8 months after approval.9

2025 Delphi Consensus on Anaphylaxis Treatment

Although the official anaphylaxis practice parameters have not been updated since the approval of epinephrine nasal spray, and may not be for some time, informal recommendations have started to emerge. In December 2025, a Delphi panel of 34 experts developed consensus recommendations for treating acute allergic reactions.10

“The number 1 question that I get when patients leave our emergency departments, when we prescribe them an autoinjector, is: When should I administer epinephrine? What symptoms should I administer epinephrine for?” first author Timothy E. Dribin, MD, from the division of emergency medicine at Cincinnati Children’s Hospital Medical Center, told HCPLive.10 “It's a very complicated answer because there's no consensus on what symptoms warrant epinephrine and what symptoms do not warrant epinephrine.”

The panel reached consensus recommending epinephrine in 21 of 24 scenarios, with strongest agreement for reactions involving multiple organ systems or isolated severe respiratory or cardiovascular symptoms.10 Mild isolated cutaneous or GI symptoms did not warrant it, and moderate mucocutaneous symptoms alone lacked consensus. The recommendations did not mention epinephrine nasal spray, nor did they recommend any epinephrine form over another.

“Epinephrine is no different for these different forms,” Golden pointed out. “The only recommendation that's strong for epinephrine is that it should be used as the first and most important treatment for anaphylaxis... From there on, it's all conditional recommendations.”

To earn a strong recommendation, Golden said double-blind, placebo-controlled, randomized trials would need to show clear superiority of 1 treatment over the other. However, that isn’t possible in anaphylaxis research.

“There's never been any proof that epinephrine works,” Golden said. “You can't really do a controlled trial of epinephrine because you can't tell someone [with] anaphylaxis: ‘Well, we're going to give you placebo, and compare it to someone else who gets epinephrine.’ That would not be a good thing to do. Conditional recommendations are recommendations that have good evidence to support them, but not the best evidence, and it leaves some room for question[s] about what every doctor wants to prescribe.”

Golden also offered advice on what not to do: prescribe antihistamines for anaphylaxis and wait to see if it improves. Jacqueline Ross, MD, a physician at Allergy Partners of New Jersey, emphasized this too in an interview with HCPLive. She said allergists still need to re-educate patients on the 2023 parameter update, which states epinephrine should be the first-line treatment.

“Antihistamines are not only not first-line in anaphylaxis or allergic reactions, [but] they aren't really a part of the standard therapy at this time,” Ross said. “We need to be identifying anaphylaxis early and administering this life-saving device.”

Epinephrine Nasal Spray and Cold or Respiratory Infection Questions

Golden estimated that it will be 3 to 5 years before a formal anaphylaxis update. In the time before anaphylaxis receives updated practice parameters, clinicians may have questions about newer epinephrine options.

“Patients have wondered, ‘Hey, I have a cold or an upper respiratory tract infection, will the nasal epinephrine work just as well?’ Oppenheimer and colleagues did a study in 2024, which also provided really good reassurance around this question,” Shaker said. The study showed that having an upper respiratory tract infection did not have a significant impact on the way epinephrine nasal spray works.11

Golden’s 3 Epinephrine Questions: “Will It Work? Can I Trust It? Is It Dangerous?”

“When doctors ask me, ‘Do I recommend?’ ‘What should I prescribe?’ what they're really [asking] is: Will it work? Can I trust it? Is it dangerous? I always address those questions with patients and with doctors:

Will it work? Yes, if you use it right away.

Can I trust it? Yes, it's FDA-approved, and everything we know about it is that it's going to work the same as any other epinephrine.

Is it dangerous? No, epinephrine is not a dangerous drug. The only thing that's dangerous is not using it when you should.”

References

1. Smith T. FDA Approves Epinephrine Nasal Spray for Emergency Treatment of Allergic Reactions. HCPLive. Published August 9, 2024. Accessed July 23, 2026. https://www.hcplive.com/view/fda-approves-epinephrine-nasal-spray-for-emergency-treatment-of-allergic-reactions

2. Golden DBK, Wang J, Waserman S, et al. Anaphylaxis: A 2023 practice parameter update. Ann Allergy Asthma Immunol. 2024;132(2):124-176. doi:10.1016/j.anai.2023.09.015

3. Epinephrine (injection route). Mayo Clinic. Accessed July 23, 2026. https://www.mayoclinic.org/drugs-supplements/epinephrine-injection-route/description/drg-20072429

4. Mack D. Epinephrine Nasal Spray Shows Strong Patient Preference, With Douglas Mack, MD. HCPLive. Published March 12, 2026. Accessed July 23, 2026. https://www.hcplive.com/view/epinephrine-nasal-spray-shows-strong-patient-preference-douglas-mack-md

5. Smith T. Thomas B. Casale, MD: Discussing New Findings on Neffy for Urticaria Flares. HCPLive. Published February 26, 2024. Accessed July 23, 2026. https://www.hcplive.com/view/thomas-casale-md-discussing-new-findings-neffy-for-urticaria-flares

6. Clayton J. How Long Does It Take for an EpiPen to Work? Pharmacist-Backed Answers to 7 EpiPen FAQs. Goodrx. Published October 8, 2024. https://www.goodrx.com/epinephrine-epipen/how-long-does-it-take-for-an-epipen-to-work?srsltid=AfmBOoqOP8_jxjrW-kpl1koiW5IjfwFllvKV8SUfdS4E56OFMYeHrQa4

7. Casale T. Epinephrine Nasal Spray Shows Comparable Efficacy to Injection, With Thomas Casale, MD. HCPLive. Published September 15, 2025. Accessed July 23, 2026. https://www.hcplive.com/view/epinephrine-nasal-spray-shows-comparable-efficacy-to-injection-with-thomas-casale-md

8. 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

9. ARS Pharmaceuticals Reports First Quarter 2025 Financial Results and Highlights Progress in U.S. Commercial Launch of neffy® (epinephrine nasal spray). ARS Pharma. Published May 14, 2025. Accessed July 23, 2026. https://ir.ars-pharma.com/news-releases/news-release-details/ars-pharmaceuticals-reports-first-quarter-2025-financial-results

10. Dribin T. International Consensus on Epinephrine Use, With Timothy E. Dribin, MD. HCPLive. Published February 25, 2026. Accessed July 23, 2026. https://www.hcplive.com/view/international-consensus-epinephrine-use-timothy-e-dribin-md

11. Oppenheimer J, Casale TB, Camargo CA Jr, et al. "Upper respiratory tract infections have minimal impact on neffy's pharmacokinetics or pharmacodynamics." J Allergy Clin Immunol Pract. 2024;12(6):1640-1643 https://www.jaci-inpractice.org/article/S2213-2198(24)00263-0/fulltext