Where Does Nasal Spray Epinephrine Fit in Allergy Treatment?

Epinephrine now available in a nasal spray formulation (neffy) is being hailed as a way to diminish barriers to use, which is critical in emergency situations such as an anaphylactic reaction.

The nasal spray formulation uses a device that has been involved in seven other FDA approvals for emergency situations like drug overdoses or frequent seizures, including naloxone (Narcan), nalmefene (Opvee), and diazepam (Valtoco). It combines epinephrine with an absorption enhancer called dodecyl maltoside (Intravail).

It may particularly come in handy in those “equivocal cases of anaphylaxis, where it’s detected early but it hasn’t quite progressed to something that might be easily characterized as a medical emergency,” said Christopher Warren, PhD, of the Center for Food Allergy and Asthma Research at Northwestern University Feinberg School of Medicine in Chicago.

“Stabbing your child in the leg with an autoinjector, or injecting yourself, is a big move, and the fact that it’s a needle is a deterrent for people,” Warren told MedPage Today. “They wait for the reaction to get worse, to figure out if they really need it.”

Scott Sicherer, MD, director of the Jaffe Food Allergy Institute at the Icahn School of Medicine at Mount Sinai in New York City, said an autoinjector like the EpiPen is “perceived, perhaps unnecessarily, as dramatic.”

“I spend a lot of time instructing families and older children to inject epinephrine promptly if they’re having a significant allergic reaction, and yet, a lot of them do not,” Sicherer told MedPage Today. “They end up hesitating, or they end up going to the emergency room without having used the epinephrine, even though it’s a very safe and effective medication that makes them feel better and has the potential to save lives.”

The hesitation comes despite the allergy community’s mantra of “Epi First, Epi Fast,” emphasizing that epinephrine works best when given early in an allergic reaction.

But how will patients, who already have an array of autoinjector options, including EpiPen and Auvi-Q, incorporate the new device into their treatment regimens?

That answer isn’t clear just yet, experts told MedPage Today, and one expert who served on the FDA advisory committee reviewing nasal spray epinephrine cautioned that it hasn’t been studied in anaphylaxis, the disorder it’s intended to treat. However, none of the available epinephrine devices has been studied in such a scenario, as that trial would be difficult to do, ethically and logistically.

In May 2023, the FDA advisory committee recommended — albeit, not unanimously — that the agency should approve the device, but members also raised concerns about a lower blood concentration of epinephrine in the 10 minutes immediately following a single dose.

A few months later, FDA declined to approve nasal spray epinephrine, asking for an additional study assessing repeat doses of the nasal spray compared with intramuscular injection of epinephrine under seasonal allergic rhinitis conditions before it could be approved.

Developer ARS Pharma completed that trial, which it announced in a press release — it has not yet been published — and nasal spray epinephrine was approved earlier this month.

Experts said it was notable that the nasal spray actually outperformed intramuscular injection in this setting, in terms of both blood levels and clinical parameters including heart rate and systolic blood pressure.

“Allergic rhinitis increased the absorption slightly,” Joel Brooks, DO, MPH, a pediatric allergist at Columbia University Irving Medical Center in New York City, told MedPage Today. “The hypothesis is that blood vessels are already more open, so it’s possible the medication is absorbed faster that way. There’s increased vascular permeability because of the allergy.”

That wasn’t the case, however, for the main study comparing nasal spray epinephrine with both the EpiPen and standard intramuscular injection of epinephrine. In that study, blood concentrations of epinephrine at 10 minutes were highest for the EpiPen, but comparable for the nasal spray and the intramuscular injection. By 20 minutes, however, the nasal spray and the EpiPen were equivalent on blood epinephrine levels, while the intramuscular injection remained slightly lower.

Despite the differences in blood concentration, the important clinical outcomes of heart rate and systolic blood pressure were comparable for the nasal spray and EpiPen at 10 minutes, but lower for the intramuscular injection.

“Does that 10-minute mark really make a clinically significant difference if the levels are lower?” Brooks asked. “The answer is probably not, especially when we look at other markers like heart rate and blood pressure. We look for the clinical improvement.”

Still, FDA advisors raised concerns during the meeting that the nasal spray wasn’t studied in patients experiencing a severe allergic reaction or anaphylaxis.

“They really didn’t test it in the population in which it’s going to be used, so it was getting by largely on surrogate data,” Lewis Nelson, MD, of Rutgers New Jersey Medical School in Newark, who served on the FDA panel, told MedPage Today. “When you’re giving it to someone without an allergic reaction, is the absorption in the nose going to be the same?”

It’s unclear if the seasonal allergic rhinitis data apply here. An article on the development of epinephrine nasal spray, which had a company representative as its corresponding author, said doing such a trial would be unethical as it’s “difficult to impossible to predict the progression, severity, and likelihood of fatality.”

In addition, such a study has never been done for any other epinephrine device that’s on the market. These have just been battle-tested over many years in use; the EpiPen was initially approved by the FDA in 1987.

Brooks suspects there will be three approaches to nasal spray epinephrine. One camp will be conservative and stick to their current devices. Another will switch right to the new product. A middle camp will keep using their autoinjectors, but will start carrying the nasal spray, too.

Warren said he hopes postmarketing surveillance data in real-world conditions will eventually deliver a “reassuring efficacy and safety signal” for the nasal spray so that patients will only have to carry one type of device.

Both Brooks and Warren said they also hope that at the very least, patients will reach for nasal spray epinephrine instead of antihistamines, which aren’t helpful in severe allergic reactions.

There are other reasons patients may prefer the nasal spray. It’s been shown to tolerate higher temperatures, up to 122°F, and has a shelf life of 30 months — longer than the EpiPen, which usually requires a new prescription every year. It may also have an advantage on price, capped at $199 for those who are uninsured or have high-deductible health plans, or with a copay of $25 for those with insurance, according to the company.

While the nasal spray currently is approved for kids and adults weighing at least 66 lb, it’s being studied in pediatric patients who weigh less, and could be available to this group next year.

Yet some may prefer to stick with what they know.

“I would still keep my EpiPen around,” Nelson told MedPage Today. “I just don’t want to create a false sense of security that we have equipoise between the devices.”

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