Epinephrine nasal spray outcomes comparable with injected delivery
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Key takeaways:
- EpiPen had the fastest time to maximum plasma concentration, followed by neffy and manual injection.
- All treatments increased systolic blood pressure, and neffy had the greatest increase.
Pharmacokinetic and pharmacodynamic responses to a nasal epinephrine spray were comparable with responses to injected epinephrine, according to a study published in The Journal of Allergy and Clinical Immunology.
The spray may be a safe and effective option for treating type I allergic reactions including anaphylaxis, Thomas B. Casale, MD, professor of internal medicine and pediatrics and chief of clinical and translational research in the division of allergy and immunology at University of South Florida Morsani College of Medicine.
“For decades, the only way to administer epinephrine has been through needle-based products — an often painful and anxiety-inducing needle injection,” Casale told Healio.
In some cases, Casale said, this anxiety results in delay or failure to administer epinephrine at the onset of symptoms and therefore increases the risk for a severe reaction or negative outcomes requiring additional emergency medical treatment.
“Regrettably, stalling or failing to promptly administer treatment when symptoms appear greatly increases the chance of hospitalization and has been associated with fatalities,” he said. “This underscores the importance of eliminating the obstacle posed by needle injections.”
Providing patients and caregivers with a needle-free option such as neffy epinephrine nasal spray (ARS Pharma) allows for improved preparedness and response as well as rapid and confident administration of epinephrine without hesitation, Casale said.
To compare the pharmacokinetics and pharmacodynamics of 2 mg neffy with 0.3 mg EpiPen (Viatris/Myan Specialty) and 0.3 mg manual intramuscular injection, researchers conducted a study comprising 54 adults aged 21 to 54 years (70.4% men; 55.6% white) with a mean BMI of 28 kg/m2. Of the adults, 39 received neffy intranasal spray and 42 received EpiPen and manual intramuscular injections.
Pharmacokinetic results
EpiPen yielded the highest mean epinephrine concentrations for approximately 20 minutes following a single dose, but neffy had greater mean concentrations from 30 to 360 minutes after single doses. Also, neffy had greater mean concentrations than EpiPen after repeated doses.
EpiPen had higher mean maximum plasma concentrations (Cmax) than neffy (753 pg/mL vs. 481 pg/mL; P = .0001) and intramuscular injection (339 pg/mL) after a single dose, but there was no statistically significant differences comparing neffy with intramuscular injection.
Additionally, EpiPen had a faster median time to maximum concentration (Tmax) at 7.5 minutes than neffy at 30 minutes (P < .0001) and intramuscular injection at 45 minutes, again with no statistically significant difference between neffy and intramuscular injection.
The nasal spray had the greatest total exposure, with a statistically significant difference between its results and those of intramuscular injection (P = .0187).
After repeated doses, neffy showed numerically higher Cmax values (992-1,000 pg/mL) than EpiPen (840 pg/mL), with no statistically significant difference between them. EpiPen had the fastest median Tmax at 15 minutes followed by neffy at 30 minutes, again with no statistically significant differences, as well as lower mean total exposure compared with neffy.
Pharmacodynamic results
The neffy nasal spray, EpiPen and manual injection all resulted in increases from baseline in systolic blood pressure, with neffy yielding the greatest increase. Researchers noted EpiPen’s increase was less pronounced and more abrupt compared with neffy, whereas manual injection yielded a nominal change.
Systolic blood pressures also returned to baseline by approximately 120 minutes after dosing, with mean maximum effects (Emax) significantly greater with neffy compared with manual injection (23.6 mm Hg vs. 11.9 mm Hg; P < .0001) and numerically greater compared with EpiPen (18.2 mm Hg).
Treatment with repeated doses of neffy also led to significantly greater mean Emax in systolic blood pressure compared with EpiPen (left/right nostril: 28.9 mm Hg and right/right nostril: 29.1 mm Hg vs. 19.1 mm Hg; P = .0004 and P = .0003).
Both single and repeated doses of neffy resulted in immediate increases in diastolic blood pressure from baseline followed by decreases, whereas single and repeat EpiPen doses and single manual injections caused immediate and more pronounced decreases in diastolic blood pressure. Single doses of nasal spray also had significantly greater diastolic blood pressure Emax than EpiPen (8.1 mm Hg vs. 5.62 mm Hg; P = .0475) and manual injection (5.48 mm Hg; P = .0363), with a similar trend seen after repeat dosing of neffy and EpiPen.
All treatments led to increases from baseline in heart rate. Decreases followed for EpiPen and manual injection, but elevations persisted for 120 minutes with neffy. Also, a single dose of neffy had significantly greater heart rate Emax than EpiPen (17.2 beats/min vs. 12.3 beats/min; P = .0006) and manual injection (9.71 beats/mine; P .0001), with the trend continuing after repeated doses.
Safety, conclusions
The treatments all were well tolerated, according to the researchers, with mild adverse events. The greatest systolic blood pressure Emax followed EpiPen, and the greatest heart rate Emax followed neffy, the researchers found.
Based on these findings, the researchers said that neffy may be an alternative first-line treatment for anaphylaxis and other type I allergic reactions, especially for patients and caregivers who may be reluctant to use injectable epinephrine.
The FDA has asked ARS Pharma to conduct one more study including twice dosing in patients who have had an allergic rhinitis episode after a nasal-allergen challenge.
“ARS Pharma already performed this study with a single dose of neffy and, in fact, showed more rapid absorption compared to normal conditions,” Casale said. “ARS Pharma will conduct this additional study and anticipates a resubmission to the FDA in the first half of 2024.”
Perspective
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Epinephrine remains the first and only approved medication for the treatment of anaphylaxis. It is safe and effective when given quickly in response to a progressive allergic reaction.
One of the most important roles health care providers have is to discuss the use of epinephrine with patients and caregivers. Despite our education efforts, up to 83% of patients and/or caregivers delay or fail to use epinephrine in a timely manner despite believing an anaphylactic reaction was occurring. When the delay or avoidance of epinephrine is analyzed, ease of use, cost, lack of training and fear of needles all play a significant role.
To address these concerns, neffy intranasal epinephrine is in late-stage development. The research noted here was a six-dose, six-period crossover study that compared the pharmacodynamics and kinetics of neffy vs. the commercially available EpiPen epinephrine autoinjector and manually injected epinephrine from a 22-guage needle.
Subjects were randomly assigned and received both one-dose and two-dose treatments over a 12-day period. Following administration, serum levels were tested a total of 17 times on each subject starting at the first minute and ending at 360 minutes post-dosing.
The data collected found subject responses to neffy to be very similar to EpiPen and manual epinephrine injection. Some post-administration changes in blood pressure and pulse were significantly different, but the overall side effect profile was similar, and all treatments were well tolerated.
The maximum serum level for neffy was 481 pg/ml, which placed it between EpiPen (753 pg/ml) and manual epinephrine intramuscular injections (339 pg/ml). The time to maximum serum concentrations also placed neffy (30 minutes) between the EpiPen (7.5 minutes) and manual intramuscular epinephrine (45 minutes).
This study shows that all epinephrine treatments for anaphylaxis were well tolerated and safe with the newest form, neffy, having pharmacokinetics that placed it between the other two commonly used administration methods. Once approved, intranasal epinephrine will add an important addition to the treatment options for patients with potentially life-threatening allergic reactions.
Perspective
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More than 33 million Americans need a more accessible, easy-to-use, and needle-free epinephrine delivery option so we can reduce barriers to the timely and appropriate use of lifesaving epinephrine to treat severe allergic reactions.
This option would eliminate one of the biggest barriers and fears that food allergy patients and parents face — jamming a needle into one’s thigh or that of your child — and enables epinephrine to be delivered pain-free. It also would be a game changer in reaching our under-resourced communities by providing a more accessible and user-friendly solution in areas where resources may be limited.
We are frustrated and extremely disappointed with the FDA’s recent decision to ask ARS Pharma for additional data before approving neffy for use. For the past 36 years, the only treatment option for a life-threatening food allergy has been an epinephrine autoinjector. Our community wants and needs a needle-free option so our treatment can be as pain free and anxiety free as possible.
Until the FDA approves neffy, we encourage our community to follow the protocols their medical providers have provided to them. When you show symptoms of anaphylaxis, use your epinephrine autoinjector and go to the ED. Also, join us in our fight to bring this innovation to fruition so we can transform the way individuals with severe food allergies handle emergency life-threatening situations.
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