Regulatory submission: NDA resubmitted September 2026

“today announced that it has resubmitted its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for Anaphylm™ (dibutepinephrine) sublingual film for the treatment of Type I allergic reactions, including anaphylaxis.” (opens the source at this quote in a new tab)
“Resubmission supported by positive topline human factors and pharmacokinetic (PK) study results announced in August 2026” (opens the source at this quote in a new tab)

Launch

No evidence found.

Investigational status

“ANAPHYLM (dibutepinephrine) sublingual film is an investigational product candidate that has not been approved by the U.S. Food and Drug Administration.” (opens the source at this quote in a new tab)

“Anaphylm™ (dibutepinephrine) sublingual film is a polymer matrix-based epinephrine prodrug investigational product.” (opens the source at this quote in a new tab)

Regulatory pathway: 505(b)(2) and Fast Track designation

“The FDA confirmed that the 505(b)(2) regulatory approval pathway is acceptable for the development of Anaphylm. The FDA granted Fast Track designation of Anaphylm in March 2022.” (opens the source at this quote in a new tab)

Orphan drug, breakthrough therapy, and priority review designations

No evidence found.

Original New Drug Application submission, filing acceptance, and PDUFA date

“The Company’s original NDA for Anaphylm was submitted in March 2025.” (opens the source at this quote in a new tab)

“Aquestive completed the Anaphylm NDA submission to the FDA in the first quarter of 2025. On June 16, 2025, the NDA submission was accepted by the FDA and a PDUFA target action date of January 31, 2026 was assigned.” (opens the source at this quote in a new tab)

“has assigned a Prescription Drug User Fee Act (PDUFA) target action date of January 31, 2026” (opens the source at this quote in a new tab)

Advisory committee meeting

“The Company was informed in September that the FDA would not hold an Advisory Committee meeting regarding the approval of Anaphylm.” (opens the source at this quote in a new tab)

Complete Response Letter dated January 30, 2026

“today announced that it received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) on January 30, 2026 for the New Drug Application (NDA) seeking approval of Anaphylm™ (dibutepinephrine) Sublingual Film for the treatment of Type I allergic reactions, including anaphylaxis, in patients weighing 30kg or more (approximately 66 pounds).” (opens the source at this quote in a new tab)
“In the CRL, which focuses on administration and labeling guidance, the FDA cited deficiencies in the Anaphylm human factors (HF) validation study.” (opens the source at this quote in a new tab)
“Due to the requirements related to HF, clinical pharmacology requested a single pharmacokinetics (PK) study to understand the impact of any modifications to packaging and labeling. The Agency indicated that the HF and PK studies can be conducted in parallel. No additional studies were requested in the CRL.” (opens the source at this quote in a new tab)
“There were also no CMC issues noted in the CRL.” (opens the source at this quote in a new tab)

“The FDA issued a Complete Response Letter (CRL) on January 30, 2026, which requested that the Company complete a human factors study addressing packaging and administration, and a confirmatory pharmacokinetic (PK) study of Anaphylm.” (opens the source at this quote in a new tab)

Type A meeting completed March 2026

“today announced the receipt of preliminary comments and successful completion of an in-person Type A meeting with the U.S. Food and Drug Administration (FDA) regarding the resubmission of the Company's New Drug Application (NDA) for Anaphylm™ (dibutepinephrine) sublingual film” (opens the source at this quote in a new tab)
“In addition, the Company and FDA aligned on the concept of including labeling language to manage potential chewing of the film rather than creating additional clinical data.” (opens the source at this quote in a new tab)
“Based on the outcome of the Type A meeting, Aquestive reaffirms its guidance to resubmit the Anaphylm NDA in the third quarter of 2026.” (opens the source at this quote in a new tab)

“Following receipt of the CRL, Aquestive held a Type A meeting with the FDA to discuss the Company’s proposed approach to addressing the matters identified in the CRL.” (opens the source at this quote in a new tab)

Topline human factors and pharmacokinetic results announced August 2026

“The new HF study shows significant improvement across each deficiency identified by the FDA.” (opens the source at this quote in a new tab)
“The median time to open a pouch decreased from 17 seconds in the previous study to 3 seconds.” (opens the source at this quote in a new tab)
“No administration errors were observed in the self-administration arm of the PK study.” (opens the source at this quote in a new tab)

“No protocol-defined use errors were observed in the self-administration arm of the PK study.” (opens the source at this quote in a new tab)

Expected review classification and timeline for the resubmission

“FDA will determine the resubmission classification and establish the applicable review timeline following its initial review of the resubmission” (opens the source at this quote in a new tab)

“The Company will request an expedited review upon resubmission, though no shortened or expedited review timeline can be guaranteed.” (opens the source at this quote in a new tab)

Regulatory filings outside the United States

“The Company remains on track to submit regulatory applications in Canada by the end of 2026 and in the European Union in the first quarter of 2027. The Company expects its existing clinical data to support regulatory submissions in additional markets in 2027, including the United Kingdom.” (opens the source at this quote in a new tab)

“The Company received positive feedback from the European Medicines Agency (EMA) that no further clinical trials are needed prior to regulatory approval submission.” (opens the source at this quote in a new tab)

“Ex-US expansion is on track – filing in Canada before the end of 2026 and the filing in the E.U. in Q1 2027” (opens the source at this quote in a new tab)

Citizen petitions relating to Anaphylm

“risks that the FDA may consider issues raised in the citizen petition submitted to the FDA regarding Anaphylm on October 1, 2025” (opens the source at this quote in a new tab)

“the risk that the FDA may consider issues raised in one or more citizen petitions or similar submissions relating to Anaphylm” (opens the source at this quote in a new tab)

Manufacturer: Aquestive Therapeutics

“Aquestive Therapeutics, Inc. (NASDAQ: AQST)” (opens the source at this quote in a new tab)
“The Company is advancing Anaphylm™ (dibutepinephrine) sublingual film for the treatment of Type I allergic reactions, including anaphylaxis, and AQST-108 (epinephrine) topical gel for various potential dermatological conditions.” (opens the source at this quote in a new tab)

Generic name: dibutepinephrine

“Anaphylm™ (dibutepinephrine) sublingual film is a polymer matrix-based epinephrine prodrug investigational product.” (opens the source at this quote in a new tab)

Brand name and development code AQST-109

“The Anaphylm trade name for AQST-109 has been conditionally approved by the FDA. Final approval of the Anaphylm proprietary name is conditioned on FDA approval of the product candidate.” (opens the source at this quote in a new tab)

Therapeutic class: epinephrine prodrug delivered as a sublingual film

“Aquestive’s AdrenaVerse™ platform contains a library of more than 20 epinephrine prodrugs enabling the pursuit of various potential allergy and dermatological indications.” (opens the source at this quote in a new tab)

“First and only non-device based, orally delivered epinephrine product candidate” (opens the source at this quote in a new tab)

Film strength: 12 mg per film

“A single dose (12 mg) of DESF administered.” (opens the source at this quote in a new tab)

“Single dose of DESF (12 mg) administered after allergen challenge” (opens the source at this quote in a new tab)

Film size and weight

“Anaphylm is similar in size to a postage stamp, weighs less than an ounce, and begins to dissolve on contact. No water or swallowing is required for administration.” (opens the source at this quote in a new tab)

PharmFilm polymer matrix

“PharmFilm is comprised of proprietary polymer compositions that serve as film formers to APIs and excipients in place.” (opens the source at this quote in a new tab)
“PharmFilm, which is similar in thickness and size to a postage stamp, can be administered via buccal, sublingual or lingual oral delivery.” (opens the source at this quote in a new tab)

Primary packaging: pouch and carton

“The primary packaging for Anaphylm is thinner and smaller than an average credit card, can be carried in a pocket, and is designed to withstand weather excursions such as exposure to rain and/or sunlight.” (opens the source at this quote in a new tab)

“To resolve the FDA’s concerns, the Company has modified the pouch opening, instructions for use, pouch and carton labeling, and plans to rapidly conduct a new HF validation study with these modifications.” (opens the source at this quote in a new tab)

Storage and weather excursions

“It’s thinner than a credit card and requires no special storage, so patients can keep it in their phone case, wallet, or pocket” (opens the source at this quote in a new tab)

Material safety data sheet

No evidence found.

Wholesale acquisition cost and average sales price

No evidence found.

Pricing research status before launch

“Payer and pricing research underway” (opens the source at this quote in a new tab)

Average sales price and wholesale acquisition cost

No evidence found.

Payer and pricing research before a possible launch

“Payer and pricing research underway” (opens the source at this quote in a new tab)
“Market access capabilities are in place, with payer insights informing the next phase of engagement” (opens the source at this quote in a new tab)
“Payers want to know WHY they should pay a premium” (opens the source at this quote in a new tab)

EpiPen 0.3 mg two-pack: national average drug acquisition cost

Field	Quoted record
Product description	“EPIPEN 2-PAK 0.3 MG AUTO-INJCT”
National Drug Code	“49502050002”
NADAC per unit	“289.96000”
Corresponding generic NADAC per unit	“141.50252”
File date	“2025-11-12”

Authorized generic epinephrine 0.3 mg auto-injector: national average drug acquisition cost

Field	Quoted record
Product description	“EPINEPHRINE 0.3 MG AUTO-INJECT”
National Drug Code	“49502010202”
NADAC per unit	“141.13969”
File date	“2026-09-16”

Auvi-Q 0.3 mg auto-injector: national average drug acquisition cost

Field	Quoted record
Product description	“AUVI-Q 0.3 MG AUTO-INJECTOR”
National Drug Code	“60842002301”
NADAC per unit	“309.37573”
File date	“2026-09-16”

Epinephrine nasal spray 2 mg: national average drug acquisition cost

Field	Quoted record
National Drug Code	“82580002002”
NADAC per unit	“359.54780”
File date	“2026-09-16”

Epinephrine nasal spray: cash price and copay support

“With our payor contracting strategy, $0 co-pay for commercially eligible patients, a $199 cash price, and patient assistance programs, we anticipate that the out-of-pocket cost for acquiring neffy to patients may be less than, or equivalent to, generic epinephrine autoinjectors, thereby minimizing cost barriers to acquiring neffy.” (opens the source at this quote in a new tab)
“our $25 co-pay savings card, $199 cash price and patient assistance programs” (opens the source at this quote in a new tab)

AHFS drug class of epinephrine

“Drug class: alpha- and beta-Adrenergic Agonists” (opens the source at this quote in a new tab)
“Written by ASHP.” (opens the source at this quote in a new tab)

Anatomical Therapeutic Chemical classification of epinephrine

“C01CA Adrenergic and dopaminergic agents” (opens the source at this quote in a new tab)

ATC code	Name	DDD	Unit	Route
“C01CA24”	“epinephrine”	“0.5”	“mg”	“P”

Proposed indication wording

“today announced that it has resubmitted its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for Anaphylm™ (dibutepinephrine) sublingual film for the treatment of Type I allergic reactions, including anaphylaxis.” (opens the source at this quote in a new tab)

Intended population: participants weighing 30 kg or more

“today announced that it received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) on January 30, 2026 for the New Drug Application (NDA) seeking approval of Anaphylm™ (dibutepinephrine) Sublingual Film for the treatment of Type I allergic reactions, including anaphylaxis, in patients weighing 30kg or more (approximately 66 pounds).” (opens the source at this quote in a new tab)

Age range studied in the pediatric program

“The pediatric study in subjects from the ages of 7 to 17 (weight greater than or equal to 30 kgs) was completed with positive topline data reported on April 1, 2025.” (opens the source at this quote in a new tab)

Epinephrine actions at alpha- and beta-adrenergic receptors in anaphylaxis

“Epinephrine acts on both alpha and beta-adrenergic receptors.” (opens the source at this quote in a new tab)
“Through its action on alpha-adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension.” (opens the source at this quote in a new tab)
“Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation and helps alleviate bronchospasm, wheezing and dyspnea that may occur during anaphylaxis.” (opens the source at this quote in a new tab)
“Epinephrine alleviates pruritus, urticaria, and angioedema. It may also relieve gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder.” (opens the source at this quote in a new tab)

Receptor subtypes: alpha-1 vasoconstriction, beta-1 cardiac stimulation, beta-2 bronchial relaxation

“Epinephrine increases cardiac output by stimulating β1-adrenergic receptors within the heart and causes vasoconstriction by the activation of α1-adrenergic receptor.” (opens the source at this quote in a new tab)
“Although systemic IM or IV administered epinephrine binds to α- and β-adrenergic receptors nonselectively, inhaled epinephrine is delivered to the pulmonary airways that predominantly contain β2-adrenergic receptors in the bronchial smooth muscles.” (opens the source at this quote in a new tab)

Combined alpha- and beta-adrenergic effects as the basis of first-line treatment

“Through its combined α- and β-adrenergic effects, epinephrine counteracts vasodilation and increased vascular permeability, improves blood pressure and coronary perfusion, relaxes bronchial smooth muscle, and reduces mucosal edema in the upper airway.” (opens the source at this quote in a new tab)

Dibutepinephrine as a polymer matrix-based epinephrine prodrug

“Anaphylm™ (dibutepinephrine) sublingual film is a polymer matrix-based epinephrine prodrug investigational product.” (opens the source at this quote in a new tab)
“Anaphylm is similar in size to a postage stamp, weighs less than an ounce, and begins to dissolve on contact.” (opens the source at this quote in a new tab)

Sublingual film application and delivery of epinephrine

“AQST-109 is a polymer matrix-based epinephrine prodrug administered as a sublingual film that is applied under the tongue for the rapid delivery of epinephrine.” (opens the source at this quote in a new tab)

Prodrug formulation delivered on PharmFilm technology

“Aquestive Therapeutics is developing a sublingual (SL) film containing AQST - 109 (a prodrug of Epinephrine) delivered using PharmFilm technology” (opens the source at this quote in a new tab)

AdrenaVerse platform: control of absorption and conversion rates

“Our AdrenaVerse™ platform contains a library of over twenty epinephrine prodrug product candidates intended to control absorption and conversion rates across a variety of possible dosage forms and delivery sites.” (opens the source at this quote in a new tab)
“Epinephrine plays a critical role in immune suppression but, until now, its role has been limited due to issues in the absorption and conversion of epinephrine in the human body.” (opens the source at this quote in a new tab)
“The AdrenaVerse platform makes it possible to deliver epinephrine locally across mucosal surfaces and the skin and, therefore, we believe that it has the potential to yield multiple product candidates focused on treating a range of diseases.” (opens the source at this quote in a new tab)

Conversion of the prodrug to epinephrine after administration

“epinephrine prodrugs can control conversion rate” (opens the source at this quote in a new tab)
“In vitro data showing instant conversion of AQST-109” (opens the source at this quote in a new tab)

Ester prodrug lipophilicity: log P of the first-generation epinephrine prodrug dipivefrin

Property	Epinephrine	Dipivefrin
Log P	“-0.43”	“3.71”

Rationale for a prodrug: overcoming the barrier properties of the oral mucosa

“Mucosal surfaces, such as the oral mucosa, are a convenient route for delivering drugs to the body due to the fact that they are highly vascularized and permeable, providing increased bioavailability and rapid onset of action because it does not pass through the digestive system and thereby avoids first pass metabolism.” (opens the source at this quote in a new tab)
“In particular, the buccal and sublingual tissues offer advantageous sites for drug delivery because they are highly permeable regions of the oral mucosa, allowing drugs diffusing from the oral mucosa to have direct access to systemic circulation.” (opens the source at this quote in a new tab)
“Since drug delivery through the buccal mucosa is limited by the barrier nature of the epithelium and the area available for absorption, various enhancement strategies are required in order to deliver therapeutically relevant amounts of drug to the systemic circulation. Various methods, including the use of chemical penetration enhancers, prodrugs, and physical methods may be employed to overcome the barrier properties of the buccal mucosa.” (opens the source at this quote in a new tab)

Sublingual delivery of a prodrug of epinephrine in an investigational film

“This medicine is a polymer‐based adrenaline prodrug in the form of a sublingual (SL) film.” (opens the source at this quote in a new tab)

Phase 3 pharmacodynamics: blood pressure and heart rate versus intramuscular comparators

“AQST-109 demonstrated more rapid and larger increases in blood pressure and heart rate than the comparators.” (opens the source at this quote in a new tab)
“RD AQST-109 had greater than dose-proportional increases in PK and PD parameters, exceeding the comparators.” (opens the source at this quote in a new tab)

Integrated phase 1 pharmacodynamics: systolic and diastolic blood pressure and heart rate

“There was also an early, rapid, and consistent increase in systolic blood pressure, diastolic blood pressure, and heart rate after the administration of AQST-109.” (opens the source at this quote in a new tab)

Pivotal study: pharmacodynamic change at the first tracked time point

“Produced a meaningful change from baseline pharmacodynamic measures of blood pressure and heart rate at the first tracked time point of 2 minutes” (opens the source at this quote in a new tab)

Pharmacodynamic responses relative to auto-injectors and manual intramuscular epinephrine

“Importantly, Anaphylm has previously demonstrated a rapid onset together with robust increases in heart rate and blood pressure; these pharmacodynamic responses were comparable to or greater than those observed with auto-injectors and manual IM epinephrine in clinical studies.” (opens the source at this quote in a new tab)

Blood pressure direction compared with manual intramuscular injection

“Both SBP and DBP increased with the SL DESF and decreased after manual IM adrenaline.” (opens the source at this quote in a new tab)

Self-administration versus clinician administration: pharmacodynamic response

“Topline PD data from the study showed no difference in the median increase in systolic blood pressure, diastolic blood pressure, and heart rate whether Anaphylm was self-administered or HCP-administered.” (opens the source at this quote in a new tab)

Pharmacodynamics under oral allergen challenge

“Pharmacodynamics were not impacted by OAC after single- and repeat-dose administration of AQST-109 vs without OAC.” (opens the source at this quote in a new tab)
“Single- and repeat-dosing PD parameters were higher with AQST-109 after OAC vs intramuscular epinephrine injection without OAC, and were nonsignificantly higher for AQST-109 with vs without OAC.” (opens the source at this quote in a new tab)

Pharmacodynamics after deliberate top-of-tongue placement

“However, top-of-tongue placement resulted in a geometric mean Cmax above 100 pg/mL (baseline unadjusted), a median Tmax of 35 minutes, and clinically meaningful PD results that were comparable to or of greater magnitude than those observed with injectable epinephrine.” (opens the source at this quote in a new tab)

Pharmacodynamics after water of differing temperature and pH

“Topline PK and PD data from the study showed no statistically significant difference in PK and PD results between the different groups based on temperature and pH variability in the mouth.” (opens the source at this quote in a new tab)

Preclinical pharmacology: minipig exposure and prodrug half-life

“MiniPig data show similar exposure at lower doses” (opens the source at this quote in a new tab)

Preclinical pharmacology: adrenergic receptor potency of epinephrine and dipivefrin

Receptor and parameter	Epinephrine	Dipivefrin	Dipivefrin versus epinephrine ratio
Alpha-1 receptors, micromolar	“0.00018”	“0.41”	“2278”

Phase 3 pivotal study: maximum concentration and time to maximum concentration

“Achieved a geometric mean Cmax of 470 pg/mL bracketed by epinephrine autoinjectors AUVI-Q at 521 pg/mL and EpiPen at 469 pg/mL” (opens the source at this quote in a new tab)
“Generated partial AUCs between (bracketed) autoinjectors and Adrenalin manual IM injection from 5 to 60 minutes” (opens the source at this quote in a new tab)
“Maintained a median Tmax of 12 minutes compared to 20 minutes for EpiPen, 30 minutes for AUVI-Q, and 50 minutes for Adrenalin” (opens the source at this quote in a new tab)

Phase 3 pivotal study: bracketing of exposure and consistency of time to maximum concentration

“After single dose AQST-109 administration, area under the curve and maximum serum concentration met the primary end point of PK bracketing of 60 minutes, exceeding that of manual intramuscular injection, equaling EpiPen, but lower than that of Auvi-Q.” (opens the source at this quote in a new tab)
“AQST-109 had a median time-to-maximum plasma concentration of 12 minutes, exceeding that of EpiPen (20 minutes), Auvi-Q (30 minutes), and intramuscular injection (50 minutes); there was also more consistency (narrower IQR) than the comparators.” (opens the source at this quote in a new tab)
“Single dose AQST-109 demonstrated PK exposures consistently bracketed within established levels for approved intramuscular epinephrine and autoinjectors, with a more rapid time-to-maximum plasma concentration and comparable PD responses.” (opens the source at this quote in a new tab)

Phase 3 pivotal study: repeat dosing

“Maintains epinephrine plasma concentrations equal to or greater than existing injection products at all but 1 timepoint out to 2 hours” (opens the source at this quote in a new tab)
“Demonstrated a median Tmax of 10 minutes after administration of the second dose” (opens the source at this quote in a new tab)

Integrated phase 1 analysis: exposure and time to maximum concentration versus injected epinephrine

“AQST-109 yielded comparable epinephrine PK and exposure to both manual intramuscular injections and epinephrine autoinjectors.” (opens the source at this quote in a new tab)
“The median time to maximum concentration (Tmax) for AQST-109 was 15 minutes, compared with EpiPen (10 minutes), generic EpiPen (15 minutes), Auvi-Q (30 minutes), and manual intramuscular injection (50 minutes).” (opens the source at this quote in a new tab)
“AQST-109 delivered epinephrine with PK and PD results within the bracketed range of approved intramuscular products.” (opens the source at this quote in a new tab)

Phase 1 single ascending dose study: 12 mg film formulations versus EpiPen

PK parameter	AQST-109 F1, 12 mg (N=6)	AQST-109 F2, 12 mg (N=8)	0.3 mg IM EpiPen (N=10)
Geometric mean Cmax, pg/mL	“552”	“762”	“341”
Median Tmax, minutes	“15”	“15”	“22”
AUC 0-t, hr*pg/mL	“634”	“603”	“328”

Dose escalation and dose proportionality in the phase 1 study

“The twenty - four subjects returned to receive single ascending SL doses up to 24 mg in a sequential fashion .” (opens the source at this quote in a new tab)
“Formulation 2 met the predefined stopping criteria after the 12 mg dose . Formulation 1 met the stopping criteria after the 18 mg dose .” (opens the source at this quote in a new tab)
“AQST - 109 SL film demonstrated consistent Tmax values in a tighter range than reported for injectable epinephrine.” (opens the source at this quote in a new tab)

Confirmatory pharmacokinetic study: self-administration versus clinician administration and manual intramuscular epinephrine

Description	Anaphylm self-administered	Anaphylm clinician-administered	Manual IM clinician-administered
Geometric mean Cmax, pg/mL	“391.7”	“357.6”	“334.5”
Median Tmax, minutes	“12”	“12”	“45”

Confirmatory pharmacokinetic study: design and self-administration accuracy

“In addition, using the revised packaging and revised instructions for use, the Company conducted a single PK study in healthy volunteers comparing self-administration to clinician-administered as well as manual intramuscular (IM) administration. No administration errors were observed in the self-administration arm of the PK study.” (opens the source at this quote in a new tab)

Earlier self-administration pharmacokinetic study: time to maximum concentration

“The median time to maximum concentration (Tmax) was 15 minutes for both the Anaphylm self-administered and HCP-administered arms, while the median Tmax for the Adrenalin IM HCP administered arm was 50 minutes post administration.” (opens the source at this quote in a new tab)
“There was no statistical difference between the Anaphylm self- administered and HCP-administered arms of the study.” (opens the source at this quote in a new tab)

Effect of food: administration after a peanut butter sandwich

“The data showed that administering the film sublingually two minutes after consuming a peanut butter sandwich had no statistical impact on the resulting pharmacokinetics when compared to previous data from the initial Part 3 dataset. The medium time to maximum concentration (Tmax) and partial area under the curve (AUC) results were comparable and the time to reach Tmax remained 12 minutes when sublingually administered after consumption of a peanut butter sandwich. The geometric mean maximum concentration, or Cmax of 286 pg/mL was also comparable to previous data from Part 3.” (opens the source at this quote in a new tab)

Effect of swallowing the film whole with water

“The data also showed that swallowing the film whole immediately with water unexpectedly resulted in significant absorption of epinephrine.” (opens the source at this quote in a new tab)
“The Cmax was 313 pg/mL and the Tmax, while slower than the sublingual administration was significantly faster than the epinephrine 0.3mg IM injection from Parts 1 and 2 of the EPIPHAST study.” (opens the source at this quote in a new tab)

Effect of water temperature and pH in the mouth

“The single-dose, five-period, randomized crossover study was designed to compare the PK and PD of Anaphylm just after consuming normal water at different temperatures (hot, cold, and room temperature) as well as water of different pHs (acidic- lemon water, and basic- baking soda water).” (opens the source at this quote in a new tab)
“Topline PK and PD data from the study showed no statistically significant difference in PK and PD results between the different groups based on temperature and pH variability in the mouth.” (opens the source at this quote in a new tab)

Effect of film placement and intraoral movement

“The analysis showed that 87.5% of subjects maintained consistent film placement during disintegration. In the 12.5% of subjects where movement was noted, there were no significant differences in Cmax and Tmax. These findings further demonstrate that initial placement or subsequent movement of the sublingual film had no impact on epinephrine PK or PD comparability to epinephrine autoinjectors.” (opens the source at this quote in a new tab)

Effect of tongue position: deliberate top-of-tongue and roof-of-mouth placement

“The FDA also requested that Aquestive include a PK arm studying purposely misplaced administration of Anaphylm on top of the tongue or on the roof of the mouth, intended to demonstrate the impact of incorrect placement on PK and PD measures and tolerability. As expected, compared with prior clinical studies where the film was administered as per the instructions, the geometric mean Cmax is significantly lower and the Tmax significantly longer than with correct placement of our sublingual film.” (opens the source at this quote in a new tab)

Effect of hold time before swallowing saliva

“Furthermore, the PK‐PD data were compared according to three different methods of administration in 24 healthy adult volunteers: keeping the film 4 min under the tongue before swallowing saliva, 2 min under the tongue before swallowing saliva and keeping the film under the tongue while swallowing saliva at the same time. The data were similar in the three situations without a benefit for keeping the film beyond 2 min [55].” (opens the source at this quote in a new tab)

Oral allergy syndrome: pharmacokinetics with and without oral allergen challenge

“During screening with OAC, 94.4% of the 36 patients experienced moderate or severe oral symptoms.” (opens the source at this quote in a new tab)
“AQST-109 PK values were similar with or without OAC.” (opens the source at this quote in a new tab)
“AQST-109 PK and PD are not diminished with oral symptoms and changes, supporting reliable absorption in allergic reactions in such contexts.” (opens the source at this quote in a new tab)

Oral allergy syndrome study: single-dose maximum concentration and time to maximum concentration

Administration	Cmax, pg/mL	Median Tmax, minutes
Manual IM (n=24)	“261.2”	“50”
Anaphylm with allergen (n=23)	“403.5”	“12”
Anaphylm without allergen (n=15)	“372.8”	“12”

Oral allergy syndrome study: repeat-dose maximum concentration and time to maximum concentration

Administration	Cmax, pg/mL	Median Tmax, minutes
Manual IM (n=22)	“538.8”	“57.5”
Anaphylm with allergen (n=23)	“1194.0”	“25”
Anaphylm without allergen (n=13)	“585.5”	“25”

Oral allergy syndrome study: consistency of the absorption profile

“The two-part study demonstrated that Anaphylm's PK and PD profile during allergen-induced oral physiological changes was consistent with its profile without an allergen challenge.” (opens the source at this quote in a new tab)
“The PK profile remained consistent, with median Tmax maintained at 12 minutes and comparable Cmax values between allergen-exposed and non-exposed cohorts.” (opens the source at this quote in a new tab)

Pediatric pharmacokinetics in participants aged 7 to 17 years

“These results demonstrate that Anaphylm maintains its consistent PK profile in pediatric patients between the ages of seven and seventeen and weighing greater than thirty kilograms.” (opens the source at this quote in a new tab)
“A total of thirty-two patients completed the study. The PK results were consistent with previous adult studies.” (opens the source at this quote in a new tab)

Comparison with nasal and oral alternatives to injected epinephrine

“Data from these studies indicate promising pharmacokinetic results comparable to those of the standard of outpatient emergency care (0.3-mg EAI) and syringe and needle IM epinephrine administration. Several products have shown maximum plasma concentration values higher than those of the 0.3-mg EAI and manual IM injection, although it remains unclear whether this has clinical relevancy in patient outcomes. Generally, these modalities show comparable time to maximum concentrations.” (opens the source at this quote in a new tab)

Epinephrine class: absence of contraindications in approved labeling

“None.” (opens the source at this quote in a new tab)

Epinephrine class: common systemic adverse reactions

“Adverse reactions to epinephrine include anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and/or respiratory difficulties.” (opens the source at this quote in a new tab)

Epinephrine class: postapproval adverse reactions

“Cardiovascular: angina, arrhythmias (including fatal ventricular fibrillation), cerebral hemorrhage, hypertension, pallor, palpitations, tachyarrhythmia, tachycardia, vasoconstriction, ventricular ectopy, and stress cardiomyopathy” (opens the source at this quote in a new tab)
“Metabolism and Nutrition Disorders: transient hyperglycemia, sweating” (opens the source at this quote in a new tab)
“Neurological: disorientation, impaired memory, panic, psychomotor agitation, sleepiness, tingling, weakness” (opens the source at this quote in a new tab)
“Psychiatric: anxiety, apprehensiveness, restlessness” (opens the source at this quote in a new tab)
“Respiratory: respiratory difficulties” (opens the source at this quote in a new tab)

Epinephrine class: coexisting conditions that increase the risk of adverse reactions

“Epinephrine should be administered with caution to patients who have heart disease, including patients with cardiac arrhythmias, coronary artery disease, or hypertension. In such patients, or in patients who are on drugs that may sensitize the heart to arrhythmias, epinephrine may precipitate or aggravate angina pectoris, as well as produce ventricular arrhythmias” (opens the source at this quote in a new tab)
“Epinephrine can temporarily exacerbate the underlying condition or increase symptoms in patients with the following: hyperthyroidism, Parkinson's disease, diabetes, renal impairment. Epinephrine should be administered with caution in patients with these conditions, including elderly patients and pregnant women.” (opens the source at this quote in a new tab)
“Despite these concerns, it should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation.” (opens the source at this quote in a new tab)

Anaphylm clinical program: overall tolerability

“These studies showed that Anaphylm was generally well-tolerated and had a safety profile similar to that of epinephrine.” (opens the source at this quote in a new tab)

Phase 3 pivotal study: serious adverse events

“No serious adverse events were reported.” (opens the source at this quote in a new tab)

Oral allergy syndrome study: treatment-emergent adverse events

“Almost all patients experienced a related mild treatment-emergent adverse event; 4 were considered moderate in severity, and no new safety signals were identified compared with previous studies.” (opens the source at this quote in a new tab)

Oral allergy syndrome study: severity and resolution of adverse events

“In addition, Anaphylm was safe and well-tolerated with all adverse events categorized as mild or moderate and resolving without medical intervention.” (opens the source at this quote in a new tab)

Phase 1 study: local administration site effects

“All formulations and dosage strengths evaluated in this study were well tolerated . No serious AE’s were observed and local administration site AE’s were mild and self - resolving” (opens the source at this quote in a new tab)

Confirmatory pharmacokinetic study: tolerability and film retention

“From a tolerability perspective, there were no participants in the HF study and no subjects in the PK study who prematurely removed the film. In the PK study there were no serious adverse events, no serious events, and no events that led to study drug discontinuation.” (opens the source at this quote in a new tab)

Reported frequency of oral and sublingual swelling in the oral allergy syndrome study

“only 6% of subjects reported tongue swelling of any severity, and 2% of subjects reported sublingual swelling of any severity)” (opens the source at this quote in a new tab)

Pediatric study: serious adverse events

“Importantly, Anaphylm was shown to be safe and well-tolerated with no serious adverse events (SAEs) reported.” (opens the source at this quote in a new tab)

Proposed labeling published by a regulator

Not applicable.

Pediatric participants aged 7 to 17 years weighing at least 30 kilograms

“today announced positive topline results from its pediatric study for Anaphylm™ (epinephrine) sublingual film in patients aged seven to seventeen and weighing greater than thirty kilograms with a personal history of allergic reactions.” (opens the source at this quote in a new tab)
“These data are an important component of the FDA review process and could enable Anaphylm to have a label that includes this pediatric patient population.” (opens the source at this quote in a new tab)

Pediatric study design and completion

“The pediatric study in subjects from the ages of 7 to 17 (weight greater than or equal to 30 kgs) was completed with positive topline data reported on April 1, 2025. A total of thirty-two patients completed the study.” (opens the source at this quote in a new tab)

“The pediatric study was a multi-site, single treatment study designed to evaluate the PK, pharmacodynamics (PD), safety, and tolerability of Anaphylm.” (opens the source at this quote in a new tab)

Epinephrine class: pregnancy

“Prolonged experience with epinephrine use in pregnant women over several decades, based on published literature, have not identified a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with anaphylaxis, and treatment with epinephrine should not be delayed” (opens the source at this quote in a new tab)
“During pregnancy, anaphylaxis can be catastrophic and can lead to hypoxic-ischemic encephalopathy and permanent central nervous system damage or death in the mother and, more commonly, in the fetus or neonate. Treatment of anaphylaxis during pregnancy should not be delayed.” (opens the source at this quote in a new tab)

Epinephrine class: lactation

“There are no data on the presence of epinephrine or its metabolite in human milk, the effects on the breastfed infant, or the effects on human milk production. However, due to its poor oral bioavailability and short half-life, transfer of epinephrine into breastmilk is expected to be low. Treatment for anaphylaxis in breastfeeding patients should not be delayed.” (opens the source at this quote in a new tab)

Epinephrine class: older adults

“Clinical studies of EpiPen or EpiPen Jr for the emergency treatment of type I allergic reactions, including anaphylaxis, were not conducted in subjects aged 65 and over to determine whether they respond differently from younger adult subjects. However, other reported clinical experience with use of epinephrine for the treatment of anaphylaxis has identified that geriatric patients may be particularly sensitive to the effects of epinephrine.” (opens the source at this quote in a new tab)

Epinephrine class: organ contributions to elimination

“Epinephrine is rapidly degraded to vanillylmandelic acid, an inactive metabolite, by monoamine oxidase and catechol-O-methyltransferase that are abundantly expressed in the liver, kidneys and other extraneuronal tissues. The tissues with the highest contribution to removal of circulating exogenous epinephrine are the liver (32%), kidneys (25%), skeletal muscle (20%), and mesenteric organs (12%).” (opens the source at this quote in a new tab)

Populations excluded from the phase 1 program

“The Phase 1 trials conducted by AQST excluded patients with CV disease, mucosal disease, concomitant medications, or other comorbidities.” (opens the source at this quote in a new tab)

Hepatic and renal impairment: dedicated studies of dibutepinephrine

No evidence found.

Epinephrine class: drugs increasing the risk of cardiac arrhythmias

“Patients who receive epinephrine while concomitantly taking cardiac glycosides, diuretics, or anti-arrhythmics should be observed carefully for the development of cardiac arrhythmias” (opens the source at this quote in a new tab)

Epinephrine class: drugs potentiating the effects of epinephrine

“The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine, and catechol-O-methyl transferase (COMT) inhibitors such as entacapone.” (opens the source at this quote in a new tab)

Epinephrine class: drugs antagonizing the effects of epinephrine

“The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta- adrenergic blocking drugs, such as propranolol.” (opens the source at this quote in a new tab)
“The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha- adrenergic blocking drugs, such as phentolamine.” (opens the source at this quote in a new tab)
“Ergot alkaloids may also reverse the pressor effects of epinephrine.” (opens the source at this quote in a new tab)

Interaction studies specific to dibutepinephrine

No evidence found.

Effect of dibutepinephrine on the pharmacokinetics of other drugs

No evidence found.

Film strength studied in adults and pediatric participants

“Geometric mean baseline adjusted epinephrine concentration over time after administration of Anaphylm 12mg in pediatric subjects (Study AQ109302) compared to adult subjects (Study AQ109301B)” (opens the source at this quote in a new tab)

Prodrug dose expressed as epinephrine equivalent

“AQST-109 delivers a prodrug equivalent to 12 mg of epinephrine” (opens the source at this quote in a new tab)

Single and repeat dosing across the clinical program

“The Company believes that the original Anaphylm NDA submission is supported by a comprehensive clinical development program consisting of eleven independent clinical studies with approximately 967 total administrations across 411 subjects, including 840 single-dose and 127 repeat-dose exposures of Anaphylm.” (opens the source at this quote in a new tab)

Repeat dosing evaluated in the phase 3 study

“In this 2-part, phase 3, open-label study, participants received single dose and RD of AQST-109 and epinephrine via manual syringe, EpiPen, or Auvi-Q autoinjector on different days.” (opens the source at this quote in a new tab)
“RD AQST-109 had greater than dose-proportional increases in PK and PD parameters, exceeding the comparators.” (opens the source at this quote in a new tab)

Pediatric dosing by age and weight in the completed pediatric study

“The pediatric study in subjects from the ages of 7 to 17 (weight greater than or equal to 30 kgs) was completed with positive topline data reported on April 1, 2025.” (opens the source at this quote in a new tab)

Sublingual placement without water or swallowing

“Anaphylm is similar in size to a postage stamp, weighs less than an ounce, and begins to dissolve on contact. No water or swallowing is required for administration.” (opens the source at this quote in a new tab)

Placement under the tongue

“However, Anaphylm would, if approved by the FDA, allow a patient to simply place a dissolvable strip, approximately the size and weight of a postage stamp, under the tongue, providing an appropriate medication where it is needed and when it is needed.” (opens the source at this quote in a new tab)

Removal of hold time from the administration instructions

“In January 2024, we completed a Type C meeting with the FDA in which the FDA found that we had adequately addressed the FDA’s previous concerns noted in the EOP2 meeting, including addressing (1) the impact of any product hold time, (2) the potential for emesis (vomiting), and (3) the impact of potential mouth conditions such as angioedema (swelling), by removing product hold time from the administration instructions and providing additional information on how to characterize emesis in our NDA submission with the FDA.” (opens the source at this quote in a new tab)

Revised packaging, pouch opening, and instructions for use

“In response to the CRL, Aquestive completed a human factors study evaluating revised packaging that incorporated modifications to the pouch opening, instructions for use, and pouch and carton labeling.” (opens the source at this quote in a new tab)

Median pouch-opening time and administration errors in the human factors validation study

“The median time to open a pouch decreased from 17 seconds in the previous study to 3 seconds. The number of participants who had difficulty opening the pouch decreased from 26 (out of 166) to 1 (out of 105). The number of participants who incorrectly administered the film in the mouth decreased from 20 (out of 166) to 2 (out of 105). In the latest HF study, no participants were observed chewing the film or removing the film.” (opens the source at this quote in a new tab)

Self-administration without protocol-defined use errors

“The Company also completed a confirmatory PK study in healthy volunteers using the revised packaging and revised instructions for use, which evaluated self-administration and clinician administration of Anaphylm and included manual intramuscular epinephrine as a comparator. No protocol-defined use errors were observed in the self-administration arm of the PK study.” (opens the source at this quote in a new tab)

Primary packaging and portability

“The primary packaging for Anaphylm is thinner and smaller than an average credit card, can be carried in a pocket, and is designed to withstand weather excursions such as exposure to rain and/or sunlight.” (opens the source at this quote in a new tab)

Allergist-first launch strategy

“As we prepare for a focused, allergist-first launch, if approved, we are moving with urgency to bring Anaphylm to the patients who need it most.” (opens the source at this quote in a new tab)

“our full attention will be to prepare for a focused, allergist-first launch of Anaphylm as quickly as possible, if approved by the FDA” (opens the source at this quote in a new tab)

Planned sales force size and prescriber targeting

“~75 SALES REPRESENTATIVES AT LAUNCH” (opens the source at this quote in a new tab)
“Engagement with priority allergists and pediatricians” (opens the source at this quote in a new tab)
“~8K Target HCPs” (opens the source at this quote in a new tab)
“Coverage metrics shown are based on the 75 representative planning scenario; final launch deployment is expected to range from 65–80 representatives” (opens the source at this quote in a new tab)

Patient support services and payer engagement

“Patient Support Services to Simplify Anaphylm Access” (opens the source at this quote in a new tab)
“Proactive Payer Engagement Supports Post-Approval Access Readiness” (opens the source at this quote in a new tab)

Out-licensing of commercialization rights outside the United States

“Continue to evaluate out-licensing opportunities for Libervant® in the U.S. and Anaphylm ex-U.S.” (opens the source at this quote in a new tab)

Additional epinephrine doses in anaphylaxis management

“Treatment of anaphylaxis typically consists of an intramuscular injection of epinephrine administered at the earliest opportunity, followed by additional intramuscular or intravenous injections as needed.” (opens the source at this quote in a new tab)
“People with known allergies and who are at risk for anaphylaxis are advised to carry two epinephrine auto-injectors with them at all times and self-administer at the first signs of an anaphylactic reaction.” (opens the source at this quote in a new tab)

Repeat-dose exposure in the clinical development program

“including 840 single-dose and 127 repeat-dose exposures of Anaphylm” (opens the source at this quote in a new tab)

Concomitant antihistamines or corticosteroids

No evidence found.

Product-specific effect on quality measures

No evidence found.

Comparator epinephrine products marketed in the United States

“Among these are needle device-based treatments that have been accepted as standard of care treatment for many years, including autoinjectors such as EpiPen® marketed by Teva, and generics of EpiPen marketed by Viatris, Inc., Adrenaclick® marketed by Amneal Pharmaceuticals, LLC, and Auvi-Q® marketed by Kaleo Inc. and syringe device Symjep® marketed by U.S. Worldmeds.” (opens the source at this quote in a new tab)
“In August 2024, ARS Pharmaceuticals, Inc. announced its product neffy®, a nasal spray epinephrine delivery device, was approved by the FDA and EMA for the treatment of severe allergic reactions, including anaphylaxis.” (opens the source at this quote in a new tab)

Route, portability, and needle-free status versus auto-injectors

“Auto-injectors can be inconvenient to transport and many patients and caregivers dislike injections as a delivery method.” (opens the source at this quote in a new tab)
“We believe Anaphylm is well positioned as a non-device based treatment option for this indication, if approved by the FDA, due to its comparable efficacy to existing auto-injector and nasal spray products, easy portability and convenience of use.” (opens the source at this quote in a new tab)

“A small, highly portable and needle-free treatment option has the potential to address important barriers associated with carrying and administering epinephrine.” (opens the source at this quote in a new tab)

Device-related limitations of epinephrine auto-injectors

“EAI device-related issues deter device carriage, increase the chances of leaving them at home, make them less accessible when needed and reduce the likelihood of carrying two devices.” (opens the source at this quote in a new tab)

Comparison with epinephrine nasal spray: no head-to-head data

“No head-to-head studies have been conducted comparing Anaphylm and Neffy®.” (opens the source at this quote in a new tab)
“Median T-max of 12 minutes” (opens the source at this quote in a new tab)
“Therapeutic blood concentrations in as little as 5 minutes (over 100 pg/ml)” (opens the source at this quote in a new tab)

Preference survey comparing the film with a nasal spray device

“96% of survey respondents preferred Anaphylm in a hands-on epinephrine preference survey” (opens the source at this quote in a new tab)

Consensus definition of anaphylaxis

“Anaphylaxis is a serious allergic (hypersensitivity) reaction that can progress rapidly and may cause death. It may involve the skin/mucosa (includes lip/tongue), respiratory (lungs, breathing), cardiovascular (heart, blood pressure), and/or gastrointestinal (stomach/gut) systems. Life-threatening anaphylaxis is characterized by respiratory and/or cardiovascular involvement and may occur without skin/mucosa involvement.” (opens the source at this quote in a new tab)

Anaphylaxis as a type I, IgE-mediated hypersensitivity reaction

“Anaphylaxis is classically described as a type 1 hypersensitivity reaction driven by IgE-mediated release of histamine and other mediators from effector cells (such as mast cells) after allergen exposure. Non-IgE-mediated anaphylaxis is also well described, particularly to some drugs and certain types of exercise-induced anaphylaxis; symptoms/signs are indistinguishable from IgE-mediated anaphylaxis.” (opens the source at this quote in a new tab)

Type I allergic pathway as the primary mechanism of anaphylaxis

“The primary mechanism behind most cases of human anaphylaxis is mediated by classic type-I allergic reactions pathway involving IgE and mast cells/basophils.” (opens the source at this quote in a new tab)

World Allergy Organization definition of anaphylaxis and severe anaphylaxis

“Anaphylaxis is a serious systemic hypersensitivity reaction that is usually rapid in onset and may cause death. Severe anaphylaxis is characterized by potentially life-threatening compromise in airway, breathing and/or the circulation, and may occur without typical skin features or circulatory shock being present.” (opens the source at this quote in a new tab)

Immunologic and non-immunologic mechanisms of hypersensitivity

“In the immunologic IgE-mediated mechanism, cross-linking of cell surface high-affinity IgE receptors (FcɛRI) initiated by the binding of IgE with antigens causes degranulation of effector cells.” (opens the source at this quote in a new tab)

Most frequent elicitor groups worldwide

“The most frequent elicitor groups worldwide are food, insect venom, and drugs” (opens the source at this quote in a new tab)
“Elicitor groups other than the above mentioned are natural rubber latex, seminal fluid, radiocontrast media, medical dyes, and a variety of substances which are administered to patients in the perioperative setting (eg, suxamethonium, rocuronium, thiopental, propofol, opioids, protamine, chlorhexidine, plasma expanders)” (opens the source at this quote in a new tab)

Food and drug elicitors by age and region

“The most frequent elicitors of food-induced anaphylaxis in children are hen's egg (in infants and pre-school children), cow's milk, wheat, and peanut.” (opens the source at this quote in a new tab)
“Peanut and tree nuts are dominating elicitors of food-induced anaphylaxis in adults in North America and Australia; whereas, shellfish is a frequent elicitor of food-induced anaphylaxis in Asia.” (opens the source at this quote in a new tab)
“Drug-induced anaphylaxis is most frequently triggered by antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), again with age and geographical variations worldwide.” (opens the source at this quote in a new tab)

Proportion of anaphylaxis attributed to food, stings, and medications

“The most common causes for anaphylaxis across all age groups include food (33%), stings (19%) and medications (14%)” (opens the source at this quote in a new tab)
“In children, food allergies account for most cases of anaphylaxis” (opens the source at this quote in a new tab)

Triggers of anaphylaxis emergency department visits in older versus younger United States adults

“Compared to younger adults, visits among older adults were more likely to involve anaphylaxis from medications (34.0% vs 21.3%; odds ratio (OR) 1.85, 95% confidence interval (CI) 1.34, 2.55) and intravenous (IV) contrast (13.2% vs 5.6%; OR 2.50, 95% CI 1.55, 4.04).” (opens the source at this quote in a new tab)

Idiopathic anaphylaxis as a proportion of cases

“Anaphylaxis is classified as idiopathic when no trigger can be identified and currently represents between 6.5 and 35.0% of cases, depending on the studies.” (opens the source at this quote in a new tab)

Cofactors that increase the severity of a reaction

“Exogenous factors, which may increase the risk of an anaphylaxis reaction, include physical exercise, infections, psychological burden, sleep deprivation, alcohol intake, and medications.” (opens the source at this quote in a new tab)

Worldwide incidence of anaphylaxis and the range reported in children

“Recent publications show a global incidence of anaphylaxis between 50 and 112 episodes per 100 000 person-years while the estimated lifetime prevalence is 0.3–5.1%, variations depending on the definitions used, study methodology, and geographical areas.” (opens the source at this quote in a new tab)
“According to a recent systematic review, in children, the incidence of anaphylaxis ranged from 1 to 761 per 100 000 person-years.” (opens the source at this quote in a new tab)

Pooled population-based incidence of all-cause anaphylaxis and its annual rate of increase

“The current incidence worldwide was found to be approximately 46 cases per 100,000 population per year (95% CI 21–103).” (opens the source at this quote in a new tab)
“Using a random effects Poisson model we calculated a yearly increase of anaphylaxis incidence by 7.4% (95% CI 7.3–7.6, p < 0.05).” (opens the source at this quote in a new tab)

United States emergency department visits for anaphylaxis among infants and toddlers, 2006 to 2015

“Among infants and toddlers, the proportion of ED visits for anaphylaxis per year increased from 20 per 100,000 visits to 50 per 100,000 visits (Ptrend <0.001). The rate of ED visits for anaphylaxis increased from 15 to 32 ED visits per 100,000 population of infants and toddlers (Ptrend <0.001).” (opens the source at this quote in a new tab)
“The proportion of hospitalization among anaphylaxis-related ED visits decreased from 19% to 6% (Ptrend <0.001).” (opens the source at this quote in a new tab)

United States emergency department visits and hospitalizations for anaphylaxis among adults aged 65 years and older, 2006 to 2014

“In 2006–2014, older adults experienced approximately 1,019,967 AAR-related ED visits; 173,844 AAR-related hospitalizations; 93,795 anaphylaxis-related ED visits; and 72,677 anaphylaxis-related hospitalizations.” (opens the source at this quote in a new tab)
“While AAR-related ED visit and hospitalization rates remained stable (P-trends=0.28 and 0.16, respectively), anaphylaxis-related ED visit and hospitalization rates significantly increased over time (37 visits per 100,000 population in 2006 to 51 in 2014, P-trend<0.001; 13 hospitalizations per 100,000 population in 2006 to 23 in 2014, P-trend<0.001), especially hospitalization rates for drug-related anaphylaxis (47 hospitalizations per 100,000 population in 2006 to 85 in 2014, P-trend<0.001).” (opens the source at this quote in a new tab)

Trend in United States pediatric emergency department visits for anaphylaxis, 2016 to 2022

“There were 42,909 ED visits for anaphylaxis with a 4.2% per year increase in visit incidence (95% CI 1.8, 6.7) during the study period.” (opens the source at this quote in a new tab)

State-level and health maintenance organization estimates of pediatric anaphylaxis rates in the United States

“A study observing emergency department visits and hospital admissions in the US State of Illinois due to anaphylaxis, estimated a 29.1% annual increase of emergency department and hospital admissions among children from 6.3 per 100,000 children in 2008 to 17.2 per 100,000 children in 2012” (opens the source at this quote in a new tab)
“These 2012 estimates are substantially higher than previous estimates of 10.5 per 100,000 person/year for all-cause anaphylaxis among pediatric patients treated from 1991-1997 by a large health maintenance organization in the state of Washington.” (opens the source at this quote in a new tab)

United Kingdom hospital admissions for food-induced anaphylaxis, 1998 to 2018

“Food anaphylaxis admissions increased from 1.23 to 4.04 per 100 000 population per year (from 1998 to 2018), an annual increase of 5.7% (95% confidence interval 5.5% to 5.9%, P<0.001).” (opens the source at this quote in a new tab)
“The largest increase in hospital admissions was observed in children younger than 15 years, with an increase from 2.1 to 9.2 admissions per 100 000 population per year (an annual increase of 6.6%, 95% confidence interval 6.3% to 7.0%).” (opens the source at this quote in a new tab)

Hospitalization incidence for food-induced anaphylaxis in Spain, 2016 to 2021

“A total of 2161 hospital admissions for FIA were recorded in Spain from 2016 to 2021. The overall incidence rate was 0.77 cases per 100,000 person-years. The highest incidence was found in those aged <15 years (3.68), with lower figures among those aged 15 to 59 years (0.25) and ≥60 years (0.29).” (opens the source at this quote in a new tab)

Lifetime prevalence of anaphylaxis in the United States

“In the US, the lifetime prevalence of anaphylaxis is approximately 5% and appears to be rising.” (opens the source at this quote in a new tab)

Prevalence of food allergy, epinephrine prescription, and emergency department use among United States adults

“Estimated convincing food allergy prevalence among US adults was 10.8% (95% CI, 10.4%-11.1%), although 19.0% (95% CI, 18.5%-19.5%) of adults self-reported a food allergy.” (opens the source at this quote in a new tab)
“The most common allergies were shellfish (2.9%; 95% CI, 2.7%-3.1%), milk (1.9%; 95% CI, 1.8%-2.1%), peanut (1.8%; 95% CI, 1.7%-1.9%), tree nut (1.2%; 95% CI, 1.1%-1.3%), and fin fish (0.9%; 95% CI, 0.8%-1.0%).” (opens the source at this quote in a new tab)
“Regarding health care utilization, 24.0% (95% CI, 22.6%-25.4%) reported a current epinephrine prescription, and 38.3% (95% CI, 36.7%-40.0%) reported at least 1 food allergy–related lifetime emergency department visit.” (opens the source at this quote in a new tab)

Prevalence of food allergy and epinephrine autoinjector prescription among United States children

“Overall, estimated current FA prevalence was 7.6% (95% confidence interval: 7.1%–8.1%) after excluding 4% of children whose parent-reported FA reaction history was inconsistent with immunoglobulin E–mediated FA.” (opens the source at this quote in a new tab)
“The most prevalent allergens were peanut (2.2%), milk (1.9%), shellfish (1.3%), and tree nut (1.2%).” (opens the source at this quote in a new tab)
“Furthermore, 19.0% reported ≥1 FA-related emergency department visit in the previous year and 42.0% reported ≥1 lifetime FA-related emergency department visit, whereas 40.7% had a current epinephrine autoinjector prescription.” (opens the source at this quote in a new tab)

Distribution of food allergy across racial, ethnic, and income groups in the United States

“Food allergies affect approximately 8% of children and 11% of adults in the US.” (opens the source at this quote in a new tab)
“Non-Hispanic White individuals across all ages had the lowest rate of self-reported or parent-reported food allergies (9.5% [95% CI, 9.2%-9.9%]) compared with Asian (10.5% [95% CI, 9.1%-12.0%]), Hispanic (10.6% [95% CI, 9.7%-11.5%]), and non-Hispanic Black (10.6% [95% CI, 9.8%-11.5%]) individuals.” (opens the source at this quote in a new tab)
“Non-Hispanic Black individuals were most likely to report allergies to multiple foods (50.6% [95% CI, 46.1%-55.1%]).” (opens the source at this quote in a new tab)

Prevalence of allergy to multiple foods among United States children and adults

“Among children and adults meeting established symptom-report criteria for FA, an estimated 40% and 48% had multi-FA, respectively.” (opens the source at this quote in a new tab)

Pooled prevalence of food allergy and food sensitization in Europe

“Pooled lifetime and point prevalence of self‐reported FA were 19.9% (95% CI 16.6–23.3) and 13.1% (95% CI 11.3–14.8), respectively.” (opens the source at this quote in a new tab)
“The point prevalence of sensitization based on specific IgE (slgE) was 16.6% (95% CI 12.3–20.8), skin prick test (SPT) 5.7% (95% CI 3.9–7.4), and positive food challenge 0.8% (95% CI 0.5–0.9).” (opens the source at this quote in a new tab)

Prevalence of Hymenoptera venom anaphylaxis in a United States beneficiary population

“Fire ant and flying Hymenoptera-venom anaphylaxis prevalence in the general population was 0.048% and 0.083%, respectively. Fire ant-venom anaphylaxis prevalence in the 14 colonized states was 0.085%.” (opens the source at this quote in a new tab)

Prevalence of documented penicillin allergy in the United States

“In the US, 8 to 10% of the population and up to 15% of hospitalized patients have a documented penicillin allergy, limiting the use of these effective antibiotics.” (opens the source at this quote in a new tab)

Growth in adrenaline autoinjector prescriptions relative to hospital admissions

“Over the same time period, prescriptions for adrenaline autoinjectors increased by 336% (estimated rate ratio 1.113, 95% confidence interval 1.112 to 1.113; an increase of 11% per year).” (opens the source at this quote in a new tab)

Case fatality rate among United States hospitalizations and emergency department presentations

“CFRs were between 0.25% and 0.33% among hospitalizations or ED presentations with anaphylaxis as the principal diagnosis (NIS+NEDS, 2006-2009). These rates represent 63 to 99 deaths per year in the United States, approximately 77% of which occurred in hospitalized patients.” (opens the source at this quote in a new tab)
“Overall mortality rates ranged from 0.63 to 0.76 per million population (186 to 225 deaths per year, MCDD), and appeared stable in the last decade (annual percent change: –0.31%; 95% CI, –1.54% to 0.93%).” (opens the source at this quote in a new tab)

Anaphylaxis deaths in the United States by cause, 1999 to 2010

“There were a total of 2,458 anaphylaxis deaths in the US from 1999 to 2010. Medications were the most common cause (58.8%), followed by unspecified anaphylaxis (19.3%), venom (15.2%), and food (6.7%).” (opens the source at this quote in a new tab)
“There was a significant increase in fatal drug anaphylaxis over twelve years: from 0.27 (95%CI: 0.23-0.30) in 1999-2001 to 0.51 (95%CI: 0.47-0.56) per million in 2008-2010, P<0.001.” (opens the source at this quote in a new tab)

Estimated annual anaphylaxis deaths in the United States

“It causes approximately 1,500 deaths in the United States annually.” (opens the source at this quote in a new tab)

Proportion of anaphylaxis presentations with a fatal outcome

“An estimated, 1% of hospitalizations and 0.1% of emergency department attendances for anaphylaxis have a fatal outcome.” (opens the source at this quote in a new tab)
“Overall, although food-related anaphylaxis is relatively common, fatalities remain rare with a reported range of approximately 0.03 to 0.3 deaths per million person years in the general population” (opens the source at this quote in a new tab)

Demographic pattern of fatal venom anaphylaxis

“Consistent findings are that fatal insect venom allergy is a disease of adult males, with 80% to 90% of cases occurring in men, at an average age of 50 to 60 years.” (opens the source at this quote in a new tab)

Time from allergen exposure to cardiorespiratory arrest in fatal food-induced anaphylaxis

“the data from case series of fatal food-induced anaphylaxis have reported a median time to cardiorespiratory arrest (from consumption of the allergen) of around 30 minutes” (opens the source at this quote in a new tab)

Predictors of fatal anaphylaxis in a systematic review of 28 studies

“Asthma, cardiovascular comorbidities, and older age (≥65 years) were frequently reported predictors of mortality. Delayed epinephrine administration defined as more than 30 min after symptom onset or failure to administer in the prehospital setting was also associated with fatal outcomes.” (opens the source at this quote in a new tab)
“In terms of triggers, FIA was described in 15 studies encompassing 1,347 patients with anaphylaxis, of which 281 (20.9%) were fatalities explicitly attributed to food exposure. Peanut was the most commonly implicated allergen, followed by cow’s milk. Venom-induced anaphylaxis was reported in five studies, involving 970 patients, among whom 181 (18.7%) experienced fatal reactions.” (opens the source at this quote in a new tab)

Biphasic anaphylaxis: reported rates in registry and multicenter cohorts

“Among 9171 patients in the cohort, 435 (4.7%) experienced biphasic anaphylaxis.” (opens the source at this quote in a new tab)
“A 2025 study from 31 North American pediatric EDs found that among 5641 children with anaphylaxis, the incidence of biphasic anaphylaxis and biphasic non-anaphylaxis was 1.5% and 4.2%, respectively.” (opens the source at this quote in a new tab)
“Early studies reported that up to 21% of patients might experience biphasic anaphylaxis, while other studies found lower rates of biphasic reactions.” (opens the source at this quote in a new tab)

Timing of biphasic reactions and reported range of prevalence

“Around half of biphasic reactions occur within the first 6–12 h following reaction.” (opens the source at this quote in a new tab)

Recurrence of anaphylaxis during follow-up

“Worrying data indicate that recurrence of reactions occurs in 26.5–54.0% of anaphylaxis patients during a follow-up time of 1.5 years–25 years.” (opens the source at this quote in a new tab)

Risk factors for severe anaphylaxis

“older patient age (>65 years), history of mastocytosis, medication trigger, and comorbidities including pulmonary (eg, asthma) and cardiac disease (coronary disease, heart failure).” (opens the source at this quote in a new tab)

Sensitization and IgE binding to high-affinity receptors on mast cells and basophils

“The initial pathogenic step in the development of IgE-dependent type I allergy is sensitization, a process mediated by the uptake of allergens by antigen-presenting cells (APCs). APCs capture and process allergens, presenting fragments on their surface via MHC class II molecules, undergo maturation, and migrate to regional lymph nodes, where they present these antigens to naïve T cells.” (opens the source at this quote in a new tab)
“During the effector phase, re-exposure to the same allergen cross-links the IgE molecules bound to FcεRI receptors on mast cells and basophils” (opens the source at this quote in a new tab)

IgE cross-linking on effector cells as the classic mechanism

“IgE-mediated anaphylaxis is considered the classic and most frequent mechanism. In this type, anaphylaxis is triggered by the interaction of an allergen (usually a protein) interacting with the allergen-specific IgE/high-affinity receptor (FcεRI) complex expressed on effector cells, predominantly mast cells and basophils.” (opens the source at this quote in a new tab)

Preformed and newly synthesized mediators released on degranulation

“Degranulation results in the release of preformed mediators (histamine, heparin, tryptase, chymase, carboxypeptidase, cathepsin G and tumor necrosis factor alpha (TNF-α), and of de novo synthesized ones such as lipid mediators (cysteinyl leukotrienes), platelet activating factor (PAF), cytokines and growth factors such as vascular endothelial growth factor (VEGF).” (opens the source at this quote in a new tab)

Histamine actions at H1 and H2 receptors

“Experimental intravenous infusion of histamine in healthy volunteers can reproduce many of the symptoms and signs of anaphylaxis: flushing, headache, wheezing and transient hemodynamic changes such as systemic hypotension and tachycardia” (opens the source at this quote in a new tab)
“Histamine binding to H1 receptor causes increased vascular permeability, bronchospasm, and GI contraction. Histamine binding to H2 receptor leads to flushing, glandular secretion, and cardiac contraction.” (opens the source at this quote in a new tab)

Mechanism of vasodilation, capillary leak, hypotension, and airway edema

“Recent data suggest that mast cell-derived histamine and PAF can activate nitric oxide production from endothelium and set into motion a signaling cascade that leads to dilatation of blood vessels and dysfunction of the endothelial barrier. The latter, characterized by the opening of adherens junctions, leads to increased capillary permeability and fluid extravasation. These changes contribute to airway edema, hypovolemia, and distributive shock, with potentially fatal consequences.” (opens the source at this quote in a new tab)

Platelet-activating factor and reaction severity

“The platelet activating factor is the most potent mast cell mediator identified to date and is associated with decreased cardiac output, vascular hyperpermeability, smooth muscle contraction, hypovolemia, and cardiac collapse” (opens the source at this quote in a new tab)

Tryptase as a mast cell mediator and biomarker

“tryptase is a serine protease released by mast cells and basophils that possesses pro-inflammatory effects triggering tissue edema, chemokine secretion, and subsequent neutrophil recruitment.” (opens the source at this quote in a new tab)

Non-IgE-mediated and non-immunologic pathways

“The most relevant non-IgE-mediated immunologic mechanisms may involve the activation of pathways such as the complement system (anaphylatoxins, C3a, and C5a),35 the contact and coagulation system activation,36, 37, 38 or immunoglobulin G (IgG)-mediated anaphylaxis.” (opens the source at this quote in a new tab)
“Mast cells may be activated through receptors such as Mas-related G-protein coupled receptor member X2 (MRGPRX2) by certain drugs such as neuromuscular blocking agents and fluoroquinolones.” (opens the source at this quote in a new tab)

How epinephrine reverses the physiology of anaphylaxis

“In anaphylaxis, effector cell mediators drive vasodilation, capillary leak and bronchospasm, which are responsible for the main clinical features” (opens the source at this quote in a new tab)
“Adrenaline's alpha‐adrenergic stimulation of vascular smooth muscle and endothelial cells mediates potent vasoconstriction, mitigating against vasodilation, further capillary leak and hypotension. Beta‐1‐adrenergic stimulation has inotropic and chronotropic effects on the heart, increasing myocardial contractility and heart rate. Beta‐2‐adrenergic stimulation produces bronchodilation, counteracting the bronchospasm and wheeze seen in anaphylaxis.” (opens the source at this quote in a new tab)

Anaphylaxis as a clinical diagnosis without a confirmatory test

“Anaphylaxis is a clinical diagnosis that lacks a definitive test.” (opens the source at this quote in a new tab)

“There is no gold-standard diagnostic test for anaphylaxis. Tryptase may be helpful to obtain, depending on the clinical scenario, for later supporting the diagnosis. Until better diagnostic tests are developed, anaphylaxis remains a clinical diagnosis.” (opens the source at this quote in a new tab)

NIAID and FAAN clinical criteria: structure and organ system requirements

“In practice, clinicians rely on clinical criteria to assess the likelihood of anaphylaxis; however, these criteria are not perfectly sensitive or specific.” (opens the source at this quote in a new tab)
“The first applies to reactions without a likely or known trigger, the second to patients with likely allergen exposure, and the third to those with known allergen exposures. The first and second criteria require multisystem involvement, whereas the third accounts for the uncommon situation where a patient develops isolated hypotension after known allergen exposure.” (opens the source at this quote in a new tab)

Test characteristics of the NIAID and FAAN criteria

“In the retrospective ED-based study (n =214), the test characteristics of the criteria were: sensitivity, 96.7% (95% CI, 88.8% to 99.1%); specificity, 82.4% (95% CI, 75.5% to 87.6%); positive predictive value, 68.6% (95% CI, 58.2% to 77.4%); negative predictive value, 98.4% (95% CI, 94.5% to 99.6%); positive likelihood ratio, 5.48; and negative likelihood ratio, 0.04.” (opens the source at this quote in a new tab)
“In contrast, for the prospective ED study (n = 174), the test characteristics were: sensitivity, 95.1% (85.4%–98.7%); specificity, 70.8% (61.4%–78.8%); positive predictive value, 63.7% (52.9%–73.4%); negative predictive value, 96.4% (89.1%–99.1%); positive likelihood ratio, 3.26; and negative likelihood ratio, 0.07.” (opens the source at this quote in a new tab)

Misapplication of the diagnostic criteria in clinical care

“The NIAID/FAAN criteria have been misused in clinical care as strict diagnostic criteria, leading clinicians to believe they can only administer epinephrine if a patient meets these criteria. In reality, they are meant to support clinical decision-making, and the decision to give epinephrine should be made independently of whether the criteria are met.” (opens the source at this quote in a new tab)

Amended World Allergy Organization criteria

“Furthermore, the WAO Anaphylaxis Committee has proposed to amend the current NIAID/FAAN criteria, as shown in Table 2. The aim is to simplify the existing criteria, by combining the first 2 NIAID/FAAN criteria and modifying the third” (opens the source at this quote in a new tab)
“Typical skin symptoms AND significant symptoms from at least 1 other organ system; OR” (opens the source at this quote in a new tab)
“Exposure to a known or probable allergen for that patient, with respiratory and/or cardiovascular compromise.” (opens the source at this quote in a new tab)

GA2LEN consensus criteria and clinical support tool

“The clinical support tool incorporates a) new clinical criteria to help determine the likelihood that patients are having anaphylaxis, b) intramuscular epinephrine indications and dosing, and c) common findings from the anaphylaxis organ systems.” (opens the source at this quote in a new tab)
“We propose that the anaphylaxis definition and clinical support tool should replace prior definitions and clinical criteria.” (opens the source at this quote in a new tab)

Serum tryptase kinetics and interpretation

“During acute anaphylaxis, serum tryptase levels are increased from 15 min to 3 h or even longer, after the onset; levels peak between 1 and 2 h after the onset with 36–40% remaining <11.4 μg/L.” (opens the source at this quote in a new tab)
“Although elevated levels support a diagnosis of anaphylaxis, normal levels do not exclude anaphylaxis having occurred” (opens the source at this quote in a new tab)

Serum tryptase threshold after suspected food-induced anaphylaxis

“The results of a serum tryptase test obtained 90 minutes to 4 hours after a suspected food-induced anaphylaxis event that show an increase by at least 1.2 times the patient’s baseline value plus 2 ng/mL is highly suggestive of mast cell degranulation and can assist allergy specialists in confirming the diagnosis.” (opens the source at this quote in a new tab)
“in which serum tryptase levels were measured before and during an oral food challenge to induce anaphylaxis, serum tryptase levels increased above baseline in 100 of 160 cases and increased above the upper limit of normal (11.4 ng/mL) in 4 out of 160 cases.” (opens the source at this quote in a new tab)

Specific IgE serology and skin prick testing

“Allergic sensitization to suspected foods can be assessed by measuring food-specific serum IgE levels or performing skin prick testing.” (opens the source at this quote in a new tab)
“Given imprecise, variable predictive values, both skin prick testing and allergen-specific IgE, whether for single foods or in multifood panels, have limited utility as screening tools for food-protein allergies when interpreted without a history of allergic symptoms to a specific suspected food.” (opens the source at this quote in a new tab)

Oral food challenge as the reference standard

“The reference standard for the diagnosis of IgE-mediated food allergy is the oral food challenge.” (opens the source at this quote in a new tab)
“In practice, oral food challenges require significant time and clinical resources and inherently incur the risk of inducing allergic reactions.” (opens the source at this quote in a new tab)

Under-recognition and under-treatment of anaphylaxis

“Despite many advances in understanding etiology, mechanisms and management, anaphylaxis remains underdiagnosed and undertreated” (opens the source at this quote in a new tab)

Recognition difficulty in infants and young children

“Likewise, recognition of anaphylaxis may be especially challenging for noncommunicative patients including infants and young children who may present with nonspecific symptoms that overlap with normal infant behavior (eg, fussiness, drooling, spitting up).” (opens the source at this quote in a new tab)

Differential diagnosis

“Differential diagnosis of anaphylaxis includes acute asthma, localized angioedema, syncope, and anxiety/panic attacks, among others” (opens the source at this quote in a new tab)

Practice parameter recommendations on applying the diagnostic criteria

“We suggest that meeting diagnostic criteria for anaphylaxis is not required before the use of epinephrine.” (opens the source at this quote in a new tab)
“We suggest that neither the clinical decision to administer epinephrine nor the clinical response to epinephrine be used as a surrogate marker to establish a diagnosis of anaphylaxis.” (opens the source at this quote in a new tab)

Multisystem involvement and reactions without skin signs

“Anaphylaxis usually occurs with multisystem involvement but can present with isolated cardiovascular or respiratory compromise. Skin/mucosa signs may be absent in up to 20% of presentations.” (opens the source at this quote in a new tab)

“Skin signs are absent in 10–20% of anaphylaxis reactions, and this may result in delays in the recognition of anaphylaxis.” (opens the source at this quote in a new tab)

“In a prospective, multicenter ED-based study (412 reactions), 31% of reactions had predominantly wheezing without any other major organ system features, while 14% were purely cardiovascular.” (opens the source at this quote in a new tab)

Cutaneous and mucosal symptoms

“Cutaneous symptoms (angioedema, flush, generalized erythema, generalized itching, generalized urticaria) were found in 294 patients (76.96%)” (opens the source at this quote in a new tab)

Finding	Adult anaphylaxis emergency department visits (n = 1,422)
Any mucocutaneous symptom	“1392 (97.9%)”
Flushing	“613 (43.1%)”
Pruritus	“675 (47.5%)”
Diffuse urticaria	“570 (40.1%)”
Throat tightness	“780 (54.9%)”
Angioedema	“824 (57.9%)”

Respiratory symptoms

“Respiratory symptoms (apnoea, dyspnoea, stridor) were found in 258 patients (67.54%)” (opens the source at this quote in a new tab)

Finding	Adult anaphylaxis emergency department visits (n = 1,422)
Any respiratory symptom	“1196 (84.1%)”
Cough	“251 (17.7%)”
Voice change	“339 (23.8%)”
Dyspnea	“987 (69.4%)”
Wheezing	“375 (26.4%)”
Hypoxemia	“87 (6.1%)”

Cardiovascular symptoms

“Cardiovascular symptoms (loss of consciousness, drop in blood pressure, collapse, cardiac arrest, dizziness, tachycardia, disorientation) were found in 279 patients (73.04%)” (opens the source at this quote in a new tab)

Finding	Adult anaphylaxis emergency department visits (n = 1,422)
Any cardiovascular symptom	“764 (53.7%)”
Hypotension	“185 (13.0%)”
Presyncope	“517 (36.4%)”
Syncope	“117 (8.2%)”
Incontinence	“34 (2.4%)”

Gastrointestinal symptoms

“Gastrointestinal symptoms (abdominal pain, diarrhoea, nausea, vomiting, incontinence) were found in 111 patients (29%)” (opens the source at this quote in a new tab)

Finding	Adult anaphylaxis emergency department visits (n = 1,422)
Any gastrointestinal symptom	“644 (45.3%)”
Emesis	“206 (14.5%)”
Nausea	“510 (35.9%)”
Abdominal cramp	“229 (16.1%)”
Diarrhea	“109 (7.7%)”

Neurological symptoms

“Nausea, vomiting, diarrhea, scrotal edema, uterine cramps, vaginal bleeding, urinary incontinence, dizziness, seizures, confusion, and syncope may also be seen” (opens the source at this quote in a new tab)

Category	Quoted findings
Neurological symptoms	“confusion, drowsy, headache”
Neurological signs	“unexplained change in mental status, lethargy, somnolence, seizure”
Neurological findings in infants	“hypotonia, persistent and unexplained irritability, inconsolability, crying, or decreased activity”
Findings not assigned to one organ system	“lower back pain in women due to uterine cramping, sense of impending doom, metallic taste, anxiety”

Signs and symptoms specific to infants and young children

“Infants with anaphylaxis may have distinct signs such as a hoarse cry (laryngeal involvement), repetitive lip licking (mucosal involvement), or abrupt non-specific behavioral changes (e.g., irritability, persistent crying).” (opens the source at this quote in a new tab)

Onset and progression of reactions

“Reactions occur along a severity spectrum including life-threatening anaphylaxis, which is characterized by airway, breathing, and/or cardiovascular (ABC) compromise. Anaphylaxis is dynamic; reactions may initially appear mild and then become severe.” (opens the source at this quote in a new tab)

Recurrence of anaphylaxis in a population-based cohort followed for 10 years

“Eight percent of the patients experienced anaphylaxis recurrence within 10 years, (recurrence rate of 2.6 per 100 person-years) with most patients having the first recurrence within four years.” (opens the source at this quote in a new tab)
“There were 46 patients who experienced one recurrence, three patients who experienced two, and one patient who experienced eight during the time period under study, for a total of 60 recurrences observed during 2290 patient-years of follow-up, resulting in a recurrence rate of 2.6 per 100 person-years.” (opens the source at this quote in a new tab)
“Patients who experienced recurrent reactions typically experienced the recurrence in a relatively short time period, as the median time between the index and recurrent anaphylaxis was about seven months, with an interquartile range between 1 month and 4 years.” (opens the source at this quote in a new tab)

Recurrence of reactions reported across follow-up studies

“Worrying data indicate that recurrence of reactions occurs in 26.5–54.0% of anaphylaxis patients during a follow-up time of 1.5 years–25 years.” (opens the source at this quote in a new tab)

Early emergency department revisits after pediatric anaphylaxis

“The median hospitalization rate was 3.5% (IQR 2.2, 6.0) and the 3-day ED revisit rate was 0.6% (IQR 0.4, 0.9).” (opens the source at this quote in a new tab)
“There were 6 fatalities reported during the study period and 0.6 % (IQR 0.4, 0.9) of patients discharged from the ED during the index encounter had a 3-day ED revisit for anaphylaxis of which 11.4% (n=31) were hospitalized.” (opens the source at this quote in a new tab)

Repeat emergency department treatment among individuals with food allergy

“More generally, recent US population-weighted survey data indicate that approximately 1 in 10 convincingly food-allergic individuals report receiving treatment for a food-allergic reaction in the emergency department within the past 12 months. Over 1 in 3 report that they have received food allergy treatment in the emergency department at some point in their lifetime.” (opens the source at this quote in a new tab)

Permanent neurological disability after near-fatal anaphylaxis

“The most devastating reactions result in death, or near-fatal episodes resulting in permanent neurological disability from hypoxic ischaemic encephalopathy.” (opens the source at this quote in a new tab)
“277 case studies and 14 case series were identified reporting 896 deaths and 28 disabilities.” (opens the source at this quote in a new tab)

Neurological outcome after out-of-hospital cardiac arrest caused by anaphylaxis

“Patients with OHCA-A had a significantly higher favourable neurological outcome rate (24.2% vs 11.7%, p<0.001) and higher survival rate at 1 month (33.2% vs 16.1%, p<0.001) than patients with OHCA-C.” (opens the source at this quote in a new tab)

Persistence and resolution of food allergy during childhood

“Allergies to peanuts, tree nuts, and seafood tend to persist, whereas those to cow’s milk, hen’s eggs, wheat, and soy are typically outgrown during the preschool years.” (opens the source at this quote in a new tab)
“From a relatively large-scale retrospective analysis of children with cow’s milk allergy in the United States with a median follow-up duration of 54 months, the resolution rates of cow’s milk allergy were 19% by 4 years, 42% by 8 years, 64% by 12 years, and 79% by 16 years” (opens the source at this quote in a new tab)

Adult-onset food allergy and severe reaction history among United States adults

“Among food-allergic adults, 51.1% (95% CI, 49.3%-52.9%) experienced a severe food allergy reaction, 45.3% (95% CI, 43.6%-47.1%) were allergic to multiple foods, and 48.0% (95% CI, 46.2%-49.7%) developed food allergies as an adult.” (opens the source at this quote in a new tab)

Population-level food allergy quality-of-life impairment among United States adults measured with the Food Allergy Independent Measure

“The overall estimated mean FAIM score was 2.87 (95% confidence interval: 2.83-2.90).” (opens the source at this quote in a new tab)
“The population-level psychosocial burden of adults with FA is substantial, broadly distributed, and differs by demographic and allergic disease characteristics.” (opens the source at this quote in a new tab)

Clinical markers associated with greater quality-of-life impairment

“Reporting a current epinephrine autoinjector (EAI) prescription, severe allergic reaction history, history of EAI use, FA-related emergency department visits, or more FAs were also associated with significantly higher FAIM scores.” (opens the source at this quote in a new tab)

Caregiver-proxy psychosocial burden among United States children with food allergy

“The overall estimated mean caregiver-proxy FAIM scores for the US pediatric population were 2.79 (SE = 0.03) for reported FA, 2.96 (SE = 0.04) for convincing FA, and 3.21 (SE = 0.05) for physician-confirmed, convincing FA.” (opens the source at this quote in a new tab)
“While heterogenous to a degree, the psychosocial burden of children with FA was substantial irrespective of sociodemographic and clinical characteristics.” (opens the source at this quote in a new tab)

Caregiver anxiety, health utility, and quality-of-life decrement in peanut allergy

“Male and female caregivers reported mean levels of anxiety significantly higher than United Kingdom population norms.” (opens the source at this quote in a new tab)
“The utility decrement was largely driven by the EQ-5D anxiety and depression domain: 44% of caregivers reported being at least slightly anxious or depressed, compared with those reporting at least slight problems with self-care (7%), mobility (9%), usual activities (17%), and pain or discomfort (19%).” (opens the source at this quote in a new tab)

Health utilities derived from food allergy specific quality-of-life instruments

“However, traditional HRQoL instruments lack the sensitivity to generate health utilities that capture the impact that food allergies, such as peanut allergies, may have on children’s mental health and daily activities.” (opens the source at this quote in a new tab)
“The DCE disutilities were highest for severe food-related anxiety, emotional distress, and social limitations.” (opens the source at this quote in a new tab)
“The mean health utility for the actual EQ-5D-3L responses was 0.8431 (SD: 0.202, range: 0.193 to 1).” (opens the source at this quote in a new tab)

Social restriction and reliance on epinephrine auto-injectors in daily management

“Previous research describes how the stress of daily food allergy management compounded by the dearth of effective treatment options impacts family relationships and often limits social activities, ultimately contributing to impaired food allergy-related quality of life.” (opens the source at this quote in a new tab)
“Moreover, among these same food-allergic individuals, 1 in 5 report having treated a food-allergic reaction with an epinephrine auto-injector with the highest rates of epinephrine auto-injector (EAI) use reported among food-allergic adolescents and young adults.” (opens the source at this quote in a new tab)

Reported epinephrine auto-injector carriage rates and device-related concerns

“Despite this, studies have revealed that only about half of patients regularly carry an unexpired EAI.” (opens the source at this quote in a new tab)
“These anticipated reactions may be layered on top of other preexisting worries among patients with severe allergic reactions and their caregivers about when to use the EAI, potential side effects, needle phobias, and the force required to inject the drug.” (opens the source at this quote in a new tab)

“Barriers to AAI carriage were believed to be inconvenience of the size and difficulty of use.” (opens the source at this quote in a new tab)
“Some were embarrassed of their AAIs and less likely to carry them because of shame, fear of being seen as different or irritation at having to explain themselves.” (opens the source at this quote in a new tab)

Total annual economic burden of food allergy in the United States

“In a 2013 study by Gupta et al, the annual economic cost of food allergy was estimated to be $24.8 billion, roughly $4,184 per year per child.” (opens the source at this quote in a new tab)
“Annual direct medical costs including hospitalizations, clinician visits, and emergency department visits were $4.3 billion.” (opens the source at this quote in a new tab)

Direct medical cost components from national healthcare database analyses

“Among US studies, a retrospective national US government healthcare database analysis of the annual direct costs of food allergy, including PA, over the years 2006 and 2007 estimated that total annual medical costs were $225 million (2007 US dollars), with office visits accounting for just over half of the cost; the rest of the cost was split among ED visits, inpatient and outpatient visits, ambulance transfers, and AAIs.” (opens the source at this quote in a new tab)

Emergency department utilization for food-allergic reactions

“More generally, recent US population-weighted survey data indicate that approximately 1 in 10 convincingly food-allergic individuals report receiving treatment for a food-allergic reaction in the emergency department within the past 12 months.” (opens the source at this quote in a new tab)

“In the United States (US), recent work suggests that it affects up to 8% of children and 10% of adults and is responsible for an emergency room admission every three minutes” (opens the source at this quote in a new tab)

Trends in anaphylaxis emergency department visits and hospitalizations among United States older adults

“In 2006–2014, older adults experienced approximately 1,019,967 AAR-related ED visits; 173,844 AAR-related hospitalizations; 93,795 anaphylaxis-related ED visits; and 72,677 anaphylaxis-related hospitalizations.” (opens the source at this quote in a new tab)
“While AAR-related ED visit and hospitalization rates remained stable (P-trends=0.28 and 0.16, respectively), anaphylaxis-related ED visit and hospitalization rates significantly increased over time (37 visits per 100,000 population in 2006 to 51 in 2014, P-trend<0.001; 13 hospitalizations per 100,000 population in 2006 to 23 in 2014, P-trend<0.001), especially hospitalization rates for drug-related anaphylaxis (47 hospitalizations per 100,000 population in 2006 to 85 in 2014, P-trend<0.001).” (opens the source at this quote in a new tab)

Inpatient severity and resource intensity of anaphylaxis admissions

“The mean length of stay for these hospitalizations was 6.4 days.” (opens the source at this quote in a new tab)
“Of the total hospitalizations for anaphylaxis occurring between 2006–2014 among older adults, 28% of these visits involved intubation/ventilation, 3% involved cardiac arrest, and 5% of these visits resulted in inpatient death.” (opens the source at this quote in a new tab)

Epinephrine auto-injector acquisition cost and cost-effectiveness at prevailing United States prices

“The retail purchase price of autoinjectors is heterogeneous and often expensive even with insurance, in some instances reaching $690 per dual-pack package (2016 dollars), although retail device costs rarely exceeded $100 before 2010.” (opens the source at this quote in a new tab)
“At a market cost of $715 per twin pack, the autoinjector incremental cost-effectiveness ratio was $2 742 697 per quality-adjusted life-year.” (opens the source at this quote in a new tab)
“The value-based price (incremental cost-effectiveness ratio, $100 000 per quality-adjusted life-year) for personal epinephrine based on 10-fold fatality risk difference was $24.” (opens the source at this quote in a new tab)

Out-of-pocket and opportunity costs borne by families of children with food allergy

“Additionally, annual out-of-pocket costs related to food allergy were $5.5 billion and annual opportunity costs such as a caregiver leaving/changing jobs to care for their food allergic child was estimated to be $14.2 billion.” (opens the source at this quote in a new tab)

“estimated annual lost labour productivity due to food allergy at $773 million, or $130 per child, associated with accompanying child to medical visits; $5.5 billion, or $931 per child, in annual out‐of‐pocket costs, including special diets/allergen‐free foods, changes in childcare, and changes in schools; and annual opportunity costs due to forgone labour market activities, at $14 billion, or $2399 per child.” (opens the source at this quote in a new tab)

Caregiver-reported direct medical costs and willingness to pay for treatment

“A survey of US caregivers of children with food allergy estimated direct medical costs of $4.3 billion annually (or $724 per child).” (opens the source at this quote in a new tab)
“The caregivers also reported a willingness to pay $3504 per year per child for a safe and effective treatment that would allow the child to eat all foods; that total cost was estimated at $20.8 billion annually, a number similar to the total estimated indirect costs spent on children with food allergy ($20.5 billion). The total annual economic burden of food allergy was estimated to be $24.8 billion, which combined direct ($4.3 billion) and indirect costs.” (opens the source at this quote in a new tab)

Caregiver work absence, productivity loss, and career impact

“The overall mean number of days absent in the last 12 months and productivity impacted among caregivers currently in paid employment due to their child’s allergy were M = 1.6 (SD: 2.2) and M = 1.9 (SD: 3.6), respectively.” (opens the source at this quote in a new tab)
“Absenteeism and productivity impacts increased with severity of child’s allergy, but not significantly (p > 0.05); however, career impact was significantly associated with increased severity (χ2 = 9.19, p = 0.01), with 43% of caregivers of children with severe peanut allergy reporting some career impact (e.g., having to change job or stop work or having restricted career choices).” (opens the source at this quote in a new tab)

Socioeconomic disparities in family-level food allergy costs

“A follow-up study identified significant socioeconomic disparities in the economic burden of childhood food allergy, with children in the lowest income stratum spending more than twice as much as those in other income groups on food allergy-related emergency department and hospitalization costs.” (opens the source at this quote in a new tab)

“Children from the lowest household income stratum incurred 2.5 times the cost that children from the highest stratum spent on emergency department and hospitalization costs” (opens the source at this quote in a new tab)

Caregiver job-related opportunity costs used in United States economic models

“Job-related opportunity costs of caregivers were estimated at $2597 per year.” (opens the source at this quote in a new tab)

Limited specificity of skin prick and specific IgE testing and the resulting cost of false positive results

“Despite the relatively high sensitivity of these tests, they have an estimated specificity of around 60%, potentially generating false positives and incurring unnecessary costs.” (opens the source at this quote in a new tab)

Direct charges and societal costs of an oral food challenge

“We also estimated the costs by utilizing Medicare physician fee schedule and device costs, and the amount (3 hours non-facility = $626.89 and 3 hours facility = $565.315) was close to the one obtained from fairhealthconsumer.org without including hospital outpatient fees (facility), which vary greatly.” (opens the source at this quote in a new tab)

Cost-effectiveness of confirmatory oral food challenges compared with food elimination

“The cost of OFC strategy was $8671 compared with $18 012 for the FE strategy for the length of the model.” (opens the source at this quote in a new tab)
“In the OFC strategy, the total cost was $9341 less than FE and the increase in QALY after OFCs led to a 0.202 higher effectiveness in the OFC strategy.” (opens the source at this quote in a new tab)

Cost of drug allergy evaluation with skin testing and drug challenge

“The base case penicillin allergy evaluation costs $220 in 2016 United States dollars: $98 for personnel, $119 for consumables, and $3 for space.” (opens the source at this quote in a new tab)
“In sensitivity analyses, lower cost estimates were achieved when only a drug challenge was performed (i.e., no skin test, $84) and a nurse practitioner provider was used ($170).” (opens the source at this quote in a new tab)

Range of costs across accounting methods for allergy evaluation

“The cost of penicillin allergy evaluation using the RCC method ranged from $225 (no E&M, 2-step challenge only) to $1,247 (two visits, penicillin skin test with ampicillin, 2-step challenge after skin testing).” (opens the source at this quote in a new tab)

Cost-effectiveness of screening infants before peanut introduction

“Early peanut introduction reduces the risk of developing peanut allergy, especially in high-risk infants. Current US recommendations endorse screening but are not cost-effective relative to other international strategies.” (opens the source at this quote in a new tab)
“In deterministic SPT sensitivity analyses at base-case sensitivity and specificity rates, screening could be cost-effective at a high disutility rate (the negative effect of a food allergic reaction) (76-148 days of life traded) for an at-home vs in-clinic reaction in combination with high baseline peanut allergy prevalence among infants at high risk for peanut allergy and not yet exposed to peanuts.” (opens the source at this quote in a new tab)

Guideline position: intramuscular epinephrine is first-line therapy

“Epinephrine is universally recommended as the first-line treatment for anaphylaxis.” (opens the source at this quote in a new tab)

Guideline position: World Allergy Organization anaphylaxis guidance

“Intramuscular epinephrine (adrenaline) continues to be the first-line treatment for anaphylaxis. Nevertheless, its use remains suboptimal.” (opens the source at this quote in a new tab)
“The dose recommended for use by healthcare professionals is 0.01 mg/kg of body weight, to a maximum total dose of 0.5 mg, given by the intramuscular route” (opens the source at this quote in a new tab)
“Dosing should be repeated every 5–15 min if symptoms are refractory to treatment.” (opens the source at this quote in a new tab)

Recommendation to prescribe and carry self-injectable epinephrine

“We recommend clinicians counsel patients at high risk of anaphylaxis to always carry self-injectable epinephrine and teach patients proper indications and use.” (opens the source at this quote in a new tab)
“We suggest clinicians routinely prescribe EAIs to patients at higher risk of anaphylaxis. When deciding whether to prescribe EAIs to lower risk patients, we suggest that clinicians engage in a shared decision-making process that considers the patients’ risk factors, values, and preferences.” (opens the source at this quote in a new tab)

Timing of administration relative to symptom onset

“We suggest that clinicians counsel patients and caregivers to give epinephrine at the first sign of suspected anaphylaxis.” (opens the source at this quote in a new tab)
“There is no evidence that preemptive use of epinephrine in asymptomatic patients prevents anaphylaxis.” (opens the source at this quote in a new tab)

Products available in the United States and device selection

“Multiple brands of EAIs are available in the United States, including the following: Auvi-Q (Kaleo), EpiPen/EpiPen Jr. (Mylan), and generic versions of EpiPen/EpiPen Jr. (Viatris, Teva) and Adrenaclick (Amneal).” (opens the source at this quote in a new tab)
“When deciding which EAI to prescribe, we suggest that clinicians consider dosage, needle length, affordability, access, and patient treatment preferences.” (opens the source at this quote in a new tab)

Approved auto-injector dosing by body weight: EpiPen and EpiPen Jr

“EpiPen and EpiPen Jr are indicated for the emergency treatment of type I allergic reactions, including anaphylaxis, in adult and pediatric patients who weigh 15 kg or greater.” (opens the source at this quote in a new tab)
“In the absence of clinical improvement or if symptoms worsen after the initial treatment, a second dose of EpiPen or EpiPen Jr may be administered with a second auto-injector starting 5 minutes after the first dose.” (opens the source at this quote in a new tab)
“It is recommended that patients are prescribed and have immediate access to two EpiPen or EpiPen Jr devices at all times.” (opens the source at this quote in a new tab)

Auto-injector dose by weight band

Patient weight	Quoted dosage
30 kg or greater	“EpiPen 0.3 mg”
15 kg to less than 30 kg	“EpiPen Jr 0.15 mg”

Auto-injector dosing for infants and toddlers under 15 kg

“We suggest clinicians prescribe either the 0.1 mg or the 0.15 mg EAI dose for infants/toddlers weighing less than 15 kg.” (opens the source at this quote in a new tab)

Safety of intramuscular epinephrine delivered by auto-injector

“Serious adverse reactions to intramuscular epinephrine are very rare and should not pose a barrier to the prescription or early administration of EAIs when indicated.” (opens the source at this quote in a new tab)
“A 2018 computer simulation study found that the serious adverse event rate for EAI administration was only 0.73%.” (opens the source at this quote in a new tab)

Storage conditions for auto-injectors

“Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)” (opens the source at this quote in a new tab)
“Protect from light. Epinephrine is light sensitive and should be stored in the outer carton provided to protect it from light.” (opens the source at this quote in a new tab)

Underuse of epinephrine in the community

“Only 21% of children and 7% of adults experiencing anaphylaxis in community settings receive epinephrine prior to hospital arrival” (opens the source at this quote in a new tab)
“Pre-hospital epinephrine is consistently associated with reduced biphasic risk and shorter emergency department stays, yet underuse persists in up to two-thirds of community events” (opens the source at this quote in a new tab)
“Autoinjector cost, limited public access, and training disparities fuel preventable deaths, particularly in low-resource settings” (opens the source at this quote in a new tab)

Carriage, fill, and refill of prescribed devices

“Even when clinicians prescribe EAIs, patients do not always adhere to their treatment plans, with researchers reporting suboptimal rates of EAI prescription fills and refills, carriage, and use.” (opens the source at this quote in a new tab)

Reported barriers to auto-injector use

“Even when prescribed, the rates of AAI use remain low, ranging from 16% to 32%.” (opens the source at this quote in a new tab)
“Common barriers to AAI use include patient reluctance due to the device’s design, fear of needles, pain at the injection site, worry about social embarrassment, and concerns about accidental needle injuries.” (opens the source at this quote in a new tab)

Needle phobia as a factor against home management

“Hesitance about the intramuscular injection (needle phobia)” (opens the source at this quote in a new tab)

Injection injuries with auto-injectors

“Other potential adverse events after an EAI administration include lacerations and embedded needles. These injuries may result when a patient or caregiver moves during administration, the device discharges off center due to malfunction, or the needle bends after hitting a bone.” (opens the source at this quote in a new tab)
“More research is needed to evaluate strategies to reduce the risk of EAI-related laceration and other injuries.” (opens the source at this quote in a new tab)

Needle length and delivery depth

“Needle length may be an important consideration in young infants with low body mass, in women, and in adults with high body mass index (>25).” (opens the source at this quote in a new tab)
“Ultrasound imaging measurements suggest that among adults, the risk of subcutaneous injection is highest in obese women.” (opens the source at this quote in a new tab)

Cost and packaging constraints in the United States

“A 2018 survey of parents of children with food allergy in the United States found that 97% felt financially burdened by the cost of EAIs.” (opens the source at this quote in a new tab)
“In the United States, the average wholesale price of 2 EpiPens increased dramatically from $113.27 in 2007 to $730.33 in 2016.” (opens the source at this quote in a new tab)
“In the United States, EAIs are sold only in packages of 2; the cost might be reduced, and access improved, if they were available in single units.” (opens the source at this quote in a new tab)

Availability and affordability of auto-injectors internationally

“The limited availability of epinephrine auto-injectors remains a major problem in many countries, as well as their affordability for some patients.” (opens the source at this quote in a new tab)

Approval of the first needle-free epinephrine product

“ARS Pharmaceuticals, Inc. (Nasdaq: SPRY), a biopharmaceutical company dedicated to empowering at-risk patients and caregivers to better protect patients from severe allergic reactions that could lead to anaphylaxis, today announced that the U.S. Food and Drug Administration (FDA) approved neffy® (epinephrine nasal spray) 2 mg for the treatment of Type I Allergic Reactions, including anaphylaxis, in adults and children who weigh ≥30 kg (66 lbs.).” (opens the source at this quote in a new tab)
“The approval of neffy is based on data from five primary registration studies with a 2 mg intranasal dose of epinephrine. These primary clinical trials were supported by numerous pilot and supportive studies. neffy met all defined clinical endpoints and its pharmacokinetic (PK) and pharmacodynamic (PD) data were within the range of approved epinephrine injection products.” (opens the source at this quote in a new tab)

Approved indication and dosing of epinephrine nasal spray

“Neffy is indicated for emergency treatment of type I allergic reactions, including anaphylaxis, in adult and pediatric patients who weigh 15 kg or greater.” (opens the source at this quote in a new tab)
“In the absence of clinical improvement or if symptoms worsen after the initial treatment, a second dose of neffy may be administered in the same nostril with a second nasal spray starting 5 minutes after the first dose.” (opens the source at this quote in a new tab)
“It is recommended that patients are prescribed and have immediate access to two neffy nasal sprays at all times.” (opens the source at this quote in a new tab)

Nasal spray dose by weight band

Patient weight	Quoted dosage
30 kg or greater	“One spray of neffy 2 mg”
15 kg to less than 30 kg	“One spray of neffy 1 mg”

Labeled restriction in structural or anatomical nasal conditions

“Clinical pharmacology studies with neffy included subjects with history of allergic rhinitis, but did not include subjects with underlying structural and anatomical nasal conditions (e.g., polyps, history of nasal fractures or injuries, or history of nasal surgery). Absorption of neffy may be affected by underlying structural and anatomical nasal conditions. Consider use of other epinephrine products given by other routes of administration for patients with underlying structural or anatomical nasal conditions.” (opens the source at this quote in a new tab)

Storage and freezing constraints for the nasal spray

“Store at 68°F to 77°F (20°C to 25°C). Excursions permitted up to 122°F (50°C).” (opens the source at this quote in a new tab)
“Do not freeze. Neffy freezes below 5°F (-15°C). If neffy is frozen, it will not deliver epinephrine. Neffy may be used if it has been thawed after being previously frozen.” (opens the source at this quote in a new tab)

Pharmacokinetic and pharmacodynamic basis of the evidence for intranasal epinephrine

“Evaluating the efficacy of nasal epinephrine in Type I allergic reactions is challenging due to ethical and practical constraints that make randomized controlled trials difficult to conduct.” (opens the source at this quote in a new tab)

Comparison of intranasal epinephrine with injected epinephrine

“Notably, its nasal absorption is not affected by simultaneous upper respiratory infections, which supports its practical use.” (opens the source at this quote in a new tab)
“New alternatives, such as intranasal and sublingual adrenaline devices, are being developed to improve access and minimize hesitation in treatment.” (opens the source at this quote in a new tab)

Absence of a clinical evidence base for noninjectable routes at the time of the 2023 update

“This practice parameter addresses only injectable epinephrine; noninjectable routes of administration have been developed and have been reported to have favorable pharmacokinetic and pharmacodynamic profiles, but no clinical evidence base was available at the time of the development of this practice parameter.” (opens the source at this quote in a new tab)

Prefilled syringe without auto-injector function

“The FDA has also approved the Symjepi epinephrine injection device, a prefilled syringe without autoinjector functionality.” (opens the source at this quote in a new tab)

Approved indication and dosing of the prefilled syringe

“SYMJEPI is intended for immediate administration in patients who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions.” (opens the source at this quote in a new tab)
“Injection: 0.3 mg (0.3 mg/0.3 mL), clear and colorless solution in single-dose, pre-filled syringe for manual injection” (opens the source at this quote in a new tab)
“Injection: 0.15 mg (0.15 mg/0.3 mL), clear and colorless solution in single-dose, pre-filled syringe for manual injection” (opens the source at this quote in a new tab)

Manual administration where auto-injectors are unavailable

“It is therefore necessary to explain to these patients why, when, and how to inject EAI or alternatives (such as marketed pre-filled epinephrine syringes or vials) where EAI are not available.” (opens the source at this quote in a new tab)

Cost position of syringes and ampules relative to auto-injectors

“In comparison, the average wholesale prices of generic EAIs, epinephrine prefilled syringes, and ampules of epinephrine are substantially lower.” (opens the source at this quote in a new tab)
“The Canadian Agency for Drugs and Technologies in Health recently reviewed the available research on the clinical and cost-effectiveness of EAIs vs manual epinephrine administration with an ampule/vial and syringe and found no relevant studies.” (opens the source at this quote in a new tab)

Second-line status of antihistamines and glucocorticoids

“Second-line medications include beta2-adrenergic agonists, glucocorticoids, and antihistamines.” (opens the source at this quote in a new tab)
“The use of H1-antihistamines has a limited role in treatment of anaphylaxis,” (opens the source at this quote in a new tab)
“Of note, antihistamines are now a third line treatment in some guidelines,” (opens the source at this quote in a new tab)

Glucocorticoids in acute management

“Glucocorticosteroids are commonly used in anaphylaxis, with the objective of preventing protracted symptoms, in particular in patients with asthmatic symptoms, and also to prevent biphasic reactions (eg, intravenous hydrocortisone, or methylprednisolone). However, there is increasing evidence that glucocorticosteroids may be of no benefit in the acute management of anaphylaxis, and may even be harmful; their routine use is becoming controversial.” (opens the source at this quote in a new tab)

Adjunctive agents do not substitute for epinephrine

“Corticosteroids may help reduce the risk of biphasic reactions, although supporting evidence is still limited. Intravenous methylprednisolone or hydrocortisone are commonly given for this purpose. Antihistamines are used as additional therapy but should never replace adrenaline as the first-line treatment. H1 antihistamines can help relieve urticaria and itching, while H2 antihistamines may offer extra benefit for gastrointestinal and cardiovascular symptoms.” (opens the source at this quote in a new tab)

Adjunctive agents and biphasic reactions

“Observation following clinical stabilization is essential to detect symptom recurrence.” (opens the source at this quote in a new tab)
“Evidence-based protocols support 4–6 hours of monitoring for low-risk uniphasic presentations” (opens the source at this quote in a new tab)

Practice pattern: adjunctive agents used in place of epinephrine

“Though there is no absolute contraindication to intramuscular epinephrine for the treatment of anaphylaxis, antihistamines and corticosteroids remain the most frequently drugs used to treat anaphylaxis.” (opens the source at this quote in a new tab)

Guideline recommendation on allergen avoidance and education

“We recommend clinicians educate patients on avoidance of potential exposure to their allergen(s).” (opens the source at this quote in a new tab)
“We recommend clinicians educate patients that the main route of food-induced anaphylaxis is by ingestion and not contact or inhalation.” (opens the source at this quote in a new tab)

Burden associated with avoidance

“Vigilant avoidance prevents anaphylaxis recurrence from culprit allergens. However, it can be frustrating and associated with impaired quality of life, including bullying of food-allergic children, fear of anaphylaxis during airline travel, and anxiety over restrictions on exercise.” (opens the source at this quote in a new tab)

Venom immunotherapy and specialist referral

“Guidelines recommend that patients with anaphylaxis be referred to an allergy/immunology specialist for confirmation of the suspected trigger, advice on prevention and, where indicated, consideration for allergen immunotherapy (eg, insect venom).” (opens the source at this quote in a new tab)

Oral immunotherapy for food-induced anaphylaxis

“Allergen immunotherapy can help prevent food-induced anaphylaxis by raising the threshold for clinical reactions and encouraging immune tolerance.” (opens the source at this quote in a new tab)
“Although oral immunotherapy (OIT) is not yet advised for routine practice because of concerns about its safety and standardization,” (opens the source at this quote in a new tab)
“Beyond showing clinical benefit, OIT has been linked to a very low rate of severe adverse reactions that would require adrenaline use during home treatment (0.0-0.04%). Successfully completed OIT may lower the risk of anaphylaxis from accidental allergen exposure.” (opens the source at this quote in a new tab)

Immunotherapy does not remove the need for rescue epinephrine

“Food oral immunotherapy (OIT) is a relatively new and promising therapy for food allergy; however, safety and tolerability concerns continue to limit its use in routine clinical practice. Many reactions to OIT are mild and resolve without intervention or with antihistamine alone. However, virtually all clinical trials report some severe allergic reactions.” (opens the source at this quote in a new tab)

Summary: limitations of current therapies

Epinephrine is recommended as first-line treatment for anaphylaxis in every major guideline, but delivery of that treatment fails at several points. Community administration is uncommon: one review reports that 21% of children and 7% of adults experiencing anaphylaxis in community settings receive epinephrine before hospital arrival, and the same review describes underuse in up to 64% of pre-hospital events. Delay is consequential, because delayed administration of more than 60 minutes from onset is an independent predictor of biphasic recurrence, and in fatality case series most people who died of anaphylaxis did not receive timely epinephrine. Failure to carry a device contributes: the 2023 practice parameter update reports suboptimal rates of auto-injector prescription fills and refills, carriage, and use, and a 2025 review reports auto-injector use rates of 16% to 32% even among people who have been prescribed one, with device design, fear of needles, injection-site pain, social embarrassment, and concern about accidental needle injuries named as barriers. The World Allergy Organization guidance adds that limited availability of auto-injectors, and their affordability for some patients, remains a problem in many countries, and that needle phobia is listed among the considerations against managing an episode at home.

Device-related problems add to the gap. Reported auto-injector injuries include lacerations and embedded needles when a person moves during administration, when the device discharges off center, or when the needle bends after striking bone. Needle length is a design constraint in infants with low body mass, in women, and in adults with a body mass index above 25, and ultrasound-based work indicates that the risk of subcutaneous rather than intramuscular delivery is highest in women with obesity. Cost is a further constraint: a 2018 survey found that 97% of parents of children with food allergy in the United States felt financially burdened by the cost of auto-injectors, and the average wholesale price of two EpiPens rose from $113.27 in 2007 to $730.33 in 2016, with United States packaging sold only in two-unit packs. Storage adds a practical limit, since auto-injectors are labeled for 20°C to 25°C with excursions permitted only to 15°C to 30°C and must be protected from light, and the approved nasal spray does not deliver epinephrine while frozen. For intranasal epinephrine, the evidence base rests on pharmacokinetic and pharmacodynamic comparisons rather than on randomized efficacy trials in anaphylaxis, because ethical and practical constraints make such trials difficult; the label also states that subjects with structural or anatomical nasal conditions were not studied and advises considering another route for those patients. The 2023 practice parameter update states explicitly that it addresses only injectable epinephrine and that noninjectable routes had no clinical evidence base at the time it was written.

Summary: anticipated place of dibutepinephrine sublingual film in treatment

Dibutepinephrine sublingual film is an investigational rescue treatment for Type I allergic reactions including anaphylaxis, positioned in the same use setting as an epinephrine auto-injector rather than as a maintenance or preventive therapy. Because most anaphylaxis occurs outside medical settings, the relevant care settings are the community locations where guidelines already direct patients to carry epinephrine: home, school and childcare, restaurants, travel, and workplaces. The 2023 practice parameter update recommends that people at high risk always carry self-injectable epinephrine, and the World Allergy Organization guidance directs that epinephrine be given at the first sign of anaphylaxis and that patients be taught self-administration; a product that removes the needle and the device addresses carriage and hesitation rather than the underlying indication.

The manufacturer describes the product as similar in size to a postage stamp, weighing less than an ounce, beginning to dissolve on contact, and requiring no water or swallowing, with primary packaging thinner and smaller than an average credit card that can be carried in a pocket and is designed to withstand exposure to rain or sunlight. Aquestive states that it is preparing a focused, allergist-first launch, with medical affairs activity directed at the allergy community and partnerships with allergy-focused patient advocacy organizations, and describes the market opportunity as conversion from older autoinjector device technology. The company has not stated that the film would replace an auto-injector for a given patient; the FDA labeling that would define whether it substitutes for or supplements an auto-injector has not been issued, because the application received a Complete Response Letter dated January 30, 2026 and was resubmitted on September 17, 2026. A 2025 review of anaphylaxis management describes sublingual delivery as an alternative developed to address low auto-injector use rather than as a replacement for guideline-recommended intramuscular epinephrine.

Product format and portability

“Anaphylm is a polymer matrix-based epinephrine prodrug product candidate. Anaphylm is similar in size to a postage stamp, weighs less than an ounce, and begins to dissolve on contact. No water or swallowing is required for administration. The primary packaging for Anaphylm is thinner and smaller than an average credit card, can be carried in a pocket, and is designed to withstand weather excursions such as exposure to rain and/or sunlight.” (opens the source at this quote in a new tab)

Allergist-first commercial positioning

“As we bring Anaphylm to market, if approved by the FDA, we believe we can be instrumental in driving conversion in the allergist office and, ultimately, the broader market. As we prepare to resubmit our application to the FDA in the coming weeks, our full attention will be to prepare for a focused, allergist-first launch of Anaphylm as quickly as possible, if approved by the FDA. In the meantime, our medical affairs team continues to interact with the allergy community on a daily basis.” (opens the source at this quote in a new tab)

Anticipated market conversion from injector devices

“The epinephrine rescue market continues to grow and remains available for conversion from older medical device technology including autoinjectors,” (opens the source at this quote in a new tab)

Independent description of sublingual delivery in the treatment landscape

“Various intranasal and sublingual delivery systems have been investigated to enhance patient compliance and improve outcomes.” (opens the source at this quote in a new tab)
“Therefore, sublingual delivery is an encouraging alternative.” (opens the source at this quote in a new tab)
“Compared to intramuscular adrenaline, Anaphylm reaches similar plasma epinephrine levels and has a comparable side effect profile, while achieving peak plasma concentration significantly faster.” (opens the source at this quote in a new tab)

Self-administration and caregiver administration in community settings

“For early self-management, it is important to educate the patient regarding the risk of anaphylaxis and self-treatment of any recurrence.” (opens the source at this quote in a new tab)

Setting in which most episodes occur

“Anaphylaxis is unpredictable and can occur anywhere, with most cases occurring outside the medical setting.” (opens the source at this quote in a new tab)

Children and adolescents: pharmacokinetic data limited to participants weighing more than 30 kg

“today announced positive topline results from its pediatric study for Anaphylm™ (epinephrine) sublingual film in patients aged seven to seventeen and weighing greater than thirty kilograms with a personal history of allergic reactions.” (opens the source at this quote in a new tab)
“The pediatric study was a multi-site, single treatment study designed to evaluate the PK, pharmacodynamics (PD), safety, and tolerability of Anaphylm. A total of thirty-two patients completed the study. The PK results were consistent with previous adult studies.” (opens the source at this quote in a new tab)

Infants and toddlers: dose and device uncertainty below 15 kg

“Thus, the actual necessary and sufficient mg/kg dose is unknown, though the 0.01 mg/kg recommendation seems to be at least anecdotally supported by evidence of efficacy.” (opens the source at this quote in a new tab)
“Lack of data to determine whether needle length of available 0.1 mg and 0.15 mg autoinjectors provides more optimal intramuscular delivery of epinephrine.” (opens the source at this quote in a new tab)

High body weight: route of delivery and bioavailability of injected epinephrine

“Overweight women were more likely to experience subcutaneous injection (n = 10 of 12) compared with non-overweight men (n = 1 of 18).” (opens the source at this quote in a new tab)
“However, when the researchers evaluated the bioavailability of epinephrine after an injection, the initial plasma peak was similar in both groups, and the overall bioavailability of epinephrine was higher in the overweight women.” (opens the source at this quote in a new tab)
“There is emerging evidence that the pharmacokinetics of epinephrine may vary between individual patients and between different devices and methods used for administration.” (opens the source at this quote in a new tab)

Oral allergy syndrome and oropharyngeal involvement

“Pollen-food allergy syndrome (PFAS) is another important factor in food-induced anaphylaxis. Although PFAS usually causes mild symptoms limited to the mouth and throat, it can sometimes lead to severe systemic reactions, including anaphylaxis.” (opens the source at this quote in a new tab)

Administration after food exposure

“Its absorption and effectiveness are not notably reduced when taken immediately after eating, which supports its practical use for managing food-related anaphylaxis.” (opens the source at this quote in a new tab)

Concomitant beta-blockers: reduced responsiveness to epinephrine

“Some patients may not respond well to standard doses of adrenaline. Beta-blockers are the most common reason of adrenaline resistance, as they block beta-adrenergic receptors. In these cases, glucagon should be considered because it works independently of these receptors. ACE inhibitors, angiotensin receptor blockers, tricyclic antidepressants, preexisting cardiovascular disease, and older age can also decrease responsiveness to adrenaline.” (opens the source at this quote in a new tab)

Concomitant beta-blockers and angiotensin-converting enzyme inhibitors: severity of reactions

“In both human and mouse models, BBs and ACEIs have been found to increase the severity of anaphylaxis and may have an additive effect when used in combination (which has become a common therapeutic approach in severe CVD).” (opens the source at this quote in a new tab)
“These medications are associated with an increased relative risk that any anaphylactic reaction will be more severe, although the absolute risk of severe anaphylaxis remains small and the risk of stopping or changing the medications may be greater than the risk of continuing them during any planned treatment or procedure.” (opens the source at this quote in a new tab)

Pregnancy: treatment should not be delayed

“Prolonged experience with epinephrine use in pregnant women over several decades, based on published literature, have not identified a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.” (opens the source at this quote in a new tab)
“During pregnancy, anaphylaxis can be catastrophic and can lead to hypoxic-ischemic encephalopathy and permanent central nervous system damage or death in the mother and, more commonly, in the fetus or neonate. Treatment of anaphylaxis during pregnancy should not be delayed.” (opens the source at this quote in a new tab)

Pregnancy: positioning during an episode

“if pregnant, position the patient in a semi-recumbent position on the left side; if unconscious, place in the recovery position.” (opens the source at this quote in a new tab)

Older adults and cardiovascular comorbidity

“Retrospective cohort studies suggest that the risk of adverse cardiac events after epinephrine use is higher in older patients (age ≥50 years).” (opens the source at this quote in a new tab)
“However, those same populations have increased risk of severe or fatal anaphylaxis.” (opens the source at this quote in a new tab)

Written anaphylaxis emergency action plans

“In addition, it is recommended that they always carry a personalized written anaphylaxis emergency action plan that illustrates how to recognize anaphylaxis symptoms (eg, tingling in the extremities, sense of heat, sense of dizziness/fainting, swollen lips-tongue-uvula, shortness of breath, wheeze, stridor, collapse) and instruct them to inject epinephrine rapidly, via the intramuscular route, in the mid-anterolateral thigh, holding the EAI in place for about 3–10 s and then to call for medical assistance.” (opens the source at this quote in a new tab)
“At the time of discharge from a health care setting, patients, at risk of another episode of anaphylaxis, should be prescribed and taught about self-administration of epinephrine (adrenaline), and have a written personalized anaphylaxis emergency action plan and medical identification method.” (opens the source at this quote in a new tab)

Patient and caregiver education and device training

“During visits with patients who have been prescribed EAIs, we recommend that clinicians routinely review the essentials of EAI carriage, storage, and use; encourage patients to regularly practice EAI administration with a trainer device; and discuss strategies to manage barriers to adherence that patients may have experienced.” (opens the source at this quote in a new tab)
“Multiple studies reveal the benefits of clinician-provided education and counseling for improving EAI-related knowledge, skills, and comfort.” (opens the source at this quote in a new tab)

Stock epinephrine and staff training in schools and childcare centers

“We suggest childcare centers and schools implement staff training for allergy and anaphylaxis management.” (opens the source at this quote in a new tab)
“We suggest that childcare centers and schools stock undesignated EAIs that can be used to treat any individual on school grounds who experiences anaphylaxis.” (opens the source at this quote in a new tab)
“Across studies, the median reported rate of anaphylaxis in childcare centers or schools was 19 per 100,000 students per year (range: 8-118/100,000).” (opens the source at this quote in a new tab)

State laws governing stock epinephrine in schools

“All 50 states and DC allow undesignated epinephrine in schools to use for allergic or anaphylactic reactions. A key difference arises in whether states allow (N=37) or mandate (N=14) that schools stock epinephrine.” (opens the source at this quote in a new tab)
“This review of stock epinephrine laws and policies highlights the significant variation in state legislation despite widespread adoption. Only one-quarter of states mandate that schools have stock epinephrine available for emergency use, underscoring need for a more unified approach with consistent guidelines, comprehensive training, and possible funding for implementation.” (opens the source at this quote in a new tab)

Dosage form specified by school stock epinephrine laws

“In addition, most states (N=45) require auto-injectable epinephrine to be available at school. One state requires pre-filled syringes (Missouri). Five states do not specify the dispense method for stock epinephrine.” (opens the source at this quote in a new tab)
“Twenty-nine states indicate students can administer stock epinephrine themselves.” (opens the source at this quote in a new tab)

School action plans and administration documentation

“Twenty-five states require schools have anaphylaxis action plans or protocols. Nineteen states require schools to document when stock epinephrine was administered.” (opens the source at this quote in a new tab)

Stock epinephrine in other community settings

“We suggest that keeping stock EAI in community settings be encouraged, if feasible.” (opens the source at this quote in a new tab)
“Although permitted, it is rare for community settings to have stock epinephrine available. There is a lack of data on the health effects, feasibility, and cost-effectiveness of stocking epinephrine in community settings outside of schools.” (opens the source at this quote in a new tab)

Emergency medical services activation after epinephrine use

“We suggest that clinicians counsel patients that immediate activation of EMS may not be required if the patient experiences prompt, complete, and durable response to treatment with epinephrine, provided that additional epinephrine and medical care are readily available, if needed. We suggest that clinicians counsel patients to always activate EMS after epinephrine use if anaphylaxis is severe, fails to resolve promptly, fails to resolve completely or nearly completely, or returns or worsens after a first dose of epinephrine.” (opens the source at this quote in a new tab)

Immediate steps taken during an episode

“Therefore, when a patient has anaphylaxis it is important to follow the steps outlined (Fig. 4): remove exposure to the trigger if possible (eg, discontinue administration of drugs/therapeutic agents), assess airways, breathing, circulation, mental status, and skin, and simultaneously call emergency services, injecting epinephrine (adrenaline) intramuscularly into the vastus lateralis of the quadriceps (antero-lateral thigh), and positioning the patient according to his/her presenting features.” (opens the source at this quote in a new tab)

Referral pathway and follow-up after an episode

“Most cases of anaphylaxis are first seen by emergency doctors or general practitioners, but only 50% are referred to a specialist for further investigation and/or treatment. Provision of advice relating to trigger avoidance and emergency protocols, at the time of discharge from the emergency room, are practically nonexistent, according to the international survey.” (opens the source at this quote in a new tab)
“One of the major concerns is the underuse of epinephrine self-infectors by patients who experience anaphylaxis recurrences, despite having the medication.” (opens the source at this quote in a new tab)

Number of devices prescribed and refill considerations

“We suggest that they routinely prescribe more than 1 EAI when patients have previously required multiple doses of epinephrine to treat an episode of anaphylaxis and/or have a history of biphasic reactions.” (opens the source at this quote in a new tab)
“To manage the potential risk of anaphylaxis requiring more than 1 dose of epinephrine, regulatory agencies including the FDA have recommended that patients at risk of anaphylaxis carry 2 EAIs at all times.” (opens the source at this quote in a new tab)

Studies required by the FDA in the Complete Response Letter

“The FDA issued a Complete Response Letter (CRL) on January 30, 2026, which requested that the Company complete a human factors study addressing packaging and administration, and a confirmatory pharmacokinetic (PK) study of Anaphylm.” (opens the source at this quote in a new tab)

“Due to the requirements related to HF, clinical pharmacology requested a single pharmacokinetics (PK) study to understand the impact of any modifications to packaging and labeling. The Agency indicated that the HF and PK studies can be conducted in parallel. No additional studies were requested in the CRL.” (opens the source at this quote in a new tab)

Manufacturing and comparability findings not questioned by the FDA

“As previously disclosed, the CRL did not identify any chemistry, manufacturing, or controls (CMC) deficiencies, and clinical results supporting comparability to autoinjectors were not questioned by the FDA.” (opens the source at this quote in a new tab)

Pediatric trial agreed with the FDA before submission

“In addition, the FDA agreed with our planned NDA content and format for the submission, planned safety evaluation, and planned pediatric trial.” (opens the source at this quote in a new tab)

Post-marketing commitments discussed during FDA review

“As the PDUFA data approached, the FDA notified the Company that it had identified deficiencies in the NDA that precluded discussion of labeling and post-marketing commitments and that the FDA review remained ongoing.” (opens the source at this quote in a new tab)

Risk evaluation and mitigation strategy, registries, and post-marketing surveillance

No evidence found.

Summary: definition of a successful treated episode

Successful treatment of an anaphylactic episode is defined in the 2023 practice parameter update as a prompt, complete, and durable response to epinephrine: signs and symptoms that were present before administration resolve within minutes, do not recur, and no additional epinephrine or emergency medical services activation is required. Under that definition the measurable outcomes of therapy are resolution of the presenting signs and symptoms, avoidance of a second epinephrine dose, avoidance of emergency medical services activation and emergency department transfer, and absence of a biphasic recurrence. Across reported series, 7.7% of anaphylaxis cases of all ages and causes were treated with more than one dose of epinephrine, and a meta-analysis of 2890 adult participants with anaphylaxis found a median biphasic reaction rate of 6.5% with a range of 0.4% to 20%. Pre-hospital epinephrine is associated with lower odds of biphasic reaction and shorter emergency department stays, and delayed administration of more than 60 minutes from onset is an independent predictor of biphasic recurrence. Aquestive has not published an efficacy endpoint in treated anaphylaxis for dibutepinephrine sublingual film; the development program used pharmacokinetic and pharmacodynamic comparisons with intramuscular epinephrine, and the company states that the resubmitted application addresses the human factors and confirmatory pharmacokinetic items raised in the Complete Response Letter.

Symptom resolution that permits observation at home

“Observe at home if signs and symptoms that had emerged before epinephrine administration resolve within minutes of epinephrine administration, without recurrence, or if the patient is asymptomatic.” (opens the source at this quote in a new tab)
“Activate EMS immediately and consider a second dose of epinephrine (do not observe at home) if signs and symptoms that had emerged before epinephrine administration are not resolving or are worsening.” (opens the source at this quote in a new tab)

Frequency of a required second dose of epinephrine

“A recent systematic review and meta-analysis found that 7.7% of anaphylaxis cases (all ages, all causes) were treated with multiple doses of epinephrine, including epinephrine administered in the community and/or health care settings.” (opens the source at this quote in a new tab)

Biphasic reaction rates and timing

“In a meta-analysis that included 2890 adult patients with anaphylaxis, the median percentage of patients with biphasic anaphylaxis was 6.5% (range, 0.4%-20%).” (opens the source at this quote in a new tab)
“The median duration between resolution of the initial episode and the secondary reaction was 10.5 hours (range, 1.75 hours-17 hours).” (opens the source at this quote in a new tab)
“Notably, a 1-hour symptom-free observation after resolution of initial anaphylaxis was associated with a 95% negative predictive value (95% CI, 90.9%-97.3%) for biphasic anaphylaxis.” (opens the source at this quote in a new tab)

Early epinephrine and avoided emergency care

“Reported incidence ranges from 4% to 20%, with large emergency department cohorts estimating the rate at approximately 7–16%” (opens the source at this quote in a new tab)
“Delayed epinephrine (>60 min), drug or idiopathic triggers, and angioedema are the strongest independent predictors of biphasic recurrence” (opens the source at this quote in a new tab)
“Pre-hospital epinephrine is consistently associated with reduced biphasic risk and shorter emergency department stays, yet underuse persists in up to two-thirds of community events” (opens the source at this quote in a new tab)

Mortality outcome of untreated or late-treated episodes

“In fatality case series, most patients who died from anaphylaxis did not receive timely treatment with epinephrine.” (opens the source at this quote in a new tab)
“In a population-based epidemiologic study using 3 national databases, the case fatality rate among patients hospitalized or with ED presentations was between 0.25% and 0.33%.” (opens the source at this quote in a new tab)

Outcome basis stated for the resubmitted application

“today announced that it has resubmitted its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for Anaphylm™ (dibutepinephrine) sublingual film for the treatment of Type I allergic reactions, including anaphylaxis.” (opens the source at this quote in a new tab)