Product information and disease description Place of product in therapy Approaches to treatment

Expected outcomes of therapy

7 evidence topics · 3 sources

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)