Sublingual epinephrine tablets versus intramuscular injection of epinephrine: Dose equivalence for potential treatment of anaphylaxis

Background: Epinephrine autoinjectors are underused in the emergency treatment of anaphylaxis in the community, perhaps in part because of fear of needles. Objectives: To determine the sublingual epinephrine dose from a novel fast-disintegrating tablet required to achieve epinephrine plasma concentrations (EPPCs) similar to those obtained after epinephrine 0.3 mg intramuscular injection. Methods: In a prospective 5-way crossover study, sublingual tablets containing epinephrine 0, 10, 20, and 40 mg, and epinephrine 0.3 mg intramuscular in the thigh (EpiPen) were compared in a validated rabbit model. Blood samples were collected before dosing and 5, 10, 15, 20, 30, 40, 60, 90, 120, 150, and 180 minutes afterward. EPPCs were measured by using high-performance liquid chromatography-electrochemical detection. Pharmacokinetic parameters were calculated by using WinNonlin. Results: The area under the curve (AUC), maximum concentration (C-max), and time at which C-max was achieved (T-max) did not differ significantly (P > .05) after epinephrine 40 mg (AUC = 1861 +/- 537 ng/mL/min, C-max = 31.0 +/- 13.1 ng/mL, and T-max = 9 +/- 2 minutes) and epinephrine 0.3 mg intramuscular (AUC = 2431 +/- 386 ng/mL/min, C-max = 50.3 +/- 17.1 ng/mL, and T-max = 21 +/- 5 minutes). The AUC after tablets containing epinephrine 0 mg (AUC = 472 +/- 126 ng/mL/min), epinephrine 10 mg (AUC 335 152 ng/mL/min), and epinephrine 20 mg (AUC = 801 160 ng/mL/min) did not differ significantly from each other, but were significantly lower (P < .05) than the AUC after epinephrine 0.3 mg intramuscularly. Conclusion: Sublingual administration of epinephrine 40 mg from this tablet formulation resulted in EPPCs similar to those obtained after epinephrine 0.3 mg intramuscular injection in the thigh. Clinical implications: For treatment of anaphylaxis in the community, self-injectable epinephrine is underused. This novel, fast-disintegrating epinephrine tablet formulation for sublingual administration is a feasible alternative that warrants further development.