FDA issues CRL for Aquestive's needle-free epinephrine film Anaphylm, citing usability concerns

The FDA on January 30, 2026 issued a Complete Response Letter for Anaphylm (dibutepinephrine sublingual film), Aquestive Therapeutics' needle-free epinephrine product designed for emergency treatment of Type I allergic reactions including anaphylaxis. The CRL cited human factors deficiencies—specifically difficulty opening the child-resistant pouch and incorrect film placement—along with a request for one additional pharmacokinetic study. Notably, the agency raised no concerns about the drug's safety, efficacy, manufacturing quality or clinical data.

Anaphylm delivers a prodrug called dibutepinephrine, which converts to active epinephrine upon sublingual absorption into the bloodstream. In clinical studies of 54 healthy volunteers, systemic epinephrine exposure fell within the approved bracketing range of intramuscular products. The sublingual film reached peak blood concentrations at a median of 12 minutes—faster than the 20 minutes reported for EpiPen—suggesting the technology could match or improve on the pharmacokinetics of injected epinephrine without requiring a needle.

The human factors issues centred on the validation study, where 19 of 166 participants placed the film on top of the tongue rather than underneath, and users struggled with the child-resistant pouch under simulated emergency conditions. In an anaphylaxis setting—where seconds count—such usability failures represent serious risks. Aquestive has outlined corrective measures including a simplified pouch-opening mechanism, placement imagery on the pouch itself, and revised labelling.

Anaphylaxis affects an estimated 1.6 million Americans, yet studies consistently show that fewer than half of at-risk patients carry their prescribed epinephrine auto-injectors, often citing needle anxiety, device bulk and the inconvenience of refrigeration-free storage. A sublingual film could address each of these barriers: it is portable, needle-free, room-temperature stable, and discreet to administer.

Aquestive now faces a competitive landscape that has shifted during its regulatory journey. ARS Pharmaceuticals' neffy—a nasal-spray epinephrine product—received FDA approval in 2024 and has already established a commercial presence. Nevertheless, sublingual delivery offers a differentiated profile: Anaphylm's formulation does not depend on nasal mucosal integrity, which can be compromised by allergic rhinitis or upper-respiratory congestion—conditions prevalent in the very population most likely to need emergency epinephrine.

Aquestive said at the time that it intended to address the FDA's concerns and resubmit. A sublingual film would add to the options available to patients living with severe allergy.

Sources: Aquestive Press Release; FDA.