FDA Issues CRL to Anaphylm, Sublingual Film Formulation of Dibutepinephrine

The FDA issued a complete response letter (CRL) to Anaphylm (Aquestive Therapeutics), a sublingual film formulation of dibutepinephrine for the treatment of type 1 allergic reactions including anaphylaxis in patients weighing 30 kg or more.¹

Anaphylaxis and Epinephrine Sublingual Film

According to Mayo Clinic, anaphylaxis is a severe and potentially life-threatening allergic reaction that can occur within seconds or minutes upon exposure to a certain allergen. It causes the immune system to release a flood of chemicals that can cause an individual to go into shock. During attacks, blood pressure drops suddenly and airways narrow, inhibiting one’s ability to breathe.²

Signs and symptoms include a rapid or weak pulse, skin rash, nausea, and vomiting. Common triggers can include certain foods (eg, peanuts, eggs), medications, insect venom, and latex. Anaphylaxis requires an injection of epinephrine and a follow-up trip to an emergency room (ER), with an ER visit being vital if patients cannot receive treatment with epinephrine. If not treated immediately, anaphylaxis can be fatal.²

The sublingual dibutepinephrine film is a polymer matrix-based epinephrine prodrug product candidate—similar in size to a postage stamp. It weighs less than an ounce and begins to dissolve on contact, meaning that water or swallowing is not required for effective administration.

Additionally, Aquestive Therapeutics describes the packaging for the product as thinner and smaller than an average credit card, allowing it to be carried in a pocket, making it easily accessible and able to be carried. It can also withstand weather excursions (eg, exposure to rain and/or sunlight).³

The CRL, which focuses on administration and labeling guidance, cited deficiencies in the Anaphylm human factors (HF) validation study. Specifically, these included instances of difficulty opening the pouch and incorrect film placement. If unaddressed, the FDA stated could cause significant safety issues in the setting of anaphylaxis.

To resolve the FDA’s concerns, the manufacturer has modified the pouch opening, instructions for use, and pouch and carton labeling. A new HF validation study with these modifications will be conducted, according to the manufacturer news release. Additionally, potential tolerability issues will be further addressed.¹

Notably, the comparability data submitted as part of the Anaphylm new drug application—such as bracketing, repeat dose, and sustainability—were not questioned in the CRL. Due to the requirements related to HF, clinical pharmacology requested a single pharmacokinetics study to understand the impact of any modifications to packaging and labeling. No additional studies were requested in the CRL.¹

“While it is unfortunate to have received a CRL, we believe that, with the clarity we now have from the FDA, we have made significant progress toward approval. We are encouraged that the issues in the letter are limited to human factors and a supportive [pharmacokinetics] study, once human factors are addressed, and we noted several labeling comments that will inform the final label for Anaphylm, if approved by the FDA,” Daniel Barber, president and CEO of Aquestive, said in the news release. “We remain confident in the effectiveness and safety of Anaphylm and its potential as an easy-to-use, easy-to-carry, fast-acting epinephrine treatment. We look forward to working with the FDA to achieve approval for Anaphylm. Our commitment to bringing this innovative therapy to the allergy community remains steadfast.”¹

REFERENCES

1. Aquestive Therapeutics. Aquestive Therapeutics Announces FDA Issuance of Complete Response Letter for Anaphylm™. News release. February 2, 2026. Accessed February 2, 2026. https://www.globenewswire.com/news-release/2026/02/02/3230115/0/en/Aquestive-Therapeutics-Announces-FDA-Issuance-of-Complete-Response-Letter-for-Anaphylm.html

2. Mayo Clinic. Anaphylaxis. Accessed January 19, 2026. https://www.mayoclinic.org/diseases-conditions/anaphylaxis/symptoms-causes/syc-20351468

3. Aquestive Therapeutics. Aquestive Therapeutics Announces FDA Acceptance of New Drug Application and PDUFA Date for Anaphylm™ for the Treatment of Severe Allergic Reactions. News release. June 16, 2025. Accessed January 19, 2026. https://investors.aquestive.com/news-releases/news-release-details/aquestive-therapeutics-announces-fda-acceptance-new-drug-0