FDA Issues CRL to Dibutepinephrine (Anaphylm) Sublingual Film for Type 1 Allergic Reactions

The US Food and Drug Administration has issued a Complete Response Letter (CRL) to Aquestive Therapeutics’ New Drug Application (NDA) for dibutepinephrine (Anaphylm) Sublingual Film for the treatment of Type I allergic reactions, including anaphylaxis, in patients weighing ≥ 30kg (approximately 66 pounds).1

Issued on January 30, 2026, the CRL detailed deficiencies in the dibutepinephrine human factors (HF) validation study, including instances of difficulty opening the pouch and incorrect film placement which, if unaddressed, the FDA believes could cause significant safety issues in the setting of anaphylaxis.1

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. The Company also described plans to further address potential tolerability issues in its resubmission.1

Of note, comparability data submitted as part of the dibutepinephrine NDA, such as bracketing, repeat dose, and sustainability, were not questioned in the CRL. There were also no CMC issues noted in the CRL.1

“As a clinician and investigator for various allergy clinical trials, I am well versed in the nuances related to clinical development and regulatory approval. FDA’s response is focused on patient experience issues and their potential impacts,” Jay Lieberman, MD, an allergist and professor at the University of Tennessee Health Science Center and a practicing physician at LeBonheur Children’s Hospital, said in a statement.1 “I am confident in Aquestive’s ability to address the issues described above and remain optimistic in having [dibutepinephrine] available for my patients in the future. Given the continued underuse of epinephrine in anaphylaxis, the availability of more treatment options remains a top priority for clinicians and the allergy community.”

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. The Agency indicated that the HF and PK studies can be conducted in parallel. No additional studies were requested in the CRL.

Aquestive described plans to closely work with the Agency to achieve approval for dibutepinephrine “as expeditiously as possible.” As an initial step, the Company will request a Type A meeting with the FDA to discuss the most efficient path forward for resubmission.

Based on its initial review of the CRL, Aquestive estimated resubmission in Q3 2026, assuming completion of the HF and PK studies and typical response times from the FDA, with plans to request rapid review by the FDA.

In April 2025, Aquestive announced positive topline results from its multi-site, single treatment pediatric study assessing pharmacokinetics, pharmacodynamics, safety, and tolerability of epinephrine sublingual film in patients 7 – 17 years of age who weighed > 30 kg and had a personal history of allergic reactions. The Company shared that children and adolescents had a mean baseline-adjusted epinephrine concentration over time of about 280 pg/mL at 10 minutes after the administration of dibutepinephrine 12 mg, compared with about 330 pg/mL for adults.

In total, 32 patients completed the study, and pharmacokinetic results were consistent with previous adult trials. The study reported no serious adverse events.

More recently, the FDA cited deficiencies in the NDA that have prevented labeling discussions for dibutepinephrine, Aquestive announced on January 9, 2026. Aquestive met with the FDA to learn more about and address these deficiencies ahead of the assigned PDUFA date.

“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 PK study, once human factors are addressed, and we noted several labeling comments that will inform the final label for [dibutepinephrine], if approved by the FDA,” Daniel Barber, President and CEO of Aquestive, said in a statement. “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 [dibutepinephrine]. Our commitment to bringing this innovative therapy to the allergy community remains steadfast.”

References

1. Aquestive Therapeutics. Aquestive Therapeutics Announces FDA Issuance of Complete Response Letter for Anaphylm™. February 2, 2026. Accessed February 2, 2026. https://investors.aquestive.com/news-releases/news-release-details/aquestive-therapeutics-announces-fda-issuance-complete-response

2. Brooks A. FDA Accepts Epinephrine (Anaphylm) Sublingual Film NDA for Type 1 Allergic Reactions. HCPLive. Published on June 19, 2025. Accessed on January 22, 2026. https://www.hcplive.com/view/fda-accepts-epinephrine-anaphylm-sublingual-film-nda-type-1-allergic-reactions

3. Derman C. Aquestive’s Anaphylm for Severe Allergic Reactions Shows Promise in Children. HCPLive Published on April 1, 2025. Accessed January 22, 2026. https://www.hcplive.com/view/aquestive-s-anaphylm-for-severe-allergic-reactions-shows-promise-in-children

4. Aquestive Therapeutics Announces Regulatory Development for Anaphylm™ (dibutepinephrine) Sublingual Film and Provides Business Update. Aquestive Therapeutics. Published on January 9, 2026. Accessed on January 22, 2026. https://investors.aquestive.com/news-releases/news-release-details/aquestive-therapeutics-announces-regulatory-development