Sublingual Epinephrine Film: FDA Issues Complete Response Letter to Anaphylm
The FDA issued a complete response letter on January 30, 2026 for Anaphylm (dibutepinephrine), the sublingual epinephrine film candidate from Aquestive Therapeutics. The agency cited human factors and packaging concerns rather than safety, efficacy, or manufacturing — and the company expects to resubmit in Q3 2026.
The Story at a Glance:
- The sublingual epinephrine film Anaphylm did not receive FDA approval at its January 31, 2026 PDUFA date; the agency issued a complete response letter (CRL).
- The CRL flagged human factors deficiencies — pouch opening difficulties and incorrect film placement — not safety, efficacy, or manufacturing.
- Aquestive plans pouch and label modifications, a new human factors validation study, a supportive PK study, and resubmission in Q3 2026.
- Intramuscular auto-injectors and the approved nasal spray neffy remain the only available out-of-hospital epinephrine options.
What Happened
The sublingual epinephrine film Anaphylm did not receive FDA approval at its January 31, 2026 PDUFA action date. On January 30, 2026, Aquestive Therapeutics received a complete response letter for the New Drug Application seeking approval of dibutepinephrine sublingual film for Type I allergic reactions, including anaphylaxis, in patients weighing at least 30 kg.
The CRL focused on the product’s human factors validation study. The FDA cited difficulty opening the foil pouch and incorrect placement of the film during user testing. The agency concluded that, in the time-sensitive setting of anaphylaxis, these issues could pose safety risks if not resolved.
The CRL did not raise concerns about chemistry, manufacturing, and controls (CMC), comparability data, clinical efficacy, or safety. Aquestive has modified the pouch opening mechanism, the instructions for use, and pouch and carton labeling, and plans a new human factors validation study. Clinical pharmacology requested one supportive pharmacokinetic study to confirm performance after the packaging changes.
Why This Sublingual Epinephrine Film Decision Matters
For pediatric care, the sublingual epinephrine film delay leaves the existing needle-free landscape unchanged. The only FDA-approved non-injectable epinephrine remains neffy (epinephrine nasal spray), approved August 2024 for patients ≥30 kg, expanded March 2025 to children weighing 15 to less than 30 kg, and updated March 2026 to remove the age requirement so any patient ≥15 kg may use it.
The clinical rationale for needle-free options is well documented. Roughly 40% of patients delay epinephrine administration during anaphylaxis, and 56% of caregivers report anxiety about injecting their child. Major guidelines from the American Academy of Allergy, Asthma & Immunology and the World Allergy Organization continue to recommend intramuscular epinephrine as first-line therapy.
Anaphylm — a postage-stamp-sized polymer film that dissolves on contact without water or swallowing — was positioned to add a third pathway, particularly for older children and adolescents who object to carrying bulky auto-injectors. With the CRL, that third pathway is delayed but not closed.
Key Numbers from the Sublingual Epinephrine Film Program
Aquestive’s clinical program for the sublingual epinephrine film included 11 independent studies and approximately 967 administrations across 411 participants, encompassing single- and repeat-dose exposures and an oral allergy syndrome study designed to evaluate performance during an allergen-induced reaction.
- Pediatric study: 32 patients aged 7 to 17 years, weighing more than 30 kg, with a personal history of allergic reactions.
- Pediatric pharmacokinetics: mean baseline-adjusted epinephrine concentration ~280 pg/mL at 10 minutes after a 12 mg dose, compared with ~330 pg/mL in adults.
- Pediatric safety: no serious adverse events reported.
- Adult and pediatric PK: profiles described by Aquestive as comparable to leading epinephrine auto-injectors.
The CRL did not dispute these data. The deficiencies cited were strictly user-experience and a related supportive PK study to confirm performance after the packaging changes.
What Experts Are Saying
Jay Lieberman, MD, professor at the University of Tennessee Health Science Center and a practicing physician at Le Bonheur Children’s Hospital, framed the FDA’s response as focused on usability rather than clinical performance. Dr. Lieberman has served as an investigator on multiple allergy clinical trials.
“FDA’s response is focused on patient experience issues and their potential impacts.” — Jay Lieberman, MD, University of Tennessee Health Science Center; allergy clinical trial investigator
David Stukus, MD, Professor of Clinical Pediatrics and Director of the Food Allergy Treatment Center at Nationwide Children’s Hospital and the Ohio State University, has separately emphasized that the persistent underuse of epinephrine is the core problem any new delivery system must solve. Dr. Stukus has previously commented in materials connected with the Anaphylm program; his independent academic position is that fear of injection and the bulk of carrying auto-injectors are the two barriers patients consistently cite.
What’s Next for Sublingual Epinephrine Film
Aquestive completed a Type A meeting with the FDA on March 30, 2026, securing clarification on the design of the additional human factors and pharmacokinetic studies. The company expects to resubmit the NDA in Q3 2026, with no additional efficacy work required.
Outside the United States, the regulatory path is also active. The European Medicines Agency has indicated that no additional clinical trials are required prior to submission, with a marketing authorization application expected in the second half of 2026. A New Drug Submission to Health Canada was planned for the first half of 2026, and discussions with United Kingdom regulators are ongoing.
Pediatric clinicians can expect roughly a six-to-twelve-month gap before any potential second FDA decision, with no change to current standards of care in the interim.
Bottom Line
- Tell families that the sublingual epinephrine film is not yet FDA-approved; do not change current prescriptions or anaphylaxis action plans on the basis of news of the delay.
- Continue to prescribe an intramuscular epinephrine auto-injector as first-line for any child at risk of anaphylaxis; reinforce the always-carry-two rule and the 5-minute redose interval.
- For families with strong needle aversion or a history of nonadherence to auto-injector carriage in patients ≥15 kg, consider neffy nasal spray as an FDA-approved needle-free alternative.
- Use the news of the CRL as a teachable moment: re-train families on auto-injector technique, expiration dates, common-trigger avoidance, and when to call EMS.
- Watch for an Anaphylm resubmission in Q3 2026 and any future pediatric data extending below the 30 kg weight threshold; counsel adolescents that a sublingual option may eventually become available.
Sources
- Aquestive Therapeutics, Inc. Aquestive Therapeutics Announces FDA Issuance of Complete Response Letter for Anaphylm. February 2, 2026. Aquestive Therapeutics Press Release — Anaphylm CRL
- Contemporary Pediatrics editors. FDA Issues Complete Response Letter for Sublingual Epinephrine Film Anaphylm. Contemporary Pediatrics, February 2026. Contemporary Pediatrics — Anaphylm CRL Coverage
- Smith J. FDA Issues CRL to Dibutepinephrine (Anaphylm) Sublingual Film for Type 1 Allergic Reactions. HCPLive, February 2026. HCPLive — Dibutepinephrine CRL
- Patient Care Online editors. FDA Issues Complete Response Letter to Dibutepinephrine (Anaphylm) Sublingual Film for Anaphylaxis. Patient Care Online, February 2026. Patient Care Online — Anaphylm CRL Analysis
- American Journal of Managed Care editors. FDA Flags Administration Concerns for Aquestive’s Noninvasive Epinephrine Film. AJMC, February 2026. AJMC — Aquestive Anaphylm Coverage
- U.S. Food and Drug Administration. FDA Approves First Nasal Spray for Treatment of Anaphylaxis. August 9, 2024. FDA Press Announcement — neffy Approval
- ARS Pharmaceuticals, Inc. FDA Approval to Remove Age Requirement From neffy 1 mg. March 27, 2026. ARS Pharmaceuticals — neffy Label Update