TIRF Manufacturers Discontinue All Products as REMS Obligations Remain Fully Active

The discontinuation of all transmucosal immediate-release fentanyl (TIRF) medicines on September 30, 2024 has left a compliance footprint that regulatory affairs teams cannot walk away from: the TIRF REMS remains legally binding for every manufacturer holding an approved NDA or ANDA, regardless of whether product is on the market.

TIRF manufacturers announced on August 28, 2024 that production across the entire class would cease. The affected products include Actiq, Fentora, Lazanda, Onsolis, Subsys, and their generic equivalents, all indicated for breakthrough cancer pain in opioid-tolerant adults. At the time of the announcement, fewer than 150 patients remained on active TIRF therapy. FDA confirmed it did not request the discontinuation and has no statutory authority to compel a manufacturer to produce or distribute a medicine.

For regulatory affairs leads, the operative principle here is unambiguous: REMS obligations survive commercial withdrawal. Under 21 CFR Part 314 and FDA's REMS framework, program requirements persist as long as the underlying application remains approved. The TIRF REMS, in place since 2011 and substantially modified in December 2020, requires continued adherence to its restricted distribution architecture even with no new enrollments being accepted. Manufacturers retain accountability for the program infrastructure until applications are formally withdrawn or FDA acts to terminate the REMS.

The 2020 REMS modification is instructive context. Following an Advisory Committee finding that opioid non-tolerant patients were receiving TIRF medicines despite the existing restricted distribution program, FDA required prescribers to document opioid tolerance with every outpatient prescription, outpatient pharmacies to assess tolerance at every dispensing, and inpatient pharmacies to establish written policies and procedures for tolerance verification. A patient registry was added to monitor for accidental exposure, misuse, abuse, and overdose. That registry and its associated reporting obligations do not lapse at product discontinuation.

Prescribers with patients still receiving TIRF medicines from remaining supply are expected to manage transition to non-TIRF opioid regimens; the REMS permits continued treatment only while supply holds. No new patient, prescriber, or pharmacy enrollments are being accepted by the TIRF REMS administrator.

The measurable outcome to track: how many NDA and ANDA holders formally withdraw their applications, and at what point FDA moves to terminate the REMS, a sequence that will define the post-market compliance timeline for this class.

Source: U.S. Food and Drug Administration, What's New: Drugs RSS Feed, May 27, 2026 (reflecting FDA TIRF REMS page updated September 16, 2024).