Approved Risk Evaluation and Mitigation Strategies (REMS)

Transmucosal Immediate-Release Fentanyl (TIRF) Products
Shared System REMS
REMS last update: 12/23/2020

What medicines are included in the REMS?

Product Name Application Number Application Holder Added to REMS DailyMed Link FDA Link
Abstral (fentanyl citrate) ( PI and MG at DailyMed , Info at Drugs@FDA ) NDA 022510 SENTYNL THERAPS INC 12/28/2011 e60f00e9-2cf4-4c20-b570-1c2ea426c8c7 http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=022510
Actiq (fentanyl citrate) ( PI and MG at DailyMed , Info at Drugs@FDA ) NDA 020747 CEPHALON 12/28/2011 90b94524-f913-48b3-3771-7b2fcffd888a http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=020747
Fentora (fentanyl citrate) ( PI and MG at DailyMed , Info at Drugs@FDA ) NDA 021947 CEPHALON 12/28/2011 8f549d95-985b-f783-1ebb-ef57bd2ecb05 http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=021947
Lazanda (fentanyl citrate) ( PI and MG at DailyMed , Info at Drugs@FDA ) NDA 022569 BTCP PHARMA 12/28/2011 39531d0c-db12-4627-81c9-6563076b637b http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=022569
Onsolis (fentanyl citrate) ( Info at Drugs@FDA ) NDA 022266 BDSI 12/28/2011 http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=022266
Subsys (fentanyl) ( PI and MG at DailyMed , Info at Drugs@FDA ) NDA 202788 BTCP PHARMA 01/04/2012 18a413e9-11e0-4a8f-86c0-d33b37b7b771 http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=202788
fentanyl buccal ( PI and MG at DailyMed , Info at Drugs@FDA ) ANDA 079075 WATSON LABS 01/08/2016 ad7ac196-4c6e-4aab-8742-bdb9f38f4be6 http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=079075
fentanyl citrate (Info at Drugs@FDA) ANDA 207338 ACTAVIS LABS FL INC 11/17/2017
fentanyl citrate ( PI and MG at DailyMed , Info at Drugs@FDA ) ANDA 078907 SPECGX LLC 01/04/2012 552ba162-76ed-4bc9-8c2c-fac7a1804da0 http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=078907

What is the purpose of the REMS?

The goals of the TIRF REMS are to:
  1. Mitigate the risk of overdose by:
    1. Requiring documentation of opioid tolerance with every TIRF prescription for outpatient use.
    2. Requiring inpatient pharmacies to develop policies and procedures to verify opioid tolerance in inpatients who require TIRF medicines while hospitalized.
    3. Educating prescribers, pharmacists and patients that the safe use of TIRF medicines requires patients to be opioid-tolerant throughout treatment.
  2. Mitigate the risk of accidental exposure by educating prescribers, pharmacists and patients about proper storage and disposal of TIRF medicines.
  3. Monitor for accidental exposure, misuse, abuse, addiction, and overdose by enrolling all patients who receive a TIRF medicine for outpatient use into a registry and using surveillance systems and other data sources.

What do participants need to know?

Below is a general overview of the REMS for all REMS participants (e.g., patients, pharmacies, and healthcare providers). See the application holder(s) REMS Website or the approved REMS materials for more information.

View application holder(s) REMS Website See Disclaimer page regarding links to external sites

Wholesalers-Distributors that distribute TIRF medicines must:

To be able to distribute
  • Establish processes and procedures to ensure that the drug is distributed only to certified pharmacies.
  • Train all relevant staff involved in distributing TIRF medicines on the procedures and the REMS Program requirements.
At all times
  • Distribute only to certified pharmacies.
  • Maintain records of shipments to certified pharmacies.
  • Comply with audits carried out by TIRF Applicants or a third party acting on behalf of the TIRF Applicants to ensure that all processes and procedures are in place and are being followed.

Healthcare Providers who prescribe TIRF medicines for outpatient use must:

To become certified to prescribe
Before treatment initiation
  • Assess the patient for risk factors of opioid addiction, abuse, and misuse.
  • Counsel the patient on the safe use of TIRF medicines using the Medication Guide for the prescribed TIRF medicine and the Patient Counseling Guide. Provide a copy of the materials to the patient. | Patient Counseling Guide |
  • Assess the patient's opioid tolerance. Document and submit to the REMS Program using the Patient Enrollment Form. | Patient Enrollment Form |
  • Enroll the patient by completing and submitting the Patient Enrollment Form to the REMS program. | Patient Enrollment Form |
During treatment, before each prescription
  • Assess the patient's health status for opioid tolerance, appropriateness of dose, misuse, abuse, addiction, and overdose. Document and submit to the REMS Program using the Patient Status and Opioid Tolerance Form. | Patient Status and Opioid Tolerance Form |
During treatment, every 2 years
  • Counsel the patient on the safe use of TIRF medicines using the Medication Guide for the prescribed TIRF medicine and the Patient Counseling Guide. Provide a copy of the materials to the patient. | Patient Counseling Guide |
  • Re-enroll the patient in the REMS by completing the Patient Enrollment Form and submitting it to the REMS Program. | Patient Enrollment Form |
Before treatment re-initiation, lapse in treatment of 6 months or longer
  • Counsel the patient on the safe use of TIRF medicines using the Medication Guide for the prescribed TIRF medicine and the Patient Counseling Guide. Provide a copy of the materials to the patient. | Patient Counseling Guide |
To maintain certification to prescribe, every 2 years
At all times
  • Counsel the patient using the Medication Guide for any new TIRF medicine not previously prescribed. Provide a copy to the patient.
  • Report serious adverse events of accidental exposure, misuse, abuse, addiction, and overdose to the REMS Program using the Adverse Events of Special Interest Reporting Form. | Adverse Events of Special Interest Reporting Form |
  • Report treatment discontinuations to the REMS Program using the Patient Discontinuation Form. | Patient Discontinuation Form |

Patients who are prescribed TIRF medicines for outpatient use:

Before treatment initiation
  • Receive counseling from the prescriber on the safe use of TIRF medicines using the Medication Guide and the Patient Counseling Guide. | Patient Counseling Guide |
  • Enroll in the REMS Program by completing the Patient Enrollment Form with the prescriber. Enrollment information will be provided to the REMS Program. | Patient Enrollment Form |
Before treatment re-initiation, lapse in treatment of 6 months or longer
  • Receive counseling from the prescriber on the safe use of TIRF medicines using the Medication Guide and the Patient Counseling Guide. | Patient Counseling Guide |
During treatment, every 2 years
  • Receive counseling from the prescriber on the safe use of TIRF medicines using the Medication Guide and the Patient Counseling Guide. | Patient Counseling Guide |
  • Re-enroll in the REMS program by completing the Patient Enrollment Form with the prescriber. Enrollment information will be provided to the REMS Program. | Patient Enrollment Form |
At all times
  • Adhere to safe use conditions: taking around-the-clock opioid pain medicine when using TIRF medicines, not sharing TIRF medicines, properly storing and disposing your TIRF medicines.
  • Inform the prescriber if your TIRF medicine does not relieve your pain. Do not change your dose or take a TIRF medicine more often than your prescriber directed.
  • Receive counseling from the prescriber on the safe use of each new TIRF medicine you are prescribed.
  • Inform the prescriber of serious adverse events of accidental exposure, abuse, misuse, addiction, and overdose.

Pharmacies that dispense TIRF medicines for outpatient use must:

To become certified to dispense
  • Designate an authorized representative to carry out the certification process and oversee implementation and compliance with the REMS Program on behalf of the pharmacy.
  • Have the authorized representative review the Pharmacy Education. | Pharmacy Education |
  • Have the authorized representative successfully complete the Pharmacy Knowledge Assessment and submit it to the REMS Program. | Pharmacy Knowledge Assessment |
  • Establish processes and procedures to assess the patient's medication use for a change in opioid tolerance.
  • Have the authorized representative enroll in the REMS Program by completing and submitting the Outpatient Pharmacy Enrollment Form. | Outpatient Pharmacy Enrollment Form |
  • Train all relevant staff involved in dispensing of TIRF medicines on the risks associated with TIRF medicines and the requirements of the REMS Program using the Pharmacy Education. | Pharmacy Education |
Before dispensing
  • Verify the patient is opioid tolerant through the processes and procedures established as a requirement of the REMS Program.
To maintain certification to dispense
At all times
  • Not distribute, transfer, loan, or sell TIRF medicines.
  • Maintain records of staff training.
  • Comply with audits carried out by the manufacturers or a third party acting on behalf of the manufacturers to ensure that all processes and procedures are in place and are being followed.
  • Not dispense TIRF medicines for outpatient use.

What materials are included in the REMS?

The REMS includes a REMS Document. In addition, the REMS includes the following materials intended for patients and healthcare providers. For a specific Medication Guide of a product in the Transmucosal Immediate-Release Fentanyl (TIRF) Products REMS, see the DailyMed link on the Products tab.

Material Name Material Name Link
Adverse Events of Special Interest Reporting Form (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Adverse_Events_of_Special_Interest_Reporting_Form.pdf
Healthcare Provider Letter (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Healthcare_Provider_Letter.pdf
Inpatient Pharmacy Enrollment Form (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Inpatient_Pharmacy_Enrollment_Form.pdf
Inpatient Pharmacy Letter (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Inpatient_Pharmacy_Letter.pdf
Outpatient Pharmacy Enrollment Form (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Outpatient_Pharmacy_Enrollment_Form.pdf
Outpatient Pharmacy Letter (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Outpatient_Pharmacy_Letter.pdf
Patient Counseling Guide (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Patient_Counseling_Guide.pdf
Patient Discontinuation Form (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Patient_Discontinuation_Form.pdf
Patient Enrollment Form (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Patient_Enrollment_Form.pdf
Patient Status and Opioid Tolerance Form (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Patient_Status_and_Opioid_Tolerance_form.pdf
Pharmacy Education (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Pharmacy_Education.pdf
Pharmacy Knowledge Assessment (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Pharmacy_Knowledge_Assessment.pdf
Prescriber Education (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Prescriber_Education.pdf
Prescriber Enrollment Form (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Prescriber_Enrollment_Form.pdf
Prescriber Knowledge Assessment (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Prescriber_Knowledge_Assessment.pdf
REMS Document (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_REMS_Document.pdf
REMS Full (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_REMS_Full.pdf
REMS Program Website Screenshots (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_REMS_Program_Website_Screenshots.pdf
Urgent Notification Regarding TIRF Products Stock Letter (PDF) https://www.accessdata.fda.gov/drugsatfda_docs/rems/TIRF_2020_12_23_Urgent_Notification_Regarding_TIRF_Products_Stock_Letter.pdf

What updates have been made to the REMS?

Date Summary of change
12/23/2020 Modified to reflect the following changes to the REMS Program:
  • Require that prescribers document a patient’s opioid tolerance with each prescription of a TIRF medicine for outpatient use;
  • Require outpatient pharmacies dispensing TIRF medicines to document and verify a patient’s opioid tolerance before dispensing;
  • Require inpatient pharmacies to develop internal policies and procedures to verify opioid tolerance in patients who require TIRF medicines while hospitalized; and
  • Require a new patient registry for use, along with other data sources, to monitor for accidental exposure, misuse, abuse, addiction, and overdose.
09/07/2017 Modified to make changes to the REMS document, and appended materials consistent with the safety label changes approved on December 16, 2016, as well as additional minor modifications.
04/11/2017 Modified to add the authorized generic and a Medication Guide that is identical to that of the branded product, except that only the authorized generic (fentanyl buccal tablets) is listed as the product name.
12/21/2015 Modified to include the new strength of 300mcg per spray in the Medication Guide.
12/24/2014 Modified to:

  1. Remove NDC Numbers from the Independent Outpatient Pharmacy Enrollment Form, Chain Outpatient Pharmacy Enrollment Form, and TIRF REMS Website.
  2. Remove reference to generic equivalents of specific products and replacement with a footnote in the Education Program for Prescribers and Pharmacists and TIRF REMS Website.
  3. Remove “Attachment 1: List of TIRF Medicines Available Only through the TIRF REMS Access Program,” and replacement with a hyperlink to the new TIRF REMS Webpage in the TIRF REMS Document, Overview for Prescribers, Prescriber Enrollment Form, Overview for Patients and Caregivers, Independent Outpatient Pharmacy Overview, Chain Outpatient Pharmacy Overview, Closed System Outpatient Pharmacy Overview, Independent Outpatient Pharmacy Enrollment Form, Chain Outpatient Pharmacy Enrollment Form, Closed System Outpatient Enrollment Form, Inpatient Pharmacy Enrollment Form, Distributor Enrollment Form, and TIRF REMS Website and Website Landing Page.
  4. Revise criteria for inactivation of Patient-Prescriber Agreement Form (PPAF) in the TIRF REMS Document.
  5. Revise to enhance knowledge about conversion of TIRF Medicines in the Education Program for Prescribers and Pharmacists and TIRF REMS Website.
  6. Add information clarifying the process to electronically transmit TIRF REMS Cash Claims in the TIRF REMS Document, TIRF REMS Access Program Frequently Asked Questions (FAQ), Independent Outpatient Pharmacy Overview, Chain Outpatient Pharmacy Overview, Closed System Outpatient Pharmacy Overview.
11/04/2014 Modified to add the Abstral product to the shared system REMS.
11/07/2013 Modified to:

  1. Revise terminology, processes, and definitions for outpatient pharmacies.
  2. Revise attestations for physicians and patients to address concerns regarding patient access.
  3. Revise Program Overview and Frequently Asked Questions to improve clarity and content.
  4. Reflect the completion of the transition phase for the TIRF REMS Access Program in the REMS materials.
06/05/2012 Modified to:

  1. Edit the Patient-Prescriber Agreement Form, add the Closed System Pharmacy Enrollment Form, add the newly approved TIRF product, Subsys (fentanyl sublingual spray), make minor editorial changes.
  2. Update the TIRF REMS Access Program “go-live” placeholder date to the actual "go-live" date of March 12, 2012.
12/28/2011 Approval of the REMS.

Disclaimer: This webpage provides general information about REMS programs to various REMS participants (e.g., patients, pharmacies, and healthcare providers). The summary information provided herein is not comprehensive and may not include all of the information relevant to REMS participants. This webpage does not constitute a replacement, modification, or revision of the approved REMS document, including any appended REMS materials. Refer to the approved REMS document for complete information on the REMS requirements for each approved application.

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