CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`202788Orig1s000
`
`
`REMS
`
`
`
`
`
`

`

`Initial REMS Approval: 1/2012
`
`
`
`
`
`
`
`
`
`
`
`PROPOSED TRANSMUCOSAL IMMEDIATE RELEASE FENTANYL (TIRF)
`RISK EVALUATION AND MITIGATION STRATEGY (REMS)
`
`
`
`Page 1 of 14
`
`Reference ID: 3066874
`
`

`

`I. GOALS
`
`The goals of the TIRF REMS Access program are to mitigate the risk of misuse, abuse,
`addiction, overdose and serious complications due to medication errors by:
`1. Prescribing and dispensing TIRF medicines only to appropriate patients, which includes
`use only in opioid-tolerant patients.
`2. Preventing inappropriate conversion between TIRF medicines.
`3. Preventing accidental exposure to children and others for whom it was not prescribed.
`4. Educating prescribers, pharmacists, and patients on the potential for misuse, abuse,
`addiction, and overdose of TIRF medicines.
`
`
`
`II. REMS ELEMENTS
`
`A. Medication Guide
`
`The product-specific TIRF Medication Guide will be dispensed with each TIRF prescription in
`accordance with 21 CFR 208.24.
`The Medication Guides for TIRF medicines are part of the TIRF REMS Access program and will
`be available on the TIRF REMS Access website (www.TIRFREMSaccess.com).
`
`
`B. Elements to Assure Safe Use
`
`1. Healthcare providers who prescribe TIRF medicines for outpatient use are
`specially certified.
`
`a. TIRF sponsors will ensure that healthcare providers who prescribe TIRF medicines for
`outpatient use are specially certified.
`b. To become certified to prescribe TIRF medicines, prescribers will be required to enroll in
`the TIRF REMS Access program. Prescribers must complete the following requirements
`to be enrolled:
`
`
`
`
`
`
`
`i. Review the TIRF REMS Access education materials (TIRF REMS Access Education
`Program), including the Full Prescribing Information (FPI) for each TIRF medicine,
`and successfully complete the Knowledge Assessment (Knowledge Assessment).
`
`ii. Complete and sign the Prescriber Enrollment Form. In signing the Prescriber
`Enrollment Form, each prescriber is required to acknowledge the following:
`
`a)
`
`I have reviewed the TIRF REMS Access Education Program, and I have
`completed the Knowledge Assessment. I understand the responsible use
`conditions for TIRF medicines and the risks and benefits of chronic opioid
`therapy.
`
`b)
`
`I understand that TIRF medicines can be abused and that this risk should be
`considered when prescribing or dispensing TIRF medicines in situations
`
`
`
`Page 2 of 14
`
`Reference ID: 3066874
`
`

`

`where I am concerned about an increased risk of misuse, abuse, or
`overdose, whether accidental or intentional.
`
`c)
`
`I understand that TIRF medicines are indicated only for the management of
`breakthrough pain in patients with cancer, who are already receiving and who
`are tolerant to around-the-clock opioid therapy for their underlying persistent
`pain.
`
`d)
`
`I understand that TIRF medicines are contraindicated for use in opioid non-
`tolerant patients, and know that fatal overdose can occur at any dose.
`
`e)
`
`I understand that TIRF medicines must not be used to treat any
`contraindicated conditions described in the FPI, such as acute or
`postoperative pain, including headache/migraine.
`f) I understand that converting patients from one TIRF medicine to a different TIRF
`medicine must not be done on a microgram-per-microgram basis. I understand
`that TIRF medicines are not interchangeable with each other, regardless of route
`of administration, and that conversion may result in fatal overdose, unless
`conversion is done in accordance with labeled product-specific conversion
`recommendations (refer to the ‘List of TIRF Medicines Available only through the
`TIRF REMS Access program’ in Attachment 1). Note, a branded TIRF medicine
`and its specific generic product(s) are interchangeable.
`
`I understand that the initial starting dose for TIRF medicines for all patients is
`the lowest dose, unless individual product labels provide product-specific
`conversion recommendations, and I understand that patients must be titrated
`individually.
`I will provide a Medication Guide for the TIRF medicine that I intend to
`prescribe to my patient or their caregiver and review it with them. If I convert
`my patient to a different TIRF medicine, the Medication Guide for the new
`TIRF medicine will be provided to, and reviewed with, my patient or their
`caregiver.
`I will complete and sign a TIRF REMS Access Patient-Prescriber Agreement
`Form with each new patient, before writing the patient’s first prescription for a
`TIRF medicine, and renew the agreement every two (2) years.
`
`g)
`
`h)
`
`i)
`
`j)
`
`I will provide a completed, signed copy of the Patient-Prescriber Agreement
`Form to the patient and retain a copy for my records. I will also provide a
`completed, signed copy to the TIRF REMS Access program (through the TIRF
`REMS Access website or by fax) within ten (10) working days.
`
`
`k) At all follow-up visits, I agree to assess the patient for appropriateness of the
`dose of the TIRF medicine, and for signs of misuse and abuse.
`
`l)
`
`I understand that TIRF medicines are only available through the TIRF REMS
`Access program. I understand and agree to comply with the TIRF REMS
`Access program requirements for prescribers.
`
`
`
`Page 3 of 14
`
`
`
`
`
`
`
`Reference ID: 3066874
`
`

`

`m) I understand that I must re-enroll in the TIRF REMS Access program and
`successfully complete the enrollment requirements every two (2) years.
`
`In signing the Patient-Prescriber Agreement Form, the prescriber documents
`the following:
`
`1) My patient is currently using around-the-clock opioid medication and
`has been for at least one (1) week.
`
`2) My patient is opioid-tolerant. Patients considered opioid-tolerant are
`those who are regularly taking at least: 60 mg oral morphine/day; 25
`micrograms transdermal fentanyl/hour; 30 mg oral oxycodone/day; 8 mg
`oral hydromorphone/day; 25 mg oral oxymorphone/day; or an
`equianalgesic dose of another opioid for one week or longer.
`
`3)
`
`4)
`
`5)
`
`6)
`
`I have provided to, and reviewed with, my patient or their caregiver the
`Medication Guide for the TIRF medicine I intend to prescribe.
`
`If I change my patient to a different TIRF medicine, I will provide the
`Medication Guide for the new TIRF medicine to my patient or my patient’s
`caregiver, and I will review it with them.
`
`I understand that if I change my patient to a different TIRF medicine, the
`initial dose of that TIRF medicine for all patients is the lowest dose, unless
`individual
`product
`labels
`provide
`product-specific
`conversion
`recommendations.
`I have counseled my patient or their caregiver about the risks, benefits,
`and appropriate use of TIRF medicines including communication of the
`following safety messages:
`
`A. If you stop taking your around-the-clock pain medicine, you
`must stop taking your TIRF medicine.
`
`B. NEVER share your TIRF medicine.
`
`C. Giving a TIRF medicine to someone for whom it has not
`been prescribed can result in a fatal overdose.
`
`D. TIRF medicines can be fatal to a child; used and unused
`dosage units must be safely stored out of the reach of children
`living in or likely to visit the home and disposed of in
`accordance with the specific disposal instructions detailed in
`the product’s Medication Guide.
`
`I will ensure that the patient and/or caregiver understand that, in signing
`the Patient-Prescriber Agreement Form, they document the following:
`1) My prescriber has given me a copy of the Medication Guide for the TIRF
`medicine I have been prescribed, and has reviewed it with me.
`
`
`
`Page 4 of 14
`
`
`
`
`
`Reference ID: 3066874
`
`

`

`2)
`
`3)
`
`4)
`
`5)
`
`6)
`
`7)
`
`8)
`
`9)
`
`I understand that before I can take any TIRF medicine, I must be
`regularly using another opioid pain medicine, around-the-clock, for my
`constant pain.
`I understand that if I stop taking my around-the-clock opioid pain medicine
`for my constant pain, I must stop taking my TIRF medicine.
`
`I understand how I should take this TIRF medicine, including how much I
`can take, and how often I can take it. If my prescriber prescribes a different
`TIRF medicine for me, I will ensure I understand how to take the new TIRF
`medicine.
`
`I understand that any TIRF medicine can cause serious side effects,
`including life-threatening breathing problems which can lead to death,
`especially if I do not take my TIRF medicine exactly as my prescriber has
`directed me to take it.
`
`I agree to contact my prescriber if my TIRF medicine does not relieve my
`pain. I will not change the dose of my TIRF medicine myself or take it more
`often than my prescriber has directed.
`I agree that I will never give my TIRF medicine to anyone else, even if
`they have the same symptoms, since it may harm them or even cause
`death.
`I will store my TIRF medicine in a safe place away from children and
`teenagers because accidental use by a child, or anyone for whom it was not
`prescribed, is a medical emergency and can cause death.
`
`I have been instructed on how to properly dispose of my partially used or
`unneeded TIRF medicine remaining from my prescription, and will
`dispose of my TIRF medicine as soon as I no longer need it.
`
`10) I understand that selling or giving away my TIRF medicine is against the
`law.
`
`11) I have asked my prescriber all the questions I have about my TIRF
`medicine. If I have any additional questions or concerns in the future
`about my treatment with my TIRF medicine, I will contact my prescriber.
`
`12) I have reviewed the “Patient Privacy Notice for the TIRF REMS Access
`Program” and I agree to its terms and conditions which authorize my
`healthcare providers to disclose my personal and medical information to
`the makers of TIRF medicines (TIRF Sponsors) and their agents and
`contractors, for the purpose of administering the TIRF REMS Access
`program.
`
`c. Prescribers are required to re-enroll every two (2) years. Additionally, prescribers must
`re-counsel their patients and complete a new Patient-Prescriber Agreement Form every
`two (2) years.
`
`
`
`Reference ID: 3066874
`
`
`
`Page 5 of 14
`
`

`

`d. TIRF Sponsors will:
`i. Ensure that prescriber enrollment can successfully be completed via the TIRF REMS
`Access website, or by mailing or faxing the forms.
`ii. Ensure that, as part of the enrollment process, the following materials that are
`part of the TIRF REMS Access program are available to prescribers. These
`materials are appended:
` TIRF REMS Access Prescriber Program Overview
` TIRF REMS Access Education Program
` Knowledge Assessment
` Prescriber Enrollment Form
` Patient-Prescriber Agreement Form
` TIRF REMS Access Patient and Caregiver Overview
` Frequently Asked Questions (FAQs)
` TIRF REMS Access Website
`the Knowledge
`iii. Ensure
`that prescribers have successfully completed
`Assessment, and ensure that enrollment forms are complete before activating a
`prescriber’s enrollment in the TIRF REMS Access program.
`iv. Ensure that prescribers are notified when they are successfully enrolled in the
`TIRF REMS Access program, and therefore, are certified to prescribe TIRF
`medicines.
`v. Monitor education and enrollment requirements for prescribers and may
`inactivate non-compliant prescribers. Upon initial activation, prescribers remain
`active until inactivation occurs or expiration of the enrollment period.
`vi. Ensure
`that prior
`to
`the
`first availability of
`the TIRF REMS Access
`program/website, Dear Healthcare Provider Letters will be sent. The target
`audience for the letters will include pain management specialists (comprised of
`anesthesiologists, physical medicine and rehabilitation physicians), primary care
`physicians, oncologists, oncology nurse practitioners who treat breakthrough
`pain in patients with cancer, and other appropriately licensed healthcare
`professionals who prescribe TIRF medicines. The letter will include information
`on the risks associated with the use of TIRF medicines and will explain to
`healthcare providers that if they wish to treat patients using TIRF medicines, they
`must enroll in the TIRF REMS Access program. The letters will be available on
`the TIRF REMS Access website for 1 year from the date of the mailing.
`
`The Dear Healthcare Provider Letter is part of the TIRF REMS Access program and
`is appended.
`
`
`
`Page 6 of 14
`
`
`
`
`
`
`
`
`Reference ID: 3066874
`
`

`

`2. TIRF medicines will only be dispensed by pharmacies that are specially certified.
`
`a. TIRF Sponsors will ensure that TIRF medicines will only be dispensed by certified
`pharmacies. To become certified to dispense TIRF medicines, each pharmacy must be
`enrolled in the TIRF REMS Access program.
`b. Each pharmacy will be required to designate an authorized pharmacy representative
`(chain pharmacy) or authorized pharmacist (outpatient and inpatient pharmacies) to
`complete enrollment on behalf of the pharmacy(s).
`c. There is a different set of enrollment requirements for outpatient pharmacies, (e.g.,
`retail, mail order, institutional outpatient pharmacies that dispense for outpatient use),
`including chain pharmacies, and inpatient pharmacies (e.g., hospitals, in-hospital
`hospices, and long-term care facilities that dispense for inpatient use).
`d. Outpatient Pharmacies:
`The authorized pharmacist/pharmacy representative must complete the following
`requirements to enroll their outpatient pharmacy:
`
`i. Review the TIRF REMS Access Education Program (TIRF REMS Access
`Education Program) and successfully complete the Knowledge Assessment.
`
`ii. Ensure the pharmacy enables its pharmacy management system to support
`communication with
`the TIRF REMS Access system, using established
`telecommunication standards, and runs the standardized validation test transaction
`to validate the system enhancements.
`iii. Complete and sign the Outpatient Pharmacy Enrollment Form or the Chain
`Pharmacy Enrollment Form for groups of associated pharmacies. In signing the
`Outpatient Pharmacy Enrollment Form or Chain Pharmacy Enrollment Form, the
`authorized pharmacist is required to acknowledge the following:
`
`a) I have reviewed the TIRF REMS Access Education Program, and I have
`completed the Knowledge Assessment. I understand the risks and benefits
`associated with TIRF medicines and the requirements of the TIRF REMS Access
`program for pharmacies.
`
`b) I will ensure that all pharmacy staff who participate in dispensing TIRF medicines
`are educated on the risks associated with TIRF medicines and the requirements
`of the TIRF REMS Access program, as described in the TIRF REMS Access
`Education Program. This training should be documented and is subject to audit.
`
`c) I understand that converting patients from one TIRF medicine to a different TIRF
`medicine must not be done on a microgram-per-microgram basis. I understand
`that TIRF medicines are not interchangeable with each other, regardless of route
`of administration, and that conversion may result in fatal overdose, unless
`conversion is done in accordance with labeled product-specific conversion
`recommendations (refer to the ‘List of TIRF Medicines available only through the
`TIRF REMS Access Program’ in Attachment 1). Note, a branded TIRF medicine
`and its specific generic product(s) are interchangeable.
`
`
`
`
`
`Reference ID: 3066874
`
`
`
`Page 7 of 14
`
`

`

`d) I understand that TIRF medicines are contraindicated for use in opioid non-
`tolerant patients.
`
`e) I understand that the initial starting dose of TIRF medicines for all patients is
`the lowest dose, unless individual product labels provide product-specific
`conversion recommendations, and I understand that patients must be titrated
`individually.
`
`f)
`
`I understand the importance of discussing the risks and benefits of TIRF
`medicines with patients and their caregivers, and in particular the importance of
`taking the drug as prescribed, not sharing with others, and proper disposal.
`
`g) I understand that the product-specific Medication Guide must be given to
`the patient or their caregiver each time a TIRF medicine is dispensed.
`
`h) I understand that TIRF medicines will not be dispensed without verifying
`through our pharmacy management system that the prescriber and pharmacy
`are enrolled and active, and that the patient has not been inactivated in the
`program.
`
`i)
`
`j)
`
`I understand that ALL TIRF medicine prescriptions, regardless of the method
`of payment, must be processed through our pharmacy management system.
`
`I understand that all dispensing locations must be enrolled in the TIRF REMS
`Access program to dispense TIRF medicines.
`
`from
`that TIRF medicines can only be obtained
`k) I understand
`wholesalers/distributors that are enrolled in the TIRF REMS Access program.
`
`l)
`
`I understand that our pharmacy will not sell, loan or transfer any TIRF
`medicine inventory to any other pharmacy, institution, distributor, or
`prescriber.
`
`m) I understand that our pharmacy must re-enroll in the TIRF REMS Access program
`and successfully complete the enrollment requirements every two (2) years.
`
`n) I understand that TIRF medicines are only available through the TIRF REMS
`Access program. I understand that the pharmacy must comply with the TIRF
`REMS Access program requirements for outpatient pharmacies.
`
`
`
`
`
`e. Inpatient Pharmacies:
`
`The authorized pharmacist must complete the following requirements to
`successfully enroll their inpatient pharmacy:
`
`i. Review the TIRF REMS Access Education Program (TIRF REMS Access
`Education Program) and successfully complete
`the pharmacy Knowledge
`Assessment.
`
`ii. Complete and sign the Inpatient Pharmacy Enrollment Form. In signing the
`Inpatient Pharmacy Enrollment Form, the authorized pharmacist is required to
`acknowledge the following:
`
`
`
`Page 8 of 14
`
`Reference ID: 3066874
`
`

`

`a) I have reviewed the TIRF REMS Access Education Program, and I have
`completed the Knowledge Assessment. I understand the benefits and
`risks associated with TIRF medicines and the requirements of the TIRF
`REMS Access program for pharmacies.
`
`b) I will ensure that our inpatient pharmacists are educated on the risks
`associated with TIRF medicines and the requirements of the TIRF REMS
`Access program, as described in the TIRF REMS Access Education
`Program.
`
`c) I understand that converting patients from one TIRF medicine to a different TIRF
`medicine must not be done on a microgram-per-microgram basis. I understand
`that TIRF medicines are not interchangeable with each other, regardless of route
`of administration, and that conversion may result in fatal overdose, unless
`conversion is done in accordance with labeled product-specific conversion
`recommendations (refer to the ‘List of TIRF Medicines available only through the
`TIRF REMS Access Program’ in Attachment 1). Note, a branded TIRF medicine
`and its specific generic product(s) are interchangeable.
`
`d) I understand that TIRF medicines are contraindicated for use in opioid non-
`tolerant patients.
`
`e) I understand that the initial starting dose for TIRF medicines for all patients is
`the lowest dose, unless individual product labels provide product-specific
`conversion recommendations, and I understand that patients must be titrated
`individually.
`
`f)
`
`I understand that pharmacies within or associated with the healthcare facility
`that dispense to outpatients must be separately enrolled in and comply with
`the TIRF REMS Access program to dispense TIRF medicines to outpatients,
`as described in section B.2.d, above.
`
`g) I understand that our inpatient pharmacy must not dispense TIRF medicines
`for outpatient use.
`
`h) I understand that a prescriber who wants to discharge a patient with a TIRF
`medicine prescription, intended to be dispensed by an outpatient pharmacy, will
`be required to enroll in the TIRF REMS Access program, as described in section
`B.1 of this REMS.
`
`i)
`
`j)
`
`I will establish, or oversee the establishment of, a system, order sets,
`protocols and/or other measures to help ensure appropriate patient selection
`and compliance with the requirements of the TIRF REMS Access program.
`
`I understand that our pharmacy will not sell, loan or transfer any TIRF
`inventory to any other pharmacy, institution, distributor, or prescriber.
`
`from
`that TIRF medicines can only be obtained
`k) I understand
`wholesalers/distributors that are enrolled in the TIRF REMS Access program.
`
`l)
`
`I understand that our pharmacy must re-enroll in the TIRF REMS Access
`program every two (2) years.
`
`
`
`Reference ID: 3066874
`
`
`
`Page 9 of 14
`
`

`

`m) I understand that TIRF medicines are available only through the TIRF
`REMS Access program. I understand and agree to comply with the TIRF
`REMS Access program requirements for inpatient pharmacies.
`
`f. Pharmacies (authorized pharmacist) are required to re-enroll every two (2) years.
`g. TIRF Sponsors will:
`i. Ensure that pharmacy enrollment can successfully be completed via the TIRF REMS
`Access website, by mailing or faxing the forms.
`
`ii. Ensure that, as part of the enrollment process, the following materials that are part of
`the TIRF REMS Access program are available to pharmacies. These materials are
`appended:
`
` The TIRF REMS Access Program Overview (Outpatient Pharmacy, Chain
`Pharmacy or Inpatient Pharmacy, as applicable)
` TIRF REMS Access Education Program
` Knowledge Assessment
` Pharmacy Enrollment Form (Outpatient, Chain, or Inpatient, as applicable)
` Frequently Asked Questions (FAQs)
` TIRF REMS Access Website
`iii. Ensure that all enrollment forms are complete, and that the authorized pharmacist
`has successfully completed the Knowledge Assessment before activating a
`pharmacy’s enrollment in the TIRF REMS Access program. For outpatient
`pharmacies (including chain pharmacies) only, TIRF Sponsors will also ensure that
`the configurations to the pharmacy management system have been validated
`before enrolling a pharmacy in the TIRF REMS Access program.
`iv. Ensure that pharmacies are notified when they are successfully enrolled in the TIRF
`REMS Access program, and therefore, certified to dispense TIRF medicines.
`v. Monitor education and enrollment requirements for pharmacies and inactivate non-
`compliant pharmacies. Upon initial activation of enrollment, pharmacies remain
`active until a corrective action of inactivation occurs or expiration of the enrollment
`period.
`vi. Ensure that prior to first availability of the TIRF REMS Access program/website, Dear
`Pharmacy Letters will be sent (one for inpatient pharmacies and one for outpatient
`pharmacies). The target audience for the letter will include outpatient and inpatient
`pharmacies that dispense Schedule II drugs and may be involved in dispensing TIRF
`medicines. The letter will include information on the risks associated with the use of
`TIRF medicines and the requirements of the TIRF REMS Access program. The letter
`will be available on the TIRF REMS Access website for 1 year from the date of the
`mailing.
`
`The Dear Pharmacy Letters (Outpatient and Inpatient) are part of the TIRF REMS
`Access program. These materials are appended.
`
`
`
`
`
`Reference ID: 3066874
`
`
`
`Page 10 of 14
`
`

`

`3. TIRF medicines will only be dispensed for outpatient use with evidence or other
`documentation of safe-use conditions.
`
`a. TIRF Sponsors will ensure that TIRF medicines will only be dispensed for outpatient use
`if there is documentation in the TIRF REMS Access system that the dispensing
`pharmacy and prescriber are enrolled and active, and the patient is not inactive in the
`TIRF REMS Access program.
`b. Patients are passively enrolled in the TIRF REMS Access program when their first TIRF
`medicine prescription is processed at the pharmacy. This enrollment will be part of the
`normal prescription processing at the pharmacy and will be captured in the TIRF REMS
`Access program. Prescribers and outpatient pharmacies are enrolled, as previously
`described in sections B.1 and B.2, respectively.
`c. Prior to dispensing TIRF medicines, enrolled outpatient pharmacies will electronically
`verify documentation of the required enrollments by processing the TIRF prescription
`through their pharmacy management system.
`i.
`If the required enrollments are verified, a unique authorization code will be issued to
`allow processing and dispensing of the prescription to the patient.
`ii. If one or more of the required enrollments cannot be verified, the TIRF REMS
`Access system will reject the prescription (prior to a claim being forwarded to the
`payer) and the pharmacy will receive a rejection notice.
`d. Following initial activation, patients remain active until a trigger for inactivation occurs.
`Triggers for patient inactivation include:
`i. The patient has not filled a prescription for more than six (6) months.
`ii. The patient receives prescriptions for TIRF medicines from multiple prescribers
`within an overlapping time frame that is suggestive of misuse, abuse, or addiction.
`e. If an active patient transfers from an enrolled prescriber to a non-enrolled or inactive
`prescriber, the TIRF REMS Access program cannot fill the prescription for TIRF
`medicines until the new prescriber is active in the TIRF REMS Access program.
`f. A patient may have more than one current prescriber (e.g., pain management specialist,
`primary care physician) provided that prescriptions for TIRF medicines are not for the
`same or overlapping period of treatment.
`g. Documentation and verification of safe-use conditions are not required for prescriptions
`ordered within an inpatient healthcare setting and given to an inpatient.
`
`
`C. Implementation System
`
`1. TIRF Sponsors will ensure that wholesalers/distributors who distribute TIRF medicines
`are enrolled in the TIRF REMS Access program. The wholesaler/distributor enrollment
`process is comprised of the following steps that must be completed by the distributor’s
`authorized representative, prior to receiving TIRF medicine inventory for distribution:
`a. Review the distributor TIRF REMS Access program materials
`b. Complete and sign the Distributor Enrollment Form and send it to the TIRF Sponsors
`(by
`fax or mail).
`In signing
`the Distributor Enrollment Form, each
`wholesaler/distributor is required to indicate they understand that TIRF medicines are
`
`
`
`Reference ID: 3066874
`
`
`
`Page 11 of 14
`
`

`

`available only through the TIRF REMS Access program and acknowledges that they
`must comply with the following program requirements:
`i. The Wholesaler/Distributor will ensure that relevant staff are trained on the TIRF
`REMS Access program procedures and will follow the requirements of the TIRF
`REMS Access program.
`ii. The Wholesaler/Distributor will ensure that TIRF medicines are only distributed to
`pharmacies whose enrollment has been validated in the TIRF REMS Access
`program.
`iii. The Wholesaler/Distributor will provide complete, unblinded and unblocked data
`(i.e. EDI 867 transmission) to the TIRF REMS Access program including
`information on shipments to enrolled pharmacies.
`iv. The Wholesaler/Distributor will cooperate with periodic audits or non-compliance
`investigations to ensure that TIRF medicines are distributed in accordance with
`the program requirements.
`c. TIRF Sponsors will ensure that all forms are complete prior to enrolling a distributor
`in the TIRF REMS Access program.
`d. TIRF Sponsors will notify distributors when they are enrolled in the TIRF REMS
`Access program and, therefore, able to distribute TIRF medicines.
`e. Upon initial activation, distributors remain active until an action of inactivation occurs,
`expiration of the enrollment period, or failure to comply with the pharmacy enrollment
`verification obligations. If a previously active distributor becomes inactive, the
`distributor may become active again by completing the distributor enrollment process
`in its entirety.
`f. Distributors will be re-educated and re-enrolled in the TIRF REMS Access program
`every two (2) years.
`g. The following distributor materials are part of the TIRF REMS Access program.
`These materials are appended:
` Dear Distributor Letter
` Distributor Enrollment Form
` Frequently Asked Questions
`
`2. TIRF Sponsors will maintain a database of all enrolled entities (prescribers, pharmacies,
`patients, and distributors) and their status (i.e. active or inactive), and will monitor and
`evaluate implementation of the TIRF REMS Access program requirements.
`3. TIRF Sponsors will develop a TIRF REMS Access system that uses existing pharmacy
`management systems that allow for the transmission of TIRF REMS Access information
`using established telecommunication standards. The TIRF REMS Access system will
`incorporate an open framework that allows a variety of distributors, systems vendors,
`pharmacies, and prescribers to participate, and that is flexible enough to support the
`expansion or modification of the TIRF REMS Access program requirements, if deemed
`necessary in the future.
`4. TIRF Sponsors will monitor distribution data and prescription data to ensure that only
`actively enrolled distributors are distributing, actively enrolled pharmacies are
`dispensing, and actively enrolled prescribers for outpatient use are prescribing TIRF
`
`
`
`Page 12 of 14
`
`
`
`
`
`Reference ID: 3066874
`
`

`

`medicines. Additionally, TIRF Sponsors will monitor to ensure that, when dispensing in
`an outpatient setting, TIRF medicines are only being dispensed to actively enrolled
`patients of actively enrolled prescribers. Corrective action or inactivation will be instituted
`by TIRF Sponsors if non-compliance is found.
`5. TIRF Sponsors will monitor prescribers’ compliance with the requirement to complete a
`Patient-Prescriber Agreement Form with each TIRF patient, and to submit it to the TIRF
`REMS Access program within ten (10) working days. A maximum of three prescriptions
`are allowed within 10 working days from when the patient has their first prescription
`filled. No further prescriptions will be dispensed after the 10 working day window until a
`completed PPAF is received. This will be accomplished by reconciling the Patient-
`Prescriber Agreements submitted to the TIRF REMS Access program with patient
`enrollment data captured through the pharmacy management system.
`6. TIRF Sponsors will monitor and evaluate all enrolled outpatient pharmacies, distributors,
`and the TIRF REMS Access program vendors to validate the necessary system
`upgrades and ensure the program is implemented as directed.
`7. TIRF Sponsors will evaluate enrolled inpatient pharmacies’ compliance with the TIRF
`REMS Access program requirements through surveys.
`8. TIRF Sponsors will maintain a call center to support patients, prescribers, pharmacies,
`and distributors in interfacing with the TIRF REMS Access program.
`9. TIRF Sponsors will ensure that all materials listed in or appended to the TIRF REMS
`Access program will be available through the TIRF REMS Access program website
`www.TIRFREMSaccess.com or by calling the TIRF REMS Access call center at 1-866-
`822-1483.
`10. TIRF Sponsors will notify pharmacies, prescribers, and distributors of forthcoming
`enrollment expiration and the need to re-enroll in the TIRF REMS Access program.
`Notifications for patients will be sent to the patient’s prescriber.
`11. If there are substantive changes to the TIRF REMS Access program, TIRF Sponsors will
`update all affected materials and notify pharmacies, prescribers, and distributors of the
`changes, as applicable. Notifications for patients will be sent to the patient’s prescriber.
`Substantive changes to the TIRF REMS Access program are defined as:
`a. Significant changes to the operation of the TIRF REMS Access program.
`b. Changes to the Prescribing Information and Medication Guide that affect the risk-
`benefit profile of TIRF medicines.
`12. Based on monitoring and evaluation of the REMS Elements to Assure Safe Use, TIRF
`Sponsors will take reasonable steps to improve implementation of these elements and to
`maintain compliance with the TIRF REMS Access program requirements, as applicable.
`
`
`III. TIMETABLE FOR SUBMISSION OF ASSESSMENTS
`
`TIRF NDA Sponsors will submit REMS Assessments to the FDA at 6 and 12 months from the
`date of the REMS approval, and annually thereafter. To facilitate inclusion of as much
`information as possible, while allowing reasonable time to prepare the submission, the reporting
`interval covered by each assessment should conclude no earlier than 60 days before the
`submission date for that asses