1

TIRF REMS - Legal Responsibilities of Fentanyl

Objectives

By completing the lesson, the pharmacist will be able to:

4
5
6
7
8
9
10

1.
2.
3.
4.
5.

Identify the clinical and legal standard for dispensing fentanyl.

Discuss the legitimate medical purpose standard.
Discuss legal considerations of the treatment of pain with fentanyl.
Discuss differences between various forms of fentanyl.
Discuss the four elements of the REMS program.

11
12
13
14
15
16
17
18
19
20
21
22
23

Look at your current inventory. Chances are, most of your dosage forms are oral and intended to
be swallowed tablets, capsules, and liquids. Unless applying a cream or ointment, patients
probably associate taking medicine as swallowing an oral dosage form. Because of some
unique properties, fentanyl is available in a wide variety of dosage forms and presents unique
dispensing challenges for the pharmacist. The Food and Drug Administration (FDA) recognized
these challenges in its Risk Evaluation and Mitigation Strategy (REMS) programs for fentanyl, a
CII opioid analgesic. In addition to REMS, this lesson will discuss:
OAC 4729-5-18 Patient Profiles
OAC 4729-5-20 Prospective Drug Utilization Review
OAC 4729-5-21 Manner of Processing a Prescription (legitimate medical purpose)
OAC 4729-5-22 Patient Counseling

24
25
26
27
28
29
30
31
32
33
34
35

In 2007, a new law that gave FDA many new authorities and responsibilities to enhance drug
safety was enacted. The Food and Drug Administration Amendments Act (FDAAA) and one of
its provisions gave FDA the authority to require a REMS from manufacturers to help ensure that
the benefits of a drug or biological product outweigh its risks. Fentanyl is a powerful CII
analgesic that requires careful monitoring. The transmucosal forms of fentanyl have specific
dispensing and prescribing requirements for pharmacist to incorporate into practice.

Introduction

History of REMS

On December 28, 2011, FDA approved a single, shared system REMS for the entire class of
transmucosal immediate-release fentanyl (TIRF) prescription medicines. This REMS, called the
TIRF REMS Access program, consists of a restricted distribution program to reduce the risk of
misuse, abuse, addiction, and overdose with TIRF medicines. The TIRF REMS Access program
was the first approved class REMS for drugs in the opioid class.

Page 1 of 12

General Overview of REMS

2
3
4
5
6
7

Not all drugs will require a REMS. Some drugs are so toxic that the small amount of benefits
provided are insufficient to allow distribution, even when some patients would benefit from use.
Likewise, some drugs are very effective and have relatively few or minor toxicities or secondary
effects. It is those chemical entities in between where REMS comes into play. The FDA
views some drugs as being effective enough to be prescribed provide certain strategies are in
effect to monitor patients.

The four elements that may be included in any REMS, discussed below, are:

9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24

Medication Guide
Communication Plan
Elements To Assure Safe Use
Implementation System

A REMS may be required by the FDA as part of the approval of a new product, or for an
approved product when new safety information arises. For purposes of consistency, the REMS
follow a standard template. See Guidance for Industry Format and Content of Proposed Risk
Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS
Modifications at:
www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm18412
8.pdf. Last accessed July 19, 2015. It is of interest that foreign-language versions of REMS
elements, such as Medication Guides, patient package inserts, communication and education
materials, enrollment forms, prescriber and patient agreements, and others, are not considered
part of the approved REMS. FDA will not review foreign-language versions of REMS.
Depending on the benefit/toxicity profile, one or more of the four elements may be required.

25

Medication Guide

26
27

A Medication Guide must be provided to the patient or the patients agent in the following four
situations:

28
29
30
31
32
33
34
35
36

1. When the patient or the patients agent requests a Medication Guide.

2. When a drug is dispensed in an outpatient setting (e.g., retail pharmacy, hospital
ambulatory care pharmacy) and the product will then be used by the patient without
direct supervision by a healthcare professional.
3. The first time a drug is dispensed to a healthcare professional for administration to a
patient in an outpatient setting, such as in a clinic or dialysis or infusion center.
4. The first time a drug is dispensed in an outpatient setting of any kind, after a Medication
Guide is materially changed (e.g., after addition of a new indication, new safety
information). FDA will provide notice when this occurs.

37
38

The two most common instances where a Medication Guide is not required are:
for inpatients, unless the patient requests one.

Page 2 of 12

1
2
3
4
5
6
7

most outpatient refills will not require a Medication Guide, unless there is a recently
updated version FDA will provide notice when this occurs. This does not apply to CII.

There are no refills for fentanyl prescription since it is a CII opiate. Of course, when the patient
is discharged from the hospital or inpatient setting with a new prescription for administration at
home, the appropriate Medication Guide(s) should be provided when the outpatient prescription
is dispensed.

Communication Plan

9
10
11
12
13
14
15

When a Communication Plan is required, the information will be directed to one of more
members of the healthcare team or drug distribution chain. For example, prescribers may be sent
written materials to review. Also, prescribers may be sent material to review in person with each
patient a sort of checklist to make sure patients understand proper use, monitoring, laboratory
testing, record keeping, and the like. In such a case, documenting review by both patient and
prescriber together is employed. These materials will be available on both the FDA.gov website
and websites provided by the manufacturers.

16
17
18
19
20
21

For pharmacies to enroll and participate in the fentanyl communication plan, a designated
authorized pharmacist must review the Education Program, successfully complete the
Knowledge Assessment, and complete an enrollment form. Only then can the authorized
pharmacist complete enrollment on behalf of the pharmacy. Additional information about the
enrollment process can be found on the TIRF REMS Access program website:
www.TIRFREMSaccess.com.

22
23
24

Pharmacist can remind their prescriber colleagues to complete the TIRF REMS program every
two years. To enroll, prescribers must review the Education Program, successfully complete the
Knowledge Assessment, and complete an enrollment form.

25

Elements To Assure Safe Use

26
27
28
29
30
31
32
33
34

FDA believes that sometimes, providing information alone is not enough. In such cases,
additional Elements To Assure Safe Use (ETASU) will be required. ETASU are essentially
mechanisms to restrict distribution of the drug. Requiring that patients not only receive
information but formally enroll in a monitoring program may be required. Similarly,
prescribers and pharmacists may face similar enrollment requirements. Mandatory laboratory
testing may be required. Requiring that certain certification stickers are placed on written
prescriptions is another mechanism to document compliance with an ETASU program. As an
aside, some third party payers may audit and refuse to pay for prescriptions not showing these
stickers. At this time, there is no patient enrollment requirement for TIRF products.

Page 3 of 12

Implementation System

2
3
4
5
6

FDA may require the implementation system to include a description of how applicable products
will be distributed. In addition, as part of the implementation system, FDA may require the
certification of wholesalers and/or distributors to ensure the product is distributed only to
certified or otherwise specified pharmacies, practitioners, or healthcare settings that dispense the
drug, or only to patients who meet the requirements of the REMS.

Fentanyl Products

8
9
10
11
12
13
14
15
16
17
18
19
20
21

Ohio law requires that all medication dispensing meet guideline to assure proper medication use.
The following four rules are particularly important to keep in mind when dispensing fentanyl:
OAC 4729-5-18 Patient Profiles
OAC 4729-5-20 Prospective Drug Utilization Review
OAC 4729-5-21 Manner of Processing a Prescription (legitimate medical purpose)
OAC 4729-5-22 Patient Counseling

22
23
24
25
26

According to the Centers for Disease Control and Prevention, fentanyl is approximately 80 to
100 times more potent than morphine and roughly 40 to 50 times more potent than
pharmaceutical grade (100% pure) heroin.
http://www.cdc.gov/niosh/ershdb/EmergencyResponseCard_29750022.html. Last accessed July
20, 2015. Due to this potency, a small amount can be very effective at relieving pain.
All varieties of fentanyl require REMS. There are essentially three types of commercially
available dosage forms:

long-acting transdermal patch, e.g. Duragesic

patient activated transdermal (similar to patient-controlled-analgesic morphine pump),
e.g. Ionsys
oral/nasal Transmucosal Immediate-Release Fentanyl (TIRF), see six entries on table
below

Page 4 of 12

Table: Fentanyl REMS Elements

Name
Duragesic (long
acting opioid)

2
3
4
5
6
7
8
9

Medication
Guide
yes

Communication
Plan

ETASU

Implementation
System

Cont. Education
and practice
support forms
Ionsys (fentanyl No inpatient
Dear Healthcare Knowledge
Hospital
iontophoretic
use in certified Provider Letter
Assess Safety
Enrollment Form
transdermal
hospitals only
Dear Hospital
Brochure:
system)
Pharmacy Letter Nurses
Pharmacists
*Abstral (TIRF) See TIRF
See TIRF
See TIRF
See TIRF product
product packet product packet
product packet
packet
*Actiq (TIRF)
See TIRF
See TIRF
See TIRF
See TIRF product
product packet product packet
product packet
packet
*Fentora
See TIRF
See TIRF
See TIRF
See TIRF product
(TIRF)
product packet product packet
product packet
packet
*Lazanda
See TIRF
See TIRF
See TIRF
See TIRF product
(TIRF)
product packet product packet
product packet
packet
*Onsolis
See TIRF
See TIRF
See TIRF
See TIRF product
(TIRF)
product packet product packet
product packet
packet
*Subsys (TIRF) See TIRF
See TIRF
See TIRF
See TIRF product
product packet product packet
product packet
packet
*TIRF stands for Transmucosal Immediate-Release Fentanyl (TIRF) Products. These may be a
nasal spray, transmucosal lozenge, sublingual spray, buccal soluble film, or buccal tablet.
Additional materials may be viewed in detail at: http://dailymed.nlm.nih.gov/dailymed.
As we review the fentanyl REMS table, different fentanyl products must meet varying REMS
criteria. The Duragesic patches must meet the same criterion as other long acting and extended
release opioid analgesics. See http://www.er-la-opioidrems.com. Last accessed July 20, 2015.
Most pharmacist are familiar with this long-acting patch form of fentanyl.

10
11
12
13
14
15
16
17

The Ionsys fentanyl patch is only distributed to hospitals meeting certain criteria more details
are available at www.IONSYSREMS.COM. Ionsys is an opioid analgesic that, unlike
Duragesic, should only be used for the short-term management of acute postoperative pain in
adult patients requiring opioid analgesia in the hospital. Ionsys is a patient-controlled analgesia
(PCA) product that enables surgical patients to push a button to dispense fentanyl transdermally
as needed for pain. Only the patient may activate Ionsys dosing. Hospital pharmacies will not
dispense Ionsys for outpatient use. Because in-patients will be personally instructed in proper
use of Ionsys, there are no Medication Guides as such.

18
19
20
21

We now turn to the transmucosal formulations, used as tablets placed under the tongue, in the
cheek, nasal spray, and sublingual spray. Fentanyl undergoes a substantial first-pass effect,
making mucosal administration more effective and predictable than oral administration. Jasek,
W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: sterreichischer
Page 5 of 12

1
2
3

Apothekerverlag. pp. 8992. ISBN 978-3-85200-181-4. Thus, bioavailability through skin and
nasal route is about 90 percent, while about 50 percent via buccal route and 33 percent via oral
route through small intestine. Thus, swallowing the drug makes it less effective.

4
5
6
7

TIRF medicines are indicated only for the management of breakthrough pain in adult cancer
patients 18 years of age and older (16 years of age and older for Actiq brand and generic
equivalents) who are already receiving, and who are tolerant to, around-the-clock opioid therapy
for their underlying persistent cancer pain.

8
9
10
11
12
13
14
15
16
17
18
19
20
21

Patients considered opioid-tolerant are those taking:

at least 60 mg of oral morphine/daily
at least 25 mcg transdermal fentanyl/hour
at least 30 mg of oral oxycodone daily
at least 8 mg oral hydromorphone daily
at least 25 mg oral oxymorphone daily
or an equianalgesic dose of another opioid daily for a week or longer.

22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43

Ohio Law Provisions

Ohio law requires that all medication dispensing meet guideline to assure proper medication use.
The following four rules are particularly important to keep in mind when dispensing fentanyl:
OAC 4729-5-18 Patient Profiles
OAC 4729-5-20 Prospective Drug Utilization Review
OAC 4729-5-21 Manner of Processing a Prescription (legitimate medical purpose)
OAC 4729-5-22 Patient Counseling

TIRF medicines are contraindicated in opioid non-tolerant patients and are contraindicated in the
management of acute or postoperative pain, including headache/migraine and dental pain, or use
in the emergency room. Each pharmacy will need to make its own decision whether and which
TIRF products to stock for inventory. When patients are in pain, they often cannot wait for the
pharmacys next CII delivery. However, stocking these medications may not make a great deal
of economic sense for pharmacies that do not serve many patients with chronic pain.

Patient profiles must include a history of or active chronic conditions or disease states. See
OAC 4729-5-18 (A) (1) (h). While these disease states may sometimes be inferred from the
medications themselves, it is best to update these conditions frequently. When TIRF products
are dispensed, the pharmacist should look for a diagnosis of cancer and treatment with a longacting opioid. TIRF products are intended to be used in conjunction with long-acting opioids,
not to replace long-acting opioids.
Before TIRF products are dispensed, the pharmacist is required to perform prospective drug
utilization review. See OAC 4729-5-20. Assessment of potential drug-drug interactions with
TIRF products is important. See OAC 4729-5-20 (A) (4). Fentanyl is metabolized mainly via
the cytochrome P450 (CYP3A4) isoenzyme system. Potential drug interactions may occur when
TIRF medicines are given concurrently with agents that affect CYP3A4 activity. For example,
ketoconazole, fluconazole, diltiazem, erythromycin, and verapamil may result in potentially
dangerous increases in fentanyl plasma concentrations, which could increase or prolong the drug
Page 6 of 12

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45

effects and may cause potentially fatal respiratory depression. Patients receiving TIRF
medicines who begin therapy with, or increase the dose of, CYP3A4 inhibitors are to be
carefully monitored for signs of opioid toxicity over an extended period of time. Dosage
increases by the prescriber should be done conservatively.
Like any other prescription, prescriptions for fentanyl must be issued for a legitimate medical
purpose in the usual course of professional practice by the prescriber: See OAC 4729-5-21 (A)
and 4729-5-30 (A):
A prescription, to be valid, must be issued for a legitimate medical purpose by an
individual prescriber acting in the usual course of his/her professional practice. The
responsibility for the proper prescribing is upon the prescriber, but a corresponding
responsibility rests with the pharmacist who dispenses the prescription. An order
purporting to be a prescription issued not in the usual course of bona fide treatment of a
patient is not a prescription and the person knowingly dispensing such a purported
prescription, as well as the person issuing it, shall be subject to the penalties of law.
By the nature of the drug and dosage form, there will be comparatively few young adult patients
who are tolerant to around-the-clock opioid therapy for underlying persistent cancer pain. Of
course, cancer can occur at any age, as can opioid tolerance. Due to limitations provided in FDA
approved labelling, particular scrutiny should be paid to prescriptions for younger patients,
particularly in community ambulatory settings. TIRF prescriptions should not be issued by a
dentist or after surgery for a broken bone or car crash ending up in the emergency room. When
contacting the prescriber, there should be ample diagnostic and treatment history demonstrating
need for TIRF products.
To take two examples, persistent cancer pain requiring at least thirty milligrams per day of longacting oxycodone, or use of Duragesic patches, should appear in the clinical history before TIRF
products are dispensed. It is of some interest to note that a dose of hydrocodone is not listed in
the manufacturers dosing guidelines. This may be due to the relatively recent rescheduling of
hydrocodone products from CIII to CII or that hydrocodone is not viewed by practitioners as
being as effective or equivalent in treating severe pain.
Patients should counseled to give extra caution to keep TIRF products out of the reach of
children or others who might want to experiment with controlled substances. See OAC 4729-522 (B) (7). Special care should be taken to help the patient understand the difference between
the long-acting pain medicine and TIRF product OAC 4729-5-22 (B) (3) and (4). Slowing of
respiration or excessive drowsiness during waking hours could be signs of overdose and require
careful monitoring. OAC 4729-5-22 (B) (5).
Counseling Duty Dosing
Patients should be advised to notify the pharmacist and prescriber if and when TIRF medicines
are being needed four or more doses per day. See OAC 4729-5-22. The prescriber may consider
increasing the dose of the around-the-clock opioid medicine (such as Oxycontin) used for
Page 7 of 12

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42

persistent cancer pain in patients experiencing more than four breakthrough cancer pain episodes
per day. In general, patients should limit the use of TIRF medicines to four or fewer doses per
day.
The pharmacist should also be aware that TIRF products are not equivalent. This is extremely
important. For example,

patients should wait at least four hours before treating another breakthrough pain episode
with FENTORA fentanyl buccal tablet
patients must wait at least two hours before treating another episode of breakthrough pain
with LAZANDA fentanyl nasal spray.
if a breakthrough pain episode is not relieved after 30 minutes of SUBSYS sublingual
spray, patients may take one additional dose of SUBSYS using the same strength.
Patients should not take more than two doses of SUBSYS per episode of breakthrough
pain.

Dosing is highly individualized. Due to complexities of dosing of breakthrough pain episodes

with differing dosing forms, it is advisable to use only one TIRF product at a time. Using
sublingual tablets and nasal spray and sublingual spray at the same time is highly undesirable
and unpredictable.
Patients should not change doses without consulting their prescriber first. Remind the patient to
be regularly using another opioid pain medicine, around-the-clock, for constant pain. If they
stop taking the around-the-clock opioid pain medicine for constant pain, they should stop taking
the TIRF medicine, and not use TIRF medicine alone to compensate. Patients can have
difficulty comprehending this concept, which must be emphasized by the pharmacist. Careful
record keeping of prescribing information, including quantity, frequency, and renewal requests is
strongly advised. Pharmacists can be strong advocates for patient care by assisting in simple
documentation of adherence and dosing.
TIRF REMS Access Program
Pharmacists who have not done so should enroll in and complete the TIRF REMS Access
Program. The program is an FDA-required program designed to ensure informed risk-benefit
decisions before initiating treatment, and while patients are treated to ensure appropriate use of
TIRF products. The purpose of the TIRF REMS Access program is to mitigate the risk of
misuse, abuse, addiction, overdose and serious complications due to medication errors with the
use of TIRF medicines. Pharmacists and prescribers must enroll in the TIRF REMS Access
program to prescribe, dispense, or distribute TIRF medicines. If you have not completed this
program, click Create-My-Account at https://www.tirfremsaccess.com/TirfUI/rems/home.action.
For assistance, please call the TIRF REMS Access program at 1-866-822-1483. There is no cost
to complete the program. To learn more, see table below for details.

Page 8 of 12

Name

Transmucosal Fentanyl Contact

Links (CTRL + click to follow)

ABSTRAL Oral sublingual tablets

888-227-8725

U.S. Prescribing Information and

Medication Guide

ACTIQ

800-896-5855

U.S. Prescribing Information and

Medication Guide

FENTORA Oral buccal tablet

800-896-5855

U.S. Prescribing Information and

Medication Guide

LAZANDA nasal spray

866-458-6389

U.S. Prescribing Information and

Medication Guide

ONSOLIS

Oral buccal soluble film

U.S. Prescribing Information and

855-365-6095 Medication Guide Not currently
available

SUBSYS

Oral sublingual spray

877-978-2797

Oral lozenge

Generic Generic Name

Contact

U.S. Prescribing Information and

Medication Guide

Link (CTRL + click to follow)

800-896-5855
Fentanyl Oral Citrate Lozenge 800-778-7898

U.S. Prescribing Information and Medication

Guide

800-828-9393

1
2
3
4
5
6
7
8
9
10
11
12
13

Take Away Points

Complete the free program at www.TIRFREMSaccess.com
Know your patient and history. Patient selection is key.
Update and review the profile and patient history each time before dispensing. Look for
potential drug interactions and duplications of therapy.
Medication Guide must be provided to the patient each time dispensing TIRF products
Remind patients that TIRF products supplement, and do not replace, treatment with longacting opioids. Also remind them to store and dispose of medication to avoid abuse.
Remind patients that dosing is highly individualized and can change when a different
fentanyl product is selected.
Verify dosage form with patient each time sublingual spray, nasal spray, buccal tablet
Discuss dosing frequency and need to communicate with pharmacist and prescriber
Page 9 of 12