Fixed-Quantity Unit-of-Use Blister Packaging for Certain Immediate-Release Opioid Analgesics for Treatment of Acute Pain; Establishment of a Public Docket; Request for Comments, 25283-25289 [2019-11283]
Download as PDF
<![CDATA[
Federal Register / Vol. 84, No. 105 / Friday, May 31, 2019 / Notices
submitting information regarding
section 403(r)(6) of the FD&C Act
statements on labels or in labeling of
dietary supplements imposes minimal
burden on respondents. We expect the
information needed is immediately
available to the manufacturer, packer, or
distributor of the dietary supplement
that bears such a statement on its label
or in its labeling. We believe also that
submission via the FARM system will
facilitate reporting for respondents. We
estimate that, each year, approximately
3,690 firms will submit the information
required by section 403(r)(6) of the
FD&C Act. Assuming firms require 0.75
hour to gather the information needed
and prepare a communication, we
calculate a total of 2,767.5 hours (3,690
total annual responses × 0.75 hour).
Notice; establishment of a
public docket; request for comments.
Electronic Submissions
Submit electronic comments in the
following way:
• Federal eRulemaking Portal:
https://www.regulations.gov. Follow the
instructions for submitting comments.
Comments submitted electronically,
including attachments, to https://
www.regulations.gov will be posted to
the docket unchanged. Because your
comment will be made public, you are
solely responsible for ensuring that your
comment does not include any
confidential information that you or a
third party may not wish to be posted,
such as medical information, your or
anyone else’s Social Security number, or
confidential business information, such
as a manufacturing process. Please note
that if you include your name, contact
information, or other information that
identifies you in the body of your
comments, that information will be
posted on https://www.regulations.gov.
• If you want to submit a comment
with confidential information that you
do not wish to be made available to the
public, submit the comment as a
written/paper submission and in the
manner detailed (see ‘‘Written/Paper
Submissions’’ and ‘‘Instructions’’).
The Food and Drug
Administration (FDA or the Agency) is
announcing the establishment of a
docket to solicit public comment on a
potential modification to the Opioid
Analgesic Risk Evaluation and
Mitigation Strategy (OA REMS) to
require that certain solid, oral dosage
forms of immediate-release (IR) opioid
analgesics commonly prescribed for
treatment of acute pain be made
available in fixed-quantity unit-of-use
blister packaging for outpatient
dispensing. This could reduce the
amount of unused opioid analgesics,
thereby reducing opportunities for
misuse, abuse, inappropriate access, and
overdose, and possibly reducing the
development of new opioid addiction.
DATES: Submit either electronic or
written comments by July 30, 2019.
ADDRESSES: You may submit comments
as follows. Please note that late,
Written/Paper Submissions
Submit written/paper submissions as
follows:
• Mail/Hand Delivery/Courier (for
written/paper submissions): Dockets
Management Staff (HFA–305), Food and
Drug Administration, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments
submitted to the Dockets Management
Staff, FDA will post your comment, as
well as any attachments, except for
information submitted, marked and
identified, as confidential, if submitted
as detailed in ‘‘Instructions.’’
Instructions: All submissions received
must include the Docket No. FDA–
2019–N–1845 for ‘‘Fixed-Quantity Unitof-Use Blister Packaging for Certain
Immediate-Release Opioid Analgesics
for Treatment of Acute Pain;
Establishment of a Public Docket;
Request for Comments.’’ Received
Dated: May 28, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019–11419 Filed 5–30–19; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2019–N–1845]
Fixed-Quantity Unit-of-Use Blister
Packaging for Certain ImmediateRelease Opioid Analgesics for
Treatment of Acute Pain;
Establishment of a Public Docket;
Request for Comments
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
SUMMARY:
khammond on DSKBBV9HB2PROD with NOTICES
untimely filed comments will not be
considered. Electronic comments must
be submitted on or before July 30, 2019.
The https://www.regulations.gov
electronic filing system will accept
comments until 11:59 p.m. Eastern Time
at the end of July 30, 2019. Comments
received by mail/hand delivery/courier
(for written/paper submissions) will be
considered timely if they are
postmarked or the delivery service
acceptance receipt is on or before that
date.
VerDate Sep<11>2014
16:42 May 30, 2019
Jkt 247001
PO 00000
Frm 00053
Fmt 4703
Sfmt 4703
25283
comments, those filed in a timely
manner (see ADDRESSES), will be placed
in the docket and, except for those
submitted as ‘‘Confidential
Submissions,’’ publicly viewable at
https://www.regulations.gov or at the
Dockets Management Staff between 9
a.m. and 4 p.m., Monday through
Friday.
• Confidential Submissions—To
submit a comment with confidential
information that you do not wish to be
made publicly available, submit your
comments only as a written/paper
submission. You should submit two
copies total. One copy will include the
information you claim to be confidential
with a heading or cover note that states
‘‘THIS DOCUMENT CONTAINS
CONFIDENTIAL INFORMATION.’’ The
Agency will review this copy, including
the claimed confidential information, in
its consideration of comments. The
second copy, which will have the
claimed confidential information
redacted/blacked out, will be available
for public viewing and posted on
https://www.regulations.gov. Submit
both copies to the Dockets Management
Staff. If you do not wish your name and
contact information to be made publicly
available, you can provide this
information on the cover sheet and not
in the body of your comments and you
must identify this information as
‘‘confidential.’’ Any information marked
as ‘‘confidential’’ will not be disclosed
except in accordance with 21 CFR 10.20
and other applicable disclosure law. For
more information about FDA’s posting
of comments to public dockets, see 80
FR 56469, September 18, 2015, or access
the information at: https://www.gpo.gov/
fdsys/pkg/FR-2015-09-18/pdf/201523389.pdf.
Docket: For access to the docket to
read background documents or the
electronic and written/paper comments
received, go to https://
www.regulations.gov and insert the
docket number, found in brackets in the
heading of this document, into the
‘‘Search’’ box and follow the prompts
and/or go to the Dockets Management
Staff, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT:
Patrick Raulerson, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6260,
Silver Spring, MD 20993, 301–796–
3522, Patrick.Raulerson@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
In 2017, opioid-involved overdoses
killed more than 47,000 people, with
E:\FR\FM\31MYN1.SGM
31MYN1
khammond on DSKBBV9HB2PROD with NOTICES
25284
Federal Register / Vol. 84, No. 105 / Friday, May 31, 2019 / Notices
more than a third of those deaths
involving prescription opioids (Ref. 1).
The volume of prescription opioid
analgesics dispensed has decreased
from a peak in 2012 and continues to
trend downward. However, opioid
analgesics continue to be prescribed at
a high rate—an estimated 196 million
retail prescriptions, resulting in an
estimated 13 billion units (e.g., tablets
or capsules) dispensed in 2017 from
U.S. outpatient retail pharmacies (Ref.
2). Approximately 89 percent of people
who report misuse or abuse of
prescription opioid pain relievers state
they obtained their most recently used
drugs from their own prescriptions or
from a friend or relative (Ref. 3). In
addition, many people who begin with
misuse or abuse of prescription opioids
transition to illicit substances (Refs. 4 to
7).
Accordingly, FDA’s efforts to address
the opioid crisis will continue to
include a focus on encouraging rational,
‘‘right-size’’ prescribing of opioid
analgesics. This includes efforts aimed
at reducing both the number of people
unnecessarily exposed to opioid
analgesics (either through legitimate
prescriptions or due to inappropriate
access) and encouraging healthcare
providers to prescribe amounts that
better reflect the quantity expected to
meet the needs of the patient with acute
pain. At the same time, we must help
ensure appropriate access to opioid
analgesics to address the medical needs
of patients experiencing acute pain
severe enough to require opioid
analgesic treatment.
The Substance Use-Disorder
Prevention that Promotes Opioid
Recovery and Treatment for Patients
and Communities Act (SUPPORT Act),
signed into law on October 24, 2018,
provides FDA several new authorities to
address the opioid crisis. The new law
allows FDA to require certain packaging
and disposal systems under a REMS for
opioids and other drugs that pose a
serious risk of abuse or overdose if,
among other things, FDA determines
that such packaging or disposal system
may mitigate such risks (see section
505–1(e)(4) of the Federal Food, Drug,
and Cosmetic Act (FD&C Act) (21 U.S.C.
355–1(e)(4))). The purpose of this notice
is to seek public comment on
application of this new authority,
including the potential application of
this authority to require under the OA
REMS that certain solid oral dosage
forms of IR opioid analgesics commonly
used to treat acute pain be made
available in fixed-quantity unit-of-use
blister packaging for outpatient
dispensing.
VerDate Sep<11>2014
16:42 May 30, 2019
Jkt 247001
FDA recognizes that the fixedquantity unit-of-use blister packaging
requirement the Agency is considering
as part of the OA REMS is just one
possible application of FDA’s new
authorities related to packaging and
disposal. We are considering, and invite
comment on, other potential mandates,
including mail-back pouches or other
safe disposal options. Furthermore, we
actively encourage drug manufacturers
and others to innovate in this space. We
are aware of many promising packaging
and disposal technologies that could
have a positive impact on reducing
misuse, abuse, inappropriate access,
accidental poisoning, or overdose, or
could otherwise facilitate the safe and
appropriate use of prescription opioid
analgesics. We believe that the potential
packaging requirement outlined here
could be a significant and readily
achievable step towards improving the
safe use of opioids, one that could be
supplemented in the future by other
safety-enhancing measures.
FDA is establishing this docket to
solicit input from stakeholders on all
aspects of this potential requirement
under the OA REMS, including
comments on specific questions posed
in section III.
II. Fixed-Quantity Unit-of-Use Blister
Packaging for Certain IR Opioid
Analgesics for Treatment of Acute Pain
In this section, we describe data
suggesting that many patients who are
prescribed an opioid analgesic to treat
acute pain use substantially fewer units
of the drug than they receive, resulting
in millions of excess opioid analgesic
tablets and capsules dispensed every
year. We then describe a potential
requirement, as part of the OA REMS,
that fixed-quantity unit-of-use blister
packs for certain IR opioid analgesics be
made available to be dispensed in the
outpatient setting. We discuss how
these proposed new packaging
configurations could encourage more
appropriate prescribing, reducing the
amount of unused opioid analgesics
available for misuse, abuse,
inappropriate access, and accidental
poisoning or overdose. We also discuss
other potential safety benefits associated
with blister packs.
A. Actual Opioid Use Compared to
Prescribed Amounts for Common
Surgical Procedures and Other
Conditions That Cause Acute Pain
FDA has reviewed published studies
that compared the amount of opioid
analgesics patients received to treat
their acute pain with their reported
actual use after several common surgical
procedures. Most of these studies
PO 00000
Frm 00054
Fmt 4703
Sfmt 4703
focused on opioid-naı¨ve adults. Opioidnaı¨ve is defined in various ways across
the studies; one common definition is a
patient who filled no opioid analgesic
prescriptions in the prior 12 months.
We also analyzed patterns of additional
fills after an initial opioid analgesic
prescription fill for acute pain in postsurgical and primary care settings. We
define an additional fill as a second
prescription fill for an opioid analgesic
in a short period after the first fill.
In the post-surgical setting, following
several common minimally or lessinvasive surgical procedures,1 most
opioid-naı¨ve adults who used an opioid
analgesic appeared to use only 1 to 3
days’ worth, or 15 or fewer, opioid
analgesic tablets or capsules despite
receiving prescriptions exceeding the
number they used (Refs. 8 to 11).
Patients reported that they usually
retain these unused tablets or capsules
and store them in unsecure locations
(Ref. 8), providing opportunities for
later misuse, abuse, inappropriate
access, and accidental poisoning or
overdose.
For example, after a less-invasive
cholecystectomy, the median number of
opioid analgesic tablets prescribed to
treat pain was 18, even though 75
percent of patients used 9 or fewer
tablets (each tablet equivalent to an
oxycodone 5 milligram (mg) dose). Of
the 75 percent of patients who used 9
or fewer tablets, 35 percent reported
using no opioids (Ref. 10). In an FDA
analysis of surgical procedures in
opioid-naı¨ve adults, our model
estimated that less than 20 percent of
patients undergoing laparoscopic
cholecystectomy might need an
additional fill if they were given a 1-day
supply of an opioid analgesic, but the
median days actually supplied to
patients was 4, with a median of 30
tablets per prescription filled (Ref. 11).
The unused tablets from each opioid
analgesic prescription for a common
surgical procedure such as
cholecystectomy—there were an
estimated 950,000 cholecystectomies in
community hospitals in the United
States in 2014 (Ref. 12)—contribute
significantly to the number of unused
tablets available for misuse, abuse,
1 These surgical procedures included
dermatologic surgery, carotid endarterectomy,
inguinal/femoral hernia repair, breast lumpectomy,
partial mastectomy, parathyroidectomy,
thyroidectomy, vaginal or laparoscopic
hysterectomy, laparoscopic cholecystectomy,
laparoscopic colectomy, laparoscopic
appendectomy, small-bowel resection/enterolysis,
minimally-invasive prostatectomy, knee
arthroscopic meniscectomy, tooth extraction,
bunionectomy, carpal tunnel release, ovarian cancer
cytoreduction, breast lumpectomy, and
arteriovenous fistula creation.
E:\FR\FM\31MYN1.SGM
31MYN1
25285
Federal Register / Vol. 84, No. 105 / Friday, May 31, 2019 / Notices
inappropriate access, and accidental
poisonings or overdose. In our analyses
of opioid analgesic prescription fills
after surgical procedures and published
studies in which patients were asked
about their opioid analgesic use after
surgical procedures, we also found that
about 30 percent of patients either never
filled their prescriptions or filled them
but did not actually consume any of the
tablets or capsules following several
types of minimally or less-invasive
surgical procedures (e.g., laparoscopic
cholecystectomy, laparoscopic
hysterectomy, laparoscopic
appendectomy) (Refs. 10 and 13).
We observed a similar pattern of
prescribing more than patients appeared
to use for several other common nonsurgical acute pain conditions in the
primary care setting. For example, for
headaches, muscular strains and
sprains, and certain forms of acute back
pain, in our modeling of additional fill
patterns, most patients could be
expected to only need an opioid
analgesic for up to 3 days, but they often
received enough doses to treat pain for
a significantly longer period (Ref. 14).
B. Proposal: 5-, 10-, and 15-Count
Blister Packages of Certain IR Opioid
and IR Opioid/Acetaminophen Products
As discussed above, we have found
that for many common, minimally or
less-invasive surgical procedures and
some common acute pain conditions
treated in the primary care setting for
which opioid analgesics are prescribed,
we expect most opioid-naı¨ve adult
patients to use significantly fewer
tablets or capsules than the average
prescription has historically provided.
Most of these patients appeared to use
an opioid for 1 to 3 days and used 15
or fewer tablets or capsules when they
used an opioid analgesic to treat their
pain.
Accordingly, we anticipate that if 5-,
10-, and 15-count blister package
configurations of certain IR opioid
analgesics commonly used for treatment
of acute pain were made available, one
or more of these options could be
expected to meet the needs of most
opioid-naı¨ve adults who require opioid
therapy following many common
minimally or less-invasive procedures
and other acute pain conditions for
which opioid analgesics are prescribed.
We further anticipate that utilization of
these fixed-quantity unit-of use blister
package configurations would
substantially reduce the quantity of
opioid analgesics dispensed per
prescription compared to the status quo.
Table 1 below compares the morphine
milligram equivalent (MME) of 5-, 10-,
and 15-count packaging of seven
commonly prescribed opioid analgesic
products to the mean MME and mean
number of tablets per ‘‘new-to-therapy
start prescriptions’’ (NTS Rx) dispensed
in 2017. This table illustrates the
potential for utilization of fixed-quantity
unit-of-use blister packages to
substantially reduce the amount of
opioid analgesics prescribed for opioidnaı¨ve patients receiving prescriptions
for seven commonly prescribed
products.
TABLE 1—5-, 10-, AND 15-COUNT PACKAGES BY MME CONTENT/PACKAGE COMPARED TO MEAN MME AND MEAN
TABLETS PER NTS RX ± DISPENSED IN 2017
MME per package
Oral tablets
5-Count
(1 days *)
Hydrocodone 5 mg/APAP 325 mg ......................................
Tramadol 50 mg ..................................................................
Oxycodone 5 mg/APAP 325 mg .........................................
Codeine 30 mg/APAP 300 mg ............................................
Hydrocodone 7.5 mg/APAP 325 mg ...................................
Hydrocodone 10 mg/APAP 325 mg ....................................
Oxycodone 5 mg .................................................................
10-Count
(2 days *)
25
25
37.5
22.5
37.5
50
37.5
2017 NTS Rx
15-Count
(3 days *)
50
50
75
45
75
100
75
75
75
112.5
67.5
112.5
150
112.5
Mean MME/
NTS Rx
108
180
199
96
192
393
261
Mean tabs/
NTS Rx
22
36
27
21
26
39
35
khammond on DSKBBV9HB2PROD with NOTICES
± New to Therapy Start Prescriptions (NTS Rx): Nationally estimated number of first opioid analgesic prescriptions dispensed to patients with
no opioid analgesic dispensed in previous 12 months. Source: IQVIA, National Prescription Audit New To Brand (NPA NTB), year 2017. Extracted January 2019.
* Days’ supply does not correlate well with the number of units to package, estimated days supply based on around-the-clock dosing of 1–2
tablets every 4–6 hours PRN.
MME Estimates based on CMS’s Opioid Oral Morphine Milligram Equivalent (MME) Conversion Factors. Accessed at https://www.cms.gov/
Medicare/Prescription-Drug-Coverage/PrescriptionDrugCovContra/Downloads/Opioid-Morphine-EQ-Conversion-Factors-Aug-2017.pdf.
Our analyses revealed that the
number of days for which opioids are
prescribed or used does not correlate
well with a specific number of tablets or
capsules per day, as what is considered
an appropriate amount of an opioid
analgesic for a day’s worth of treatment
varies across procedures and patients.
This type of variation is reflected in the
labeling of IR opioid analgesics, which
describes the need to individualize
dosing regimens based on patient
treatment goals. Accordingly, we are
considering requiring that applicants or
application holders make available 5-,
10-, and 15-count blister pack
configurations without prespecifying
that any of these given configurations
constitutes an appropriate amount of
VerDate Sep<11>2014
16:42 May 30, 2019
Jkt 247001
opioid analgesic for a specified
duration, such as a specific number of
days of treatment. Rather, we anticipate
that prescribers would use their
expertise and consult appropriate
prescribing guidelines to determine
which, if any, of the newly available
blister packages is appropriate for their
patients on a case-by-case basis.
We note that several existing
prescribing guidelines recommend
outpatient days of treatment or quantity
of tablets or capsules for common
minimally or less-invasive surgical
procedures or acute pain conditions
treated in primary care and emergency
department settings that are in line with
our proposal for 5-, 10-, and 15-count
packages of certain IR opioid analgesics
PO 00000
Frm 00055
Fmt 4703
Sfmt 4703
(Refs. 15 to 21). Additionally, section
3002 of the SUPPORT Act requires FDA
to develop evidence-based opioid
analgesic prescribing guidelines for the
indication-specific treatment of acute
pain only for the relevant therapeutic
areas where such guidelines do not
exist. These guidelines, once available,
should help to encourage more
appropriate, ‘‘right-sized’’ opioid
analgesic prescribing. We anticipate that
these prescribing guidelines, as well as
prescribing guidelines developed by
others, would provide appropriate
recommendations regarding the use of
blister pack configurations made
available pursuant to an OA REMS
packaging requirement, facilitating
E:\FR\FM\31MYN1.SGM
31MYN1
25286
Federal Register / Vol. 84, No. 105 / Friday, May 31, 2019 / Notices
prescriber understanding and uptake of
such product packaging configurations.
C. New Packaging/Disposal REMS
Element
Section 3032 of the SUPPORT Act
amends FDA’s REMS authority.
Specifically, as a part of a REMS, FDA
may now require that a drug for which
there is a serious risk of an adverse
event occurring from abuse or overdose
be made available for dispensing to
certain patients in unit-dose packaging,
packaging that provides a set duration,
or another packaging system that FDA
determines may mitigate such serious
risk (21 U.S.C. 355–1(e)(4)). FDA may
also require that such drugs be
dispensed to certain patients with a safe
disposal packaging or safe disposal
system for purposes of rendering drugs
non-retrievable if FDA determines that
such safe disposal packaging or system
may mitigate a serious risk of an adverse
event occurring from abuse or overdose
of the drug and is sufficiently available
(see section 505–1(e)(4) of the FD&C
Act).
A packaging or disposal requirement
under this provision is applicable to
prescription drugs that are the subject of
applications approved under section
505(b) of the FD&C Act (21 U.S.C.
355(b)) or section 351 of the Public
Health Service Act (42 U.S.C. 242), as
well as drugs that are the subject of
abbreviated new drug applications
(ANDAs) approved under section 505(j)
of the FD&C Act if a packaging or
disposal requirement is required for the
applicable listed drug (see section
505(i)(1)(B) of the FD&C Act). The law
provides that FDA will permit
packaging systems and safe disposal
packaging or safe disposal systems for
drugs that are the subject of ANDAs that
are different from those required for the
applicable listed drugs (see section
505(i)(2)(B) of the FD&C Act). FDA must
take into consideration the burden on
patients’ access to the drug and the
burden on the healthcare delivery
system that would be associated with
any such packaging or disposal
requirement and must consult with
other relevant Federal Agencies with
authorities over drug disposal packaging
in certain circumstances (see section
505–1(e)(4) of the FD&C Act).
FDA is contemplating using this new
authority to require fixed-quantity unitof-use blister packaging for certain IR
opioid analgesics under the OA REMS,
as described in this notice. For purposes
of soliciting comments, FDA is
considering the following general
process for any packaging requirement
under the OA REMS.
First, for already-approved opioid
analgesic products, FDA would notify
the application holders by letter that the
Agency is requiring a modification to
the OA REMS to include a packaging
requirement. The notification letter
would set forth details of the required
modification, including the specific
products subject to the new
requirement, the number of blister
packaging configurations required for
each product and the number of units in
each, key information regarding safe and
effective use of opioid analgesics to be
printed on the blister packaging, and
other data and information needed for
FDA to review and approve new blister
package configurations (e.g., stability
data).
Second, the application holders
subject to the OA REMS would submit
a proposed REMS modification within
120 days or such other reasonable time
as FDA specifies. FDA anticipates that
the proposed OA REMS modification
would include all necessary
specifications and timeframes for the
blister packages. FDA would expect for
the notification letters, the proposed
REMS modifications, and the REMS
approval to be sufficiently general that
they are uniform across all affected
application holders and products, to the
extent possible.
Third, the application holders of
products that are subject to the blister
packaging requirement would
individually submit a prior approval
supplement (PAS) to their respective
applications to obtain approval of the
new packaging configurations.
For new drug applications (NDAs) or
ANDAs for opioid analgesics that have
not yet been approved, FDA anticipates
that it would work with applicants at an
appropriate stage in the application
process to discuss blister packaging
configurations that should be included
as a part of the application to comply
with the REMS.
FDA is also considering whether a
staggered blister packaging requirement,
a conditional requirement, or both
would be appropriate. First, we are
considering whether it may be
appropriate to first require blister
packages be made available for the most
commonly prescribed IR opioid
analgesics for treatment of acute pain,
and then to require the blister packages
be made available for other, less
commonly prescribed products. In table
2, FDA has identified four opioid
analgesics, alone or in combination with
acetaminophen, formulated as seven
specific drugs at specific strengths, that
together account for almost 90 percent
of all NTS Rx.2
TABLE 2—NATIONALLY ESTIMATED NUMBER OF FIRST OPIOID ANALGESIC PRESCRIPTIONS DISPENSED TO PATIENTS WITH
NO OPIOID ANALGESIC PRESCRIPTION DISPENSED IN PREVIOUS 12 MONTHS FROM U.S. OUTPATIENT RETAIL PHARMACIES
Prescriptions dispensed as ‘‘New to Opioid Analgesic Patients’’ year 2017
Oral solid formulations
khammond on DSKBBV9HB2PROD with NOTICES
NTS Rx *
Hydrocodone 5 mg/APAP 325 mg ..........................
Tramadol 50 mg ......................................................
Oxycodone 5 mg/APAP 325 mg .............................
Codeine 30 mg/APAP 300 mg ................................
Hydrocodone 7.5 mg/APAP 325 mg .......................
Hydrocodone 10 mg/APAP 325 mg ........................
Oxycodone 5 mg .....................................................
All Others .................................................................
2 These data reflect recent dispensing patterns
and should not be interpreted as appropriate
starting doses for opioid-naı¨ve patients. The data
may include patients who are not, in fact, opioidnaı¨ve because they received opioids not captured in
VerDate Sep<11>2014
16:42 May 30, 2019
Jkt 247001
Percent
11.2M ................................
5.8M ..................................
4.7M ..................................
4.6M ..................................
2.7M ..................................
14M ...................................
1.3M ..................................
2.7M ..................................
Tabs
32
17
14
13
8
4
4
8
242M .................................
208M .................................
126M .................................
98M ...................................
69M ...................................
55M ...................................
46M ...................................
92M ...................................
the database (e.g., inpatient or emergency room
prescribing).
PO 00000
Frm 00056
Fmt 4703
Sfmt 4703
E:\FR\FM\31MYN1.SGM
31MYN1
Percent
26
22
13
10
7
6
5
10
25287
Federal Register / Vol. 84, No. 105 / Friday, May 31, 2019 / Notices
TABLE 2—NATIONALLY ESTIMATED NUMBER OF FIRST OPIOID ANALGESIC PRESCRIPTIONS DISPENSED TO PATIENTS WITH
NO OPIOID ANALGESIC PRESCRIPTION DISPENSED IN PREVIOUS 12 MONTHS FROM U.S. OUTPATIENT RETAIL PHARMACIES—Continued
Prescriptions dispensed as ‘‘New to Opioid Analgesic Patients’’ year 2017
Oral solid formulations
NTS Rx *
Total New to Opioids Prescriptions ..................
Percent
34.4M ................................
100
Tabs
937M .................................
Percent
100
khammond on DSKBBV9HB2PROD with NOTICES
Source: IQVIA, National Prescription Audit New to Brand (NPA NTB), year 2017. Extracted January 2019.
* New-to-Therapy Start Prescriptions (NTS Rx): Nationally estimated number of first opioid analgesic prescriptions dispensed to patients with
no opioid analgesic dispensed in previous 12 months.
Starting with these products could
help expedite the availability of blister
packs for products in a way that could
have the greatest public health impact,
based on current prescribing patterns.
We are continuing to consider the
potential public health consequences of
requiring these specific products to be
made available in fixed-quantity unit-ofuse blister packages, and, if so, in what
specific configurations, including the
precise number of units to be included
in each configuration. We are also
continuing to consider for which other
products, in addition to those identified
in table 2, it could be appropriate to
mandate blister packaging, and, if so, in
what specific configurations. We
recognize that the products in table 2 do
not represent the lowest available
strengths available for opioid analgesics.
For example, although hydrocodone 2.5
mg/325 mg acetaminophen combination
products are available, they accounted
for less than 0.1 percent of total
prescriptions dispensed to patients with
no previous opioid analgesic
prescription dispensed in the prior 12month period. Additionally, we note
that the proposed fixed-quantity unit-ofuse blister packages containing
hydrocodone 10 mg would have a
substantially higher MME than the other
products on this list in the same
quantities.
Furthermore, we are considering
whether it may be appropriate to impose
only a conditional mandate on approved
but discontinued products, whereby the
application holders of such products
would only need to seek approval to
produce blister package configurations
of those products if they decide to
reintroduce them to the market. This
would reduce the burden on both
application holders and FDA associated
with the production and evaluation of
blister package configurations for
products that may not ever be marketed.
Finally, we are considering what
measures may be appropriate to help
ensure that blister packaging required as
part of the OA REMS is sufficiently
available in the market. How could the
REMS be designed to set bright-line and
VerDate Sep<11>2014
16:42 May 30, 2019
Jkt 247001
evenhanded standards for the
availability of blister packages and
facilitate the Agency’s ability to monitor
compliance? For example, should FDA
consider requiring that a certain fraction
of marketed product be in blister
package configurations to encourage the
broader use of these products, or that
the application holder continually has
product available for sale in the
required blister package configurations?
Should FDA consider requiring that
application holders periodically report
on the production and uptake of their
blister package configurations?
D. Safety-Enhancing Benefits of FixedQuantity Blister Packaging for Opioid
Analgesics for Treatment of Acute Pain
The availability of fixed-quantity unitof-use blister packages for certain IR
opioid analgesics dispensed in the
outpatient setting could help encourage
and facilitate more rational ‘‘right-size’’
opioid analgesic prescribing by
providing a range of convenient options
to prescribers that corresponds well
with the expected needs of many
opioid-naı¨ve patients with acute pain.
The availability of such product
configurations could help ‘‘nudge’’
prescribers to more carefully consider
prescribing an amount of opioid
analgesics better matched to the
patient’s needs. We anticipate that
opioid prescribing guidelines, including
those required to be developed under
the SUPPORT Act, will provide
appropriate recommendations regarding
the use of any available blister
packaging configurations. Furthermore,
assuming these configurations are on
their drug formularies, prescribers could
readily select one of these
configurations in computer physician
order entry systems. Of course,
prescribers will continue to exercise
their clinical judgement to prescribe
opioid analgesics in the quantity
appropriate for a given patient; the
blister packaging configurations
contemplated in this notice would not
be required to be the only packaging
option available for these products.
PO 00000
Frm 00057
Fmt 4703
Sfmt 4703
In short, FDA anticipates that the
widespread availability of fixedquantity unit-of-use blister packaging
could play a significant role in reducing
overprescribing that leads to unused
opioid analgesics without impairing
access to opioid analgesics for patients
who need them. Unused opioid
medication is often retained and stored
in unsecure locations (Ref. 8) where it
can be accessed for prescription opioid
analgesic misuse and abuse. Reducing
the amount of unused opioid analgesics
reduces opportunities for misuse, abuse,
inappropriate access, or overdose, and
could reduce the development of new
addiction.
In addition, blister packaging could
help reduce the incidence of accidental
childhood poisoning. FDA expects that,
for blister packaging that may be
required under the OA REMS, each
tablet or capsule would be individually
protected with child-resistant
packaging,3 making it harder for a child
to be exposed to a toxic or lethal dose
compared to a child-resistant pill bottle
in the event that the child-resistant
packaging is defeated. That is, even if a
child accesses one of the tablets or
capsules (for example, from a broken
seal on a blister pack well), the
remaining tablets or capsules would
remain sealed. Furthermore, blister
packaging offers passive protection with
no further intervention required from an
adult to keep the packaging child
resistant. In contrast, when an adult
opens a child-resistant pill bottle, he or
she must take an additional step to close
the cap properly to prevent a child from
accessing the contents.
Blister packaging can also be designed
to include additional information
regarding the safe and appropriate use
of the drug. If this information were
printed on the blister packaging itself, it
could not be easily separated from the
drug nor could it be easily discarded. As
3 All drugs consisting in whole or in part of a
controlled substance in a dosage form intended for
oral administration must be in child-resistant
packaging (see 16 CFR 1700.14(a)(4), 16 CFR
1700.15; see generally 15 U.S.C. 1471–76, 16 CFR
part 1700).
E:\FR\FM\31MYN1.SGM
31MYN1
25288
Federal Register / Vol. 84, No. 105 / Friday, May 31, 2019 / Notices
khammond on DSKBBV9HB2PROD with NOTICES
such, blister packaging presents an
opportunity to educate patients each
time the drug is administered,
potentially improving patient
understanding of and compliance with
key information regarding appropriate
dosing, storage, disposal, or other
important information regarding the safe
and appropriate use of opioid
analgesics. FDA is continuing to
consider what information concerning
the safe and appropriate use of opioid
analgesics would be beneficial to
include on blister packaging.
Furthermore, blister packaging may
make it easier for a patient or caregiver
to identify whether a third party, such
as a member of the household or a
visitor, has inappropriately accessed the
opioid medication. While such
packaging would not thwart a
determined attempt to access the drug,
the patient or caregiver is more likely to
be alerted to inappropriate access of
opioids contained in a blister pack
compared to opioids contained in a
standard pill bottle. Additionally, the
fact that monitoring for inappropriate
access may be easier with certain blister
packaging (compared to a standard pill
bottle) may serve as a partial deterrent
to inappropriate access.
III. Request for Comments
FDA is soliciting comment from
stakeholders regarding the potential
blister packaging requirement described
in this notice. In addition to any other
aspects of or issues raised by the
potential mandate stakeholders may
care to comment upon, FDA is
interested in comments on the following
topics:
1. Comment on the potential safety
advantages and public health impact of
broadly available, fixed-quantity unit-ofuse blister packages of opioid analgesics
for treatment of acute pain in adults.
2. Comment on the specific IR opioid
analgesic drug products for which it
may be appropriate to require that
blister packaging be made available, as
well as the specific blister packaging
configuration(s) it may be appropriate to
require for each product or class of
products, including the number of
tablets or capsules to be included in the
configuration(s). Specifically, please
comment on the potential utility of the
5-, 10-, and 15-count configurations
discussed in section II.B.
3. Comment on what specific
information regarding the safe and
effective use of opioid analgesics would
be most beneficial to include in blister
packaging configurations of these
products.
4. Comment on possible negative
impacts of mandatory blister packaging,
VerDate Sep<11>2014
16:42 May 30, 2019
Jkt 247001
including any unintended
consequences. For example, what steps
could help ensure that the blister
packaging contemplated here would not
inadvertently lead to underprescribing
for patients who need opioid analgesics
to treat acute pain conditions and blister
packs being inappropriately prescribed
and/or dispensed to patients who may
have difficulty accessing drugs
contained in blister packaging?
5. Comment on the potential
challenges, including technical and
logistical challenges, with the potential
blister packaging requirement. What
factors could impact application
holders’ ability to produce blister
packaging of the type described in this
notice?
6. How much time would be needed
for application holders to submit prior
approval supplements for blister
packaging that would satisfy the
proposed REMS requirements discussed
in section II.C? How much time would
be needed for an application holder to
develop REMS-compliant packaging and
manufacture sufficient quantities to
perform the stability and other product
quality testing necessary to support the
approval of a PAS, and how much time
would be needed to perform such
testing? How much time after approval
of a PAS would be needed for an
application holder to manufacture and
make the product commercially
available?
7. Comment on the idea of
implementing a blister packaging
mandate in a staggered fashion,
targeting the products most commonly
prescribed to treat acute pain first, as
well as the idea of imposing a
conditional mandate for discontinued
products. Are there other ways the
Agency could consider staggering
implementation of this requirement to
minimize burden on manufacturers and
other stakeholders, while maximizing
the public health benefit?
8. Comment on how the OA REMS
modification could be designed and
implemented to help ensure that
required blister packaging is sufficiently
available. Comment on the impact of
any opioid analgesic blister packaging
requirement on other stakeholders,
including prescribers, payers, and
pharmacies. What steps could be taken
to help encourage uptake and mitigate
any adverse impacts associated with
such a mandate?
9. As noted, FDA recognizes that the
approach described in this notice is
only one possible use of the Agency’s
REMS authority concerning packaging.
Comment on other possible uses of this
authority.
PO 00000
Frm 00058
Fmt 4703
Sfmt 4703
IV. References
The following references marked with
an asterisk (*) are on display at the
Dockets Management Staff (see
ADDRESSES) and are available for
viewing by interested persons between
9 a.m. and 4 p.m., Monday through
Friday; they also are available
electronically at https://
www.regulations.gov. References
without asterisks are not on public
display at https://www.regulations.gov
because they have copyright restriction.
Some may be available at the website
address, if listed. References without
asterisks are available for viewing only
at the Dockets Management Staff. FDA
has verified the website addresses, as of
the date this document publishes in the
Federal Register, but websites are
subject to change over time.
* 1. Scholl, L., Seth, P., Kariisa, M., et al.,
‘‘Drug And Opioid-Involved Overdose
Deaths—United States, 2013–2017.’’
Morbidity and Mortality Weekly Report
(MMWR), vol. 67, pp. 67:1419–1427,
2019 (available at https://dx.doi.org/
10.15585/mmwr.mm675152e1).
* 2. Mundkur, M., ‘‘Background and
Rationale for the Development of OpioidSparing and Opioid-Replacement
Drugs.’’ Anesthetic and Analgesic Drug
Products Advisory Committee Meeting.
Presented on November 15, 2018.
Available at: https://www.fda.gov/
downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/
AnestheticAndAnalgesicDrugProducts
AdvisoryCommittee/UCM626666.pdf.
Accessed April 1, 2019.
* 3. Substance Abuse and Mental Health
Services Administration (2018), ‘‘Key
Substance Use and Mental Health
Indicators in the United States: Results
from the 2017 National Survey on Drug
Use and Health’’ (HHS Publication No.
SMA 18–5068, NSDUH Series H–53).
Rockville, MD: Center for Behavioral
Health Statistics and Quality, Substance
Abuse and Mental Health Services
Administration (available at https://
www.samhsa.gov/data/).
4. Carlson, R., Nahhas, R., Martins, S., et al.,
‘‘Predictors of Transition to Heroin Use
Among Initially Non-Opioid Dependent
Illicit Pharmaceutical Opioid Users: A
Natural History Study.’’ Drug and
Alcohol Dependence, vol. 160, pp. 127–
134, 2016.
5. Harocopos, A., Allen, B., and Paone, D.,
‘‘Circumstances and Contexts of Heroin
Initiation Following Non-Medical Opioid
Analgesic Use in New York City.’’
International Journal of Drug Policy, vol.
28, pp. 106–112, 2016.
6. Surratt, H., Kurtz, S., Buttram, M., et al.,
‘‘Heroin Use Onset Among Nonmedical
Prescription Opioid Users in the Club
Scene.’’ Drug and Alcohol Dependence,
vol. 179, pp. 131–138, 2017.
7. Lankenau, S., Teti, M., Silva, K., et al.,
‘‘Initiation into Prescription Opioid
Misuse Among Young Injection Drug
E:\FR\FM\31MYN1.SGM
31MYN1
khammond on DSKBBV9HB2PROD with NOTICES
Federal Register / Vol. 84, No. 105 / Friday, May 31, 2019 / Notices
Users.’’ International Journal of Drug
Policy, vol. 33, pp. 23:37–44, 2012.
8. Bicket, M., Long, J., Pronovost, P., et al.,
‘‘Prescription Opioid Analgesics
Commonly Used After Surgery: A
Systematic Review.’’ JAMA Surgery, vol.
152, pp. 1066–1071, 2017 (available at
doi:10.1001/jamasurg.2017.0831,
published online August 2, 2017).
9. Howard, R., Fry, B., Gunaseelan, V., et al.,
‘‘Association of Opioid Prescribing with
Opioid Consumption After Surgery in
Michigan.’’ JAMA Surgery, vol. 154, p.
e184234, 2019 (available at doi:10.001/
jamasurg.2018.4234, published online
November 7, 2018).
10. Thiels, C., Ubl, D., Yost, K., et al.,
‘‘Results of a Prospective, Multicenter
Initiative Aimed at Developing OpioidPrescribing Guidelines After Surgery.’’
Annals of Surgery, vol. 268, pp. 457–468,
2018 (available at doi:10.1097/
SLA.0000000000002919).
11. Mundkur, M., Meyer, T., Menzin, T., et
al., ‘‘Estimating the Optimal Duration of
Initial Opioid Analgesic Prescriptions in
Post-Surgical Populations Using FDA’s
Sentinel Distributed Database.’’
Pharmacoepidemiology and Drug Safety,
S2: Abstracts of the 34th International
Conference on Pharmacoepidemiology &
Therapeutic Risk Management, Abstract
#392, vol. 27, p. 181 (available at
doi:10.1002/pds.4629).
12. Steiner, C.A., Karaca, Z., Moore, B.J., et
al., ‘‘Surgeries in Hospital-Based
Ambulatory Surgery and Hospital
Inpatient Settings, 2014.’’ HCUP
Statistical Brief #223, 2017 (available at
www.hcup-us.ahrq.gov/reports/
statbriefs/sb223-Ambulatory-InpatientSurgeries-2014.pdf).
13. Mundkur, M., unpublished data.
* 14. Mundkur, M., Franklin, J., Abdia, Y., et
al., ‘‘Days’ Supply of Initial Opioid
Analgesic Prescriptions and Additional
Fills for Acute Pain Conditions Treated
in the Primary Care Setting—United
States, 2014.’’ Morbidity and Mortality
Weekly Report, vol. 68, pp. 140–143,
2019.
* 15. Dowel, D., Haegerich, T., and Chou, R.,
‘‘CDC Guideline for Prescribing Opioids
for Chronic Pain—United States, 2016.’’
Morbidity and Mortality Recommended
Weekly Report, vol. 65(1), pp. 1–49,
2016.
16. Opiate Prescribing Engagement Network,
‘‘Emergency Department Prescribing
Recommendations’’ (available at https://
michigan-open.org/emergencydepartment-prescribingrecommendations/), accessed January 5,
2019.
17. Ohio Opiate Action Team, ‘‘Ohio
Guidelines for Emergency and Acute
Care Facility Opioid and Other
Controlled Substances (OOCS)
Prescribing’’ (available at https://
mha.ohio.gov/Portals/0/assets/
Initiatives/GCOAT/Guidelines-ED-AcuteCare.pdf), accessed January 5, 2019.
18. New York City Emergency Department,
‘‘Discharge Opioid Prescribing
Guidelines’’ (available at https://
www1.nyc.gov/assets/doh/downloads/
VerDate Sep<11>2014
16:42 May 30, 2019
Jkt 247001
pdf/basas/opioid-prescribingguidelines.pdf), accessed January 5,
2019.
19. Thiels, C., Ubl, D., Yost, K., et al.,
‘‘Results of a Prospective, Multicenter
Initiative Aimed at Developing OpioidPrescribing Guidelines After Surgery.’’
Annals of Surgery, vol. 268, pp. 457–468,
2018.
20. The Regents of the University of
Michigan, ‘‘Opioid Prescribing
Recommendations for Surgery’’
(available at https://
opioidprescribing.info/), last updated
April 11, 2019, accessed April 17, 2019.
21. Overton, H., Hanna, M., Bruhn, W., et al.,
‘‘Opioid-Prescribing Guidelines for
Common Surgical Procedures: An Expert
Panel Consensus.’’ Journal of the
American College of Surgeons, vol. 227,
pp. 411–418, 2018.
Dated: May 24, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019–11283 Filed 5–30–19; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
Center for Scientific Review; Amended
Notice of Meeting
Notice is hereby given of a change in
the meeting of the Lung Cellular,
Molecular, and Immunobiology Study
Section, June 4, 2019, 08:00 a.m. to June
5, 2019, 03:00 p.m., Hilton Baltimore
Inner Harbor, 401 W Pratt Street,
Baltimore, MD 21201, which was
published in the Federal Register on
April 16, 2019, 84 FR PG 15624.
The meeting location is being changed
to Hilton Baltimore Inner Harbor, 401 W
Pratt Street, Baltimore, MD 21201.
Meeting dates remain the same. The
meeting is closed to the public.
Dated: May 24, 2019.
Natasha M. Copeland,
Program Analyst, Office of Federal Advisory
Committee Policy.
[FR Doc. 2019–11328 Filed 5–30–19; 8:45 am]
BILLING CODE 4140–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Institutes of Health
National Institute of Mental Health;
Notice of Closed Meeting
Pursuant to section 10(d) of the
Federal Advisory Committee Act, as
amended, notice is hereby given of the
following meetings.
The meeting will be closed to the
public in accordance with the
PO 00000
Frm 00059
Fmt 4703
Sfmt 4703
25289
provisions set forth in sections
552b(c)(4) and 552b(c)(6), Title 5 U.S.C.,
as amended. The grant applications and
the discussions could disclose
confidential trade secrets or commercial
property such as patentable material,
and personal information concerning
individuals associated with the grant
applications, the disclosure of which
would constitute a clearly unwarranted
invasion of personal privacy.
Name of Committee: National Institute of
Mental Health Special Emphasis Panel;
NIMH Pilot Effectiveness Trials for
Treatment, Preventive, and Services
Interventions (R34).
Date: June 18, 2019.
Time: 11:00 a.m. to 5:00 p.m.
Agenda: To review and evaluate grant
applications.
Place: National Institutes of Health,
Neuroscience Center Building (NSC), 6001
Executive Boulevard, Rockville, MD 20852
(Virtual Meeting).
Contact Person: Marcy Ellen Burstein,
Ph.D., Scientific Review Officer, Division of
Extramural Activities, National Institute of
Mental Health, NIH, Neuroscience Center,
6001 Executive Blvd., Room 6143, MSC 9606,
Bethesda, MD 20892, 301–443–9699,
bursteinme@mail.nih.gov.
Name of Committee: National Institute of
Mental Health Special Emphasis Panel;
NCDDG & First in Human and Early Stage
Clinical Trials for Psychiatric Disorders.
Date: June 18, 2019.
Time: 3:30 p.m. to 5:30 p.m.
Agenda: To review and evaluate grant
applications.
Place: National Institutes of Health,
Neuroscience Center Building (NSC), 6001
Executive Boulevard, Rockville, MD 20852
(Virtual Meeting).
Contact Person: Vinod Charles, Ph.D.,
Scientific Review Officer, Division of
Extramural Activities, National Institute of
Mental Health, NIH, Neuroscience Center,
6001 Executive Blvd., Room 6151, MSC 9606,
Bethesda, MD 20892, 301–443–1606,
charlesvi@mail.nih.gov.
Name of Committee: National Institute of
Mental Health Special Emphasis Panel;
Building in vivo Preclinical Assays of Circuit
Engagement for Application in Therapeutic
Development (R01).
Date: June 25, 2019.
Time: 12:00 p.m. to 3:00 p.m.
Agenda: To review and evaluate grant
applications.
Place: National Institutes of Health,
Neuroscience Center Building (NSC), 6001
Executive Boulevard, Rockville, MD 20852
(Virtual Meeting).
Contact Person: Rebecca Steiner Garcia,
Ph.D., Scientific Review Officer, Division of
Extramural Activities, National Institute of
Mental Health, NIH, Neuroscience Center,
6001 Executive Blvd., Room 6149, MSC 9608,
Bethesda, MD 20892, 301–443–4525,
steinerr@mail.nih.gov.
(Catalogue of Federal Domestic Assistance
Program No. 93.242, Mental Health Research
Grants, National Institutes of Health, HHS)
E:\FR\FM\31MYN1.SGM
31MYN1
]]>Agencies
[Federal Register Volume 84, Number 105 (Friday, May 31, 2019)]
[Notices]
[Pages 25283-25289]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-11283]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2019-N-1845]
Fixed-Quantity Unit-of-Use Blister Packaging for Certain
Immediate-Release Opioid Analgesics for Treatment of Acute Pain;
Establishment of a Public Docket; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; establishment of a public docket; request for comments.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or the Agency) is
announcing the establishment of a docket to solicit public comment on a
potential modification to the Opioid Analgesic Risk Evaluation and
Mitigation Strategy (OA REMS) to require that certain solid, oral
dosage forms of immediate-release (IR) opioid analgesics commonly
prescribed for treatment of acute pain be made available in fixed-
quantity unit-of-use blister packaging for outpatient dispensing. This
could reduce the amount of unused opioid analgesics, thereby reducing
opportunities for misuse, abuse, inappropriate access, and overdose,
and possibly reducing the development of new opioid addiction.
DATES: Submit either electronic or written comments by July 30, 2019.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before July 30, 2019. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of July 30, 2019. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are postmarked or the delivery service
acceptance receipt is on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2019-N-1845 for ``Fixed-Quantity Unit-of-Use Blister Packaging for
Certain Immediate-Release Opioid Analgesics for Treatment of Acute
Pain; Establishment of a Public Docket; Request for Comments.''
Received comments, those filed in a timely manner (see ADDRESSES), will
be placed in the docket and, except for those submitted as
``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Patrick Raulerson, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6260, Silver Spring, MD 20993, 301-796-
3522, [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
In 2017, opioid-involved overdoses killed more than 47,000 people,
with
[[Page 25284]]
more than a third of those deaths involving prescription opioids (Ref.
1). The volume of prescription opioid analgesics dispensed has
decreased from a peak in 2012 and continues to trend downward. However,
opioid analgesics continue to be prescribed at a high rate--an
estimated 196 million retail prescriptions, resulting in an estimated
13 billion units (e.g., tablets or capsules) dispensed in 2017 from
U.S. outpatient retail pharmacies (Ref. 2). Approximately 89 percent of
people who report misuse or abuse of prescription opioid pain relievers
state they obtained their most recently used drugs from their own
prescriptions or from a friend or relative (Ref. 3). In addition, many
people who begin with misuse or abuse of prescription opioids
transition to illicit substances (Refs. 4 to 7).
Accordingly, FDA's efforts to address the opioid crisis will
continue to include a focus on encouraging rational, ``right-size''
prescribing of opioid analgesics. This includes efforts aimed at
reducing both the number of people unnecessarily exposed to opioid
analgesics (either through legitimate prescriptions or due to
inappropriate access) and encouraging healthcare providers to prescribe
amounts that better reflect the quantity expected to meet the needs of
the patient with acute pain. At the same time, we must help ensure
appropriate access to opioid analgesics to address the medical needs of
patients experiencing acute pain severe enough to require opioid
analgesic treatment.
The Substance Use-Disorder Prevention that Promotes Opioid Recovery
and Treatment for Patients and Communities Act (SUPPORT Act), signed
into law on October 24, 2018, provides FDA several new authorities to
address the opioid crisis. The new law allows FDA to require certain
packaging and disposal systems under a REMS for opioids and other drugs
that pose a serious risk of abuse or overdose if, among other things,
FDA determines that such packaging or disposal system may mitigate such
risks (see section 505-1(e)(4) of the Federal Food, Drug, and Cosmetic
Act (FD&C Act) (21 U.S.C. 355-1(e)(4))). The purpose of this notice is
to seek public comment on application of this new authority, including
the potential application of this authority to require under the OA
REMS that certain solid oral dosage forms of IR opioid analgesics
commonly used to treat acute pain be made available in fixed-quantity
unit-of-use blister packaging for outpatient dispensing.
FDA recognizes that the fixed-quantity unit-of-use blister
packaging requirement the Agency is considering as part of the OA REMS
is just one possible application of FDA's new authorities related to
packaging and disposal. We are considering, and invite comment on,
other potential mandates, including mail-back pouches or other safe
disposal options. Furthermore, we actively encourage drug manufacturers
and others to innovate in this space. We are aware of many promising
packaging and disposal technologies that could have a positive impact
on reducing misuse, abuse, inappropriate access, accidental poisoning,
or overdose, or could otherwise facilitate the safe and appropriate use
of prescription opioid analgesics. We believe that the potential
packaging requirement outlined here could be a significant and readily
achievable step towards improving the safe use of opioids, one that
could be supplemented in the future by other safety-enhancing measures.
FDA is establishing this docket to solicit input from stakeholders
on all aspects of this potential requirement under the OA REMS,
including comments on specific questions posed in section III.
II. Fixed-Quantity Unit-of-Use Blister Packaging for Certain IR Opioid
Analgesics for Treatment of Acute Pain
In this section, we describe data suggesting that many patients who
are prescribed an opioid analgesic to treat acute pain use
substantially fewer units of the drug than they receive, resulting in
millions of excess opioid analgesic tablets and capsules dispensed
every year. We then describe a potential requirement, as part of the OA
REMS, that fixed-quantity unit-of-use blister packs for certain IR
opioid analgesics be made available to be dispensed in the outpatient
setting. We discuss how these proposed new packaging configurations
could encourage more appropriate prescribing, reducing the amount of
unused opioid analgesics available for misuse, abuse, inappropriate
access, and accidental poisoning or overdose. We also discuss other
potential safety benefits associated with blister packs.
A. Actual Opioid Use Compared to Prescribed Amounts for Common Surgical
Procedures and Other Conditions That Cause Acute Pain
FDA has reviewed published studies that compared the amount of
opioid analgesics patients received to treat their acute pain with
their reported actual use after several common surgical procedures.
Most of these studies focused on opioid-na[iuml]ve adults. Opioid-
na[iuml]ve is defined in various ways across the studies; one common
definition is a patient who filled no opioid analgesic prescriptions in
the prior 12 months. We also analyzed patterns of additional fills
after an initial opioid analgesic prescription fill for acute pain in
post-surgical and primary care settings. We define an additional fill
as a second prescription fill for an opioid analgesic in a short period
after the first fill.
In the post-surgical setting, following several common minimally or
less-invasive surgical procedures,\1\ most opioid-na[iuml]ve adults who
used an opioid analgesic appeared to use only 1 to 3 days' worth, or 15
or fewer, opioid analgesic tablets or capsules despite receiving
prescriptions exceeding the number they used (Refs. 8 to 11). Patients
reported that they usually retain these unused tablets or capsules and
store them in unsecure locations (Ref. 8), providing opportunities for
later misuse, abuse, inappropriate access, and accidental poisoning or
overdose.
---------------------------------------------------------------------------
\1\ These surgical procedures included dermatologic surgery,
carotid endarterectomy, inguinal/femoral hernia repair, breast
lumpectomy, partial mastectomy, parathyroidectomy, thyroidectomy,
vaginal or laparoscopic hysterectomy, laparoscopic cholecystectomy,
laparoscopic colectomy, laparoscopic appendectomy, small-bowel
resection/enterolysis, minimally-invasive prostatectomy, knee
arthroscopic meniscectomy, tooth extraction, bunionectomy, carpal
tunnel release, ovarian cancer cytoreduction, breast lumpectomy, and
arteriovenous fistula creation.
---------------------------------------------------------------------------
For example, after a less-invasive cholecystectomy, the median
number of opioid analgesic tablets prescribed to treat pain was 18,
even though 75 percent of patients used 9 or fewer tablets (each tablet
equivalent to an oxycodone 5 milligram (mg) dose). Of the 75 percent of
patients who used 9 or fewer tablets, 35 percent reported using no
opioids (Ref. 10). In an FDA analysis of surgical procedures in opioid-
na[iuml]ve adults, our model estimated that less than 20 percent of
patients undergoing laparoscopic cholecystectomy might need an
additional fill if they were given a 1-day supply of an opioid
analgesic, but the median days actually supplied to patients was 4,
with a median of 30 tablets per prescription filled (Ref. 11).
The unused tablets from each opioid analgesic prescription for a
common surgical procedure such as cholecystectomy--there were an
estimated 950,000 cholecystectomies in community hospitals in the
United States in 2014 (Ref. 12)--contribute significantly to the number
of unused tablets available for misuse, abuse,
[[Page 25285]]
inappropriate access, and accidental poisonings or overdose. In our
analyses of opioid analgesic prescription fills after surgical
procedures and published studies in which patients were asked about
their opioid analgesic use after surgical procedures, we also found
that about 30 percent of patients either never filled their
prescriptions or filled them but did not actually consume any of the
tablets or capsules following several types of minimally or less-
invasive surgical procedures (e.g., laparoscopic cholecystectomy,
laparoscopic hysterectomy, laparoscopic appendectomy) (Refs. 10 and
13).
We observed a similar pattern of prescribing more than patients
appeared to use for several other common non-surgical acute pain
conditions in the primary care setting. For example, for headaches,
muscular strains and sprains, and certain forms of acute back pain, in
our modeling of additional fill patterns, most patients could be
expected to only need an opioid analgesic for up to 3 days, but they
often received enough doses to treat pain for a significantly longer
period (Ref. 14).
B. Proposal: 5-, 10-, and 15-Count Blister Packages of Certain IR
Opioid and IR Opioid/Acetaminophen Products
As discussed above, we have found that for many common, minimally
or less-invasive surgical procedures and some common acute pain
conditions treated in the primary care setting for which opioid
analgesics are prescribed, we expect most opioid-na[iuml]ve adult
patients to use significantly fewer tablets or capsules than the
average prescription has historically provided. Most of these patients
appeared to use an opioid for 1 to 3 days and used 15 or fewer tablets
or capsules when they used an opioid analgesic to treat their pain.
Accordingly, we anticipate that if 5-, 10-, and 15-count blister
package configurations of certain IR opioid analgesics commonly used
for treatment of acute pain were made available, one or more of these
options could be expected to meet the needs of most opioid-na[iuml]ve
adults who require opioid therapy following many common minimally or
less-invasive procedures and other acute pain conditions for which
opioid analgesics are prescribed. We further anticipate that
utilization of these fixed-quantity unit-of use blister package
configurations would substantially reduce the quantity of opioid
analgesics dispensed per prescription compared to the status quo. Table
1 below compares the morphine milligram equivalent (MME) of 5-, 10-,
and 15-count packaging of seven commonly prescribed opioid analgesic
products to the mean MME and mean number of tablets per ``new-to-
therapy start prescriptions'' (NTS Rx) dispensed in 2017. This table
illustrates the potential for utilization of fixed-quantity unit-of-use
blister packages to substantially reduce the amount of opioid
analgesics prescribed for opioid-na[iuml]ve patients receiving
prescriptions for seven commonly prescribed products.
Table 1--5-, 10-, and 15-Count Packages by MME Content/Package Compared to Mean MME and Mean Tablets per NTS Rx
Dispensed in 2017
----------------------------------------------------------------------------------------------------------------
MME per package 2017 NTS Rx
--------------------------------------------------------------------------------
Oral tablets 5-Count (1 10-Count (2 15-Count (3 Mean MME/NTS Mean tabs/NTS
days *) days *) days *) Rx Rx
----------------------------------------------------------------------------------------------------------------
Hydrocodone 5 mg/APAP 325 mg... 25 50 75 108 22
Tramadol 50 mg................. 25 50 75 180 36
Oxycodone 5 mg/APAP 325 mg..... 37.5 75 112.5 199 27
Codeine 30 mg/APAP 300 mg...... 22.5 45 67.5 96 21
Hydrocodone 7.5 mg/APAP 325 mg. 37.5 75 112.5 192 26
Hydrocodone 10 mg/APAP 325 mg.. 50 100 150 393 39
Oxycodone 5 mg................. 37.5 75 112.5 261 35
----------------------------------------------------------------------------------------------------------------
New to Therapy Start Prescriptions (NTS Rx): Nationally estimated number of first opioid analgesic
prescriptions dispensed to patients with no opioid analgesic dispensed in previous 12 months. Source: IQVIA,
National Prescription Audit New To Brand (NPA NTB), year 2017. Extracted January 2019.
* Days' supply does not correlate well with the number of units to package, estimated days supply based on
around-the-clock dosing of 1-2 tablets every 4-6 hours PRN.
MME Estimates based on CMS's Opioid Oral Morphine Milligram Equivalent (MME) Conversion Factors. Accessed at
https://www.cms.gov/Medicare/Prescription-Drug-Coverage/PrescriptionDrugCovContra/Downloads/Opioid-Morphine-EQ-Conversion-Factors-Aug-2017.pdf.
Our analyses revealed that the number of days for which opioids are
prescribed or used does not correlate well with a specific number of
tablets or capsules per day, as what is considered an appropriate
amount of an opioid analgesic for a day's worth of treatment varies
across procedures and patients. This type of variation is reflected in
the labeling of IR opioid analgesics, which describes the need to
individualize dosing regimens based on patient treatment goals.
Accordingly, we are considering requiring that applicants or
application holders make available 5-, 10-, and 15-count blister pack
configurations without prespecifying that any of these given
configurations constitutes an appropriate amount of opioid analgesic
for a specified duration, such as a specific number of days of
treatment. Rather, we anticipate that prescribers would use their
expertise and consult appropriate prescribing guidelines to determine
which, if any, of the newly available blister packages is appropriate
for their patients on a case-by-case basis.
We note that several existing prescribing guidelines recommend
outpatient days of treatment or quantity of tablets or capsules for
common minimally or less-invasive surgical procedures or acute pain
conditions treated in primary care and emergency department settings
that are in line with our proposal for 5-, 10-, and 15-count packages
of certain IR opioid analgesics (Refs. 15 to 21). Additionally, section
3002 of the SUPPORT Act requires FDA to develop evidence-based opioid
analgesic prescribing guidelines for the indication-specific treatment
of acute pain only for the relevant therapeutic areas where such
guidelines do not exist. These guidelines, once available, should help
to encourage more appropriate, ``right-sized'' opioid analgesic
prescribing. We anticipate that these prescribing guidelines, as well
as prescribing guidelines developed by others, would provide
appropriate recommendations regarding the use of blister pack
configurations made available pursuant to an OA REMS packaging
requirement, facilitating
[[Page 25286]]
prescriber understanding and uptake of such product packaging
configurations.
C. New Packaging/Disposal REMS Element
Section 3032 of the SUPPORT Act amends FDA's REMS authority.
Specifically, as a part of a REMS, FDA may now require that a drug for
which there is a serious risk of an adverse event occurring from abuse
or overdose be made available for dispensing to certain patients in
unit-dose packaging, packaging that provides a set duration, or another
packaging system that FDA determines may mitigate such serious risk (21
U.S.C. 355-1(e)(4)). FDA may also require that such drugs be dispensed
to certain patients with a safe disposal packaging or safe disposal
system for purposes of rendering drugs non-retrievable if FDA
determines that such safe disposal packaging or system may mitigate a
serious risk of an adverse event occurring from abuse or overdose of
the drug and is sufficiently available (see section 505-1(e)(4) of the
FD&C Act).
A packaging or disposal requirement under this provision is
applicable to prescription drugs that are the subject of applications
approved under section 505(b) of the FD&C Act (21 U.S.C. 355(b)) or
section 351 of the Public Health Service Act (42 U.S.C. 242), as well
as drugs that are the subject of abbreviated new drug applications
(ANDAs) approved under section 505(j) of the FD&C Act if a packaging or
disposal requirement is required for the applicable listed drug (see
section 505(i)(1)(B) of the FD&C Act). The law provides that FDA will
permit packaging systems and safe disposal packaging or safe disposal
systems for drugs that are the subject of ANDAs that are different from
those required for the applicable listed drugs (see section
505(i)(2)(B) of the FD&C Act). FDA must take into consideration the
burden on patients' access to the drug and the burden on the healthcare
delivery system that would be associated with any such packaging or
disposal requirement and must consult with other relevant Federal
Agencies with authorities over drug disposal packaging in certain
circumstances (see section 505-1(e)(4) of the FD&C Act).
FDA is contemplating using this new authority to require fixed-
quantity unit-of-use blister packaging for certain IR opioid analgesics
under the OA REMS, as described in this notice. For purposes of
soliciting comments, FDA is considering the following general process
for any packaging requirement under the OA REMS.
First, for already-approved opioid analgesic products, FDA would
notify the application holders by letter that the Agency is requiring a
modification to the OA REMS to include a packaging requirement. The
notification letter would set forth details of the required
modification, including the specific products subject to the new
requirement, the number of blister packaging configurations required
for each product and the number of units in each, key information
regarding safe and effective use of opioid analgesics to be printed on
the blister packaging, and other data and information needed for FDA to
review and approve new blister package configurations (e.g., stability
data).
Second, the application holders subject to the OA REMS would submit
a proposed REMS modification within 120 days or such other reasonable
time as FDA specifies. FDA anticipates that the proposed OA REMS
modification would include all necessary specifications and timeframes
for the blister packages. FDA would expect for the notification
letters, the proposed REMS modifications, and the REMS approval to be
sufficiently general that they are uniform across all affected
application holders and products, to the extent possible.
Third, the application holders of products that are subject to the
blister packaging requirement would individually submit a prior
approval supplement (PAS) to their respective applications to obtain
approval of the new packaging configurations.
For new drug applications (NDAs) or ANDAs for opioid analgesics
that have not yet been approved, FDA anticipates that it would work
with applicants at an appropriate stage in the application process to
discuss blister packaging configurations that should be included as a
part of the application to comply with the REMS.
FDA is also considering whether a staggered blister packaging
requirement, a conditional requirement, or both would be appropriate.
First, we are considering whether it may be appropriate to first
require blister packages be made available for the most commonly
prescribed IR opioid analgesics for treatment of acute pain, and then
to require the blister packages be made available for other, less
commonly prescribed products. In table 2, FDA has identified four
opioid analgesics, alone or in combination with acetaminophen,
formulated as seven specific drugs at specific strengths, that together
account for almost 90 percent of all NTS Rx.\2\
---------------------------------------------------------------------------
\2\ These data reflect recent dispensing patterns and should not
be interpreted as appropriate starting doses for opioid-na[iuml]ve
patients. The data may include patients who are not, in fact,
opioid-na[iuml]ve because they received opioids not captured in the
database (e.g., inpatient or emergency room prescribing).
Table 2--Nationally Estimated Number of First Opioid Analgesic Prescriptions Dispensed to Patients With No
Opioid Analgesic Prescription Dispensed in Previous 12 Months From U.S. Outpatient Retail Pharmacies
----------------------------------------------------------------------------------------------------------------
Prescriptions dispensed as ``New to Opioid Analgesic Patients'' year 2017
Oral solid formulations -----------------------------------------------------------------------------
NTS Rx * Percent Tabs Percent
----------------------------------------------------------------------------------------------------------------
Hydrocodone 5 mg/APAP 325 mg...... 11.2M................ 32 242M................ 26
Tramadol 50 mg.................... 5.8M................. 17 208M................ 22
Oxycodone 5 mg/APAP 325 mg........ 4.7M................. 14 126M................ 13
Codeine 30 mg/APAP 300 mg......... 4.6M................. 13 98M................. 10
Hydrocodone 7.5 mg/APAP 325 mg.... 2.7M................. 8 69M................. 7
Hydrocodone 10 mg/APAP 325 mg..... 14M.................. 4 55M................. 6
Oxycodone 5 mg.................... 1.3M................. 4 46M................. 5
All Others........................ 2.7M................. 8 92M................. 10
-----------------------------------------------------------------------------
[[Page 25287]]
Total New to Opioids 34.4M................ 100 937M................ 100
Prescriptions.
----------------------------------------------------------------------------------------------------------------
Source: IQVIA, National Prescription Audit New to Brand (NPA NTB), year 2017. Extracted January 2019.
* New-to-Therapy Start Prescriptions (NTS Rx): Nationally estimated number of first opioid analgesic
prescriptions dispensed to patients with no opioid analgesic dispensed in previous 12 months.
Starting with these products could help expedite the availability
of blister packs for products in a way that could have the greatest
public health impact, based on current prescribing patterns.
We are continuing to consider the potential public health
consequences of requiring these specific products to be made available
in fixed-quantity unit-of-use blister packages, and, if so, in what
specific configurations, including the precise number of units to be
included in each configuration. We are also continuing to consider for
which other products, in addition to those identified in table 2, it
could be appropriate to mandate blister packaging, and, if so, in what
specific configurations. We recognize that the products in table 2 do
not represent the lowest available strengths available for opioid
analgesics. For example, although hydrocodone 2.5 mg/325 mg
acetaminophen combination products are available, they accounted for
less than 0.1 percent of total prescriptions dispensed to patients with
no previous opioid analgesic prescription dispensed in the prior 12-
month period. Additionally, we note that the proposed fixed-quantity
unit-of-use blister packages containing hydrocodone 10 mg would have a
substantially higher MME than the other products on this list in the
same quantities.
Furthermore, we are considering whether it may be appropriate to
impose only a conditional mandate on approved but discontinued
products, whereby the application holders of such products would only
need to seek approval to produce blister package configurations of
those products if they decide to reintroduce them to the market. This
would reduce the burden on both application holders and FDA associated
with the production and evaluation of blister package configurations
for products that may not ever be marketed.
Finally, we are considering what measures may be appropriate to
help ensure that blister packaging required as part of the OA REMS is
sufficiently available in the market. How could the REMS be designed to
set bright-line and evenhanded standards for the availability of
blister packages and facilitate the Agency's ability to monitor
compliance? For example, should FDA consider requiring that a certain
fraction of marketed product be in blister package configurations to
encourage the broader use of these products, or that the application
holder continually has product available for sale in the required
blister package configurations? Should FDA consider requiring that
application holders periodically report on the production and uptake of
their blister package configurations?
D. Safety-Enhancing Benefits of Fixed-Quantity Blister Packaging for
Opioid Analgesics for Treatment of Acute Pain
The availability of fixed-quantity unit-of-use blister packages for
certain IR opioid analgesics dispensed in the outpatient setting could
help encourage and facilitate more rational ``right-size'' opioid
analgesic prescribing by providing a range of convenient options to
prescribers that corresponds well with the expected needs of many
opioid-na[iuml]ve patients with acute pain. The availability of such
product configurations could help ``nudge'' prescribers to more
carefully consider prescribing an amount of opioid analgesics better
matched to the patient's needs. We anticipate that opioid prescribing
guidelines, including those required to be developed under the SUPPORT
Act, will provide appropriate recommendations regarding the use of any
available blister packaging configurations. Furthermore, assuming these
configurations are on their drug formularies, prescribers could readily
select one of these configurations in computer physician order entry
systems. Of course, prescribers will continue to exercise their
clinical judgement to prescribe opioid analgesics in the quantity
appropriate for a given patient; the blister packaging configurations
contemplated in this notice would not be required to be the only
packaging option available for these products.
In short, FDA anticipates that the widespread availability of
fixed-quantity unit-of-use blister packaging could play a significant
role in reducing overprescribing that leads to unused opioid analgesics
without impairing access to opioid analgesics for patients who need
them. Unused opioid medication is often retained and stored in unsecure
locations (Ref. 8) where it can be accessed for prescription opioid
analgesic misuse and abuse. Reducing the amount of unused opioid
analgesics reduces opportunities for misuse, abuse, inappropriate
access, or overdose, and could reduce the development of new addiction.
In addition, blister packaging could help reduce the incidence of
accidental childhood poisoning. FDA expects that, for blister packaging
that may be required under the OA REMS, each tablet or capsule would be
individually protected with child-resistant packaging,\3\ making it
harder for a child to be exposed to a toxic or lethal dose compared to
a child-resistant pill bottle in the event that the child-resistant
packaging is defeated. That is, even if a child accesses one of the
tablets or capsules (for example, from a broken seal on a blister pack
well), the remaining tablets or capsules would remain sealed.
Furthermore, blister packaging offers passive protection with no
further intervention required from an adult to keep the packaging child
resistant. In contrast, when an adult opens a child-resistant pill
bottle, he or she must take an additional step to close the cap
properly to prevent a child from accessing the contents.
---------------------------------------------------------------------------
\3\ All drugs consisting in whole or in part of a controlled
substance in a dosage form intended for oral administration must be
in child-resistant packaging (see 16 CFR 1700.14(a)(4), 16 CFR
1700.15; see generally 15 U.S.C. 1471-76, 16 CFR part 1700).
---------------------------------------------------------------------------
Blister packaging can also be designed to include additional
information regarding the safe and appropriate use of the drug. If this
information were printed on the blister packaging itself, it could not
be easily separated from the drug nor could it be easily discarded. As
[[Page 25288]]
such, blister packaging presents an opportunity to educate patients
each time the drug is administered, potentially improving patient
understanding of and compliance with key information regarding
appropriate dosing, storage, disposal, or other important information
regarding the safe and appropriate use of opioid analgesics. FDA is
continuing to consider what information concerning the safe and
appropriate use of opioid analgesics would be beneficial to include on
blister packaging.
Furthermore, blister packaging may make it easier for a patient or
caregiver to identify whether a third party, such as a member of the
household or a visitor, has inappropriately accessed the opioid
medication. While such packaging would not thwart a determined attempt
to access the drug, the patient or caregiver is more likely to be
alerted to inappropriate access of opioids contained in a blister pack
compared to opioids contained in a standard pill bottle. Additionally,
the fact that monitoring for inappropriate access may be easier with
certain blister packaging (compared to a standard pill bottle) may
serve as a partial deterrent to inappropriate access.
III. Request for Comments
FDA is soliciting comment from stakeholders regarding the potential
blister packaging requirement described in this notice. In addition to
any other aspects of or issues raised by the potential mandate
stakeholders may care to comment upon, FDA is interested in comments on
the following topics:
1. Comment on the potential safety advantages and public health
impact of broadly available, fixed-quantity unit-of-use blister
packages of opioid analgesics for treatment of acute pain in adults.
2. Comment on the specific IR opioid analgesic drug products for
which it may be appropriate to require that blister packaging be made
available, as well as the specific blister packaging configuration(s)
it may be appropriate to require for each product or class of products,
including the number of tablets or capsules to be included in the
configuration(s). Specifically, please comment on the potential utility
of the 5-, 10-, and 15-count configurations discussed in section II.B.
3. Comment on what specific information regarding the safe and
effective use of opioid analgesics would be most beneficial to include
in blister packaging configurations of these products.
4. Comment on possible negative impacts of mandatory blister
packaging, including any unintended consequences. For example, what
steps could help ensure that the blister packaging contemplated here
would not inadvertently lead to underprescribing for patients who need
opioid analgesics to treat acute pain conditions and blister packs
being inappropriately prescribed and/or dispensed to patients who may
have difficulty accessing drugs contained in blister packaging?
5. Comment on the potential challenges, including technical and
logistical challenges, with the potential blister packaging
requirement. What factors could impact application holders' ability to
produce blister packaging of the type described in this notice?
6. How much time would be needed for application holders to submit
prior approval supplements for blister packaging that would satisfy the
proposed REMS requirements discussed in section II.C? How much time
would be needed for an application holder to develop REMS-compliant
packaging and manufacture sufficient quantities to perform the
stability and other product quality testing necessary to support the
approval of a PAS, and how much time would be needed to perform such
testing? How much time after approval of a PAS would be needed for an
application holder to manufacture and make the product commercially
available?
7. Comment on the idea of implementing a blister packaging mandate
in a staggered fashion, targeting the products most commonly prescribed
to treat acute pain first, as well as the idea of imposing a
conditional mandate for discontinued products. Are there other ways the
Agency could consider staggering implementation of this requirement to
minimize burden on manufacturers and other stakeholders, while
maximizing the public health benefit?
8. Comment on how the OA REMS modification could be designed and
implemented to help ensure that required blister packaging is
sufficiently available. Comment on the impact of any opioid analgesic
blister packaging requirement on other stakeholders, including
prescribers, payers, and pharmacies. What steps could be taken to help
encourage uptake and mitigate any adverse impacts associated with such
a mandate?
9. As noted, FDA recognizes that the approach described in this
notice is only one possible use of the Agency's REMS authority
concerning packaging. Comment on other possible uses of this authority.
IV. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.
* 1. Scholl, L., Seth, P., Kariisa, M., et al., ``Drug And Opioid-
Involved Overdose Deaths--United States, 2013-2017.'' Morbidity and
Mortality Weekly Report (MMWR), vol. 67, pp. 67:1419-1427, 2019
(available at https://dx.doi.org/10.15585/mmwr.mm675152e1).
* 2. Mundkur, M., ``Background and Rationale for the Development of
Opioid-Sparing and Opioid-Replacement Drugs.'' Anesthetic and
Analgesic Drug Products Advisory Committee Meeting. Presented on
November 15, 2018. Available at: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM626666.pdf.
Accessed April 1, 2019.
* 3. Substance Abuse and Mental Health Services Administration
(2018), ``Key Substance Use and Mental Health Indicators in the
United States: Results from the 2017 National Survey on Drug Use and
Health'' (HHS Publication No. SMA 18-5068, NSDUH Series H-53).
Rockville, MD: Center for Behavioral Health Statistics and Quality,
Substance Abuse and Mental Health Services Administration (available
at https://www.samhsa.gov/data/).
4. Carlson, R., Nahhas, R., Martins, S., et al., ``Predictors of
Transition to Heroin Use Among Initially Non-Opioid Dependent
Illicit Pharmaceutical Opioid Users: A Natural History Study.'' Drug
and Alcohol Dependence, vol. 160, pp. 127-134, 2016.
5. Harocopos, A., Allen, B., and Paone, D., ``Circumstances and
Contexts of Heroin Initiation Following Non-Medical Opioid Analgesic
Use in New York City.'' International Journal of Drug Policy, vol.
28, pp. 106-112, 2016.
6. Surratt, H., Kurtz, S., Buttram, M., et al., ``Heroin Use Onset
Among Nonmedical Prescription Opioid Users in the Club Scene.'' Drug
and Alcohol Dependence, vol. 179, pp. 131-138, 2017.
7. Lankenau, S., Teti, M., Silva, K., et al., ``Initiation into
Prescription Opioid Misuse Among Young Injection Drug
[[Page 25289]]
Users.'' International Journal of Drug Policy, vol. 33, pp. 23:37-
44, 2012.
8. Bicket, M., Long, J., Pronovost, P., et al., ``Prescription
Opioid Analgesics Commonly Used After Surgery: A Systematic
Review.'' JAMA Surgery, vol. 152, pp. 1066-1071, 2017 (available at
doi:10.1001/jamasurg.2017.0831, published online August 2, 2017).
9. Howard, R., Fry, B., Gunaseelan, V., et al., ``Association of
Opioid Prescribing with Opioid Consumption After Surgery in
Michigan.'' JAMA Surgery, vol. 154, p. e184234, 2019 (available at
doi:10.001/jamasurg.2018.4234, published online November 7, 2018).
10. Thiels, C., Ubl, D., Yost, K., et al., ``Results of a
Prospective, Multicenter Initiative Aimed at Developing Opioid-
Prescribing Guidelines After Surgery.'' Annals of Surgery, vol. 268,
pp. 457-468, 2018 (available at doi:10.1097/SLA.0000000000002919).
11. Mundkur, M., Meyer, T., Menzin, T., et al., ``Estimating the
Optimal Duration of Initial Opioid Analgesic Prescriptions in Post-
Surgical Populations Using FDA's Sentinel Distributed Database.''
Pharmacoepidemiology and Drug Safety, S2: Abstracts of the 34th
International Conference on Pharmacoepidemiology & Therapeutic Risk
Management, Abstract #392, vol. 27, p. 181 (available at
doi:10.1002/pds.4629).
12. Steiner, C.A., Karaca, Z., Moore, B.J., et al., ``Surgeries in
Hospital-Based Ambulatory Surgery and Hospital Inpatient Settings,
2014.'' HCUP Statistical Brief #223, 2017 (available at www.hcup-us.ahrq.gov/reports/statbriefs/sb223-Ambulatory-Inpatient-Surgeries-2014.pdf).
13. Mundkur, M., unpublished data.
* 14. Mundkur, M., Franklin, J., Abdia, Y., et al., ``Days' Supply
of Initial Opioid Analgesic Prescriptions and Additional Fills for
Acute Pain Conditions Treated in the Primary Care Setting--United
States, 2014.'' Morbidity and Mortality Weekly Report, vol. 68, pp.
140-143, 2019.
* 15. Dowel, D., Haegerich, T., and Chou, R., ``CDC Guideline for
Prescribing Opioids for Chronic Pain--United States, 2016.''
Morbidity and Mortality Recommended Weekly Report, vol. 65(1), pp.
1-49, 2016.
16. Opiate Prescribing Engagement Network, ``Emergency Department
Prescribing Recommendations'' (available at https://michigan-open.org/emergency-department-prescribing-recommendations/),
accessed January 5, 2019.
17. Ohio Opiate Action Team, ``Ohio Guidelines for Emergency and
Acute Care Facility Opioid and Other Controlled Substances (OOCS)
Prescribing'' (available at https://mha.ohio.gov/Portals/0/assets/Initiatives/GCOAT/Guidelines-ED-Acute-Care.pdf), accessed January 5,
2019.
18. New York City Emergency Department, ``Discharge Opioid
Prescribing Guidelines'' (available at https://www1.nyc.gov/assets/doh/downloads/pdf/basas/opioid-prescribing-guidelines.pdf), accessed
January 5, 2019.
19. Thiels, C., Ubl, D., Yost, K., et al., ``Results of a
Prospective, Multicenter Initiative Aimed at Developing Opioid-
Prescribing Guidelines After Surgery.'' Annals of Surgery, vol. 268,
pp. 457-468, 2018.
20. The Regents of the University of Michigan, ``Opioid Prescribing
Recommendations for Surgery'' (available at https://opioidprescribing.info/), last updated April 11, 2019, accessed
April 17, 2019.
21. Overton, H., Hanna, M., Bruhn, W., et al., ``Opioid-Prescribing
Guidelines for Common Surgical Procedures: An Expert Panel
Consensus.'' Journal of the American College of Surgeons, vol. 227,
pp. 411-418, 2018.
Dated: May 24, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-11283 Filed 5-30-19; 8:45 am]
BILLING CODE 4164-01-P
