[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, Patrick.Raulerson@fda.hhs.gov.

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 http://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 http://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


