[Federal Register Volume 89, Number 248 (Friday, December 27, 2024)]
[Notices]
[Pages 105613-105617]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-30776]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2024-N-5381]
Modifications to Labeling of Buprenorphine-Containing
Transmucosal Products for the Treatment of Opioid Dependence
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is
announcing that we have concluded that certain statements set forth in
the FDA-approved labeling for buprenorphine-containing transmucosal
products for the treatment of opioid dependence (BTODs) related to the
recommended maintenance dosage and dosage adjustments during pregnancy
can be modified. We believe that certain statements in BTOD labeling
can be modified because the labeling for these products may be
misinterpreted by some as establishing a maximum dosage when none
exists. FDA is concerned that misinterpretation of these labeling
statements may be adversely impacting patients' access to BTODs. We
encourage sponsors of approved applications for BTODs to submit
supplemental new drug applications (NDAs) (labeling supplements) to
modify these labeling statements as described in this notice.
FOR FURTHER INFORMATION CONTACT: Kimberly Compton, Center for Drug
Evaluation and Research (HFD-170), Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 22, Rm. 3168, Silver Spring, MD 20993, 301-
796-1191, [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
A. FDA-Approved BTODs
Buprenorphine is a mu-opioid receptor partial agonist and a kappa-
opioid receptor antagonist. BUPRENEX (buprenorphine hydrochloride
(HCl)) injection (under NDA 018401) is a schedule III controlled
substance under the Controlled Substances Act (CSA) and was the first
buprenorphine product to be approved in the United States (approved in
1981) for management of moderate to severe pain. Other buprenorphine
products were subsequently approved for the treatment of opioid use
disorder (OUD) \1\ and are also controlled under schedule III of the
CSA.\2\ BTODs have been approved by FDA since 2002. BTODs are available
both as products containing buprenorphine alone and as fixed
combination drug products containing buprenorphine and naloxone. BTODs
include ZUBSOLV (buprenorphine HCl and naloxone HCl) sublingual
tablets; SUBOXONE (buprenorphine HCl and naloxone HCl) sublingual film
(for sublingual or buccal use); Buprenorphine and Naloxone Sublingual
Film; and Buprenorphine and Naloxone Sublingual Tablets.
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\1\ For the purposes of this notice, the terms opioid dependence
and opioid use disorder are used interchangeably.
\2\ 21 CFR 1308.13(e).
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The first BTODs approved were SUBUTEX (buprenorphine HCl)
sublingual tablets (NDA 020732)and SUBOXONE (buprenorphine HCl and
naloxone HCl) sublingual tablets (NDA 020733).\3\ Approval of these
products was based, in part, on clinical studies of Buprenorphine
Sublingual Tablets with and without Naloxone Sublingual Tablets, and on
studies of sublingual administration of a more bioavailable ethanolic
solution of buprenorphine (Ref. 1). Dosing recommendations were based
on data from one trial of both buprenorphine products and two trials of
the ethanolic solutions. In a double-blind, parallel-group, 16-week
study, 731 subjects were randomized to receive 1 of 4 dosages of
buprenorphine ethanolic solution: 1 milligram (mg), 4 mg, 8 mg, and 16
mg. For comparison purposes 1 mg of solution would be equivalent to
less than 2 mg of buprenorphine in sublingual tablets; 4 mg, 8 mg, and
16 mg of buprenorphine in the solution would be roughly equivalent to 6
mg, 12 mg, and 24 mg of buprenorphine in sublingual tablets,
respectively. Buprenorphine (administered once daily) was titrated to a
maintenance dosage over 1 to 4 days and continued for 16 weeks. Based
on retention in treatment and the percentage of thrice-weekly urine
samples negative for non-study opioids, the three highest tested
dosages of the ethanolic solution (i.e., 4 mg, 8 mg, and 16 mg once
daily dosages) were superior to the 1 mg once daily dosage. This study
and the additional information submitted to support the approval of
SUBUTEX and SUBOXONE demonstrated Buprenorphine Sublingual Tablets are
effective from 4 mg to 24 mg once daily. The ``Dosage and
Administration'' section of the original labeling for these products in
describing the appropriate maintenance dosage read, in part:
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\3\ Approvals of Subutex and Suboxone sublingual tablets were
withdrawn on September 15, 2022 (87 FR 50337, August 16, 2022).
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The dosage of SUBOXONE should be progressively adjusted in
increments/decrements of 2 mg or 4 mg to a level that holds the patient
in treatment and suppresses opioid withdrawal effects. This is likely
to be in the range of 4 mg to 24 mg per day depending on the individual
[Ref. 1].
In 2011, the Agency took several actions including the approval of
two additional strengths, updates to the labeling, and modifications to
the risk evaluation and mitigation strategy (REMS) for SUBUTEX and
SUBOXONE sublingual tablets (Refs. 2, 3, 4, 5). The goals of the REMS
for SUBUTEX and SUBOXONE were to mitigate the risks of accidental
overdose, particularly in the pediatric population, and to mitigate the
risks of misuse and abuse, as well as to inform patients of the serious
risks associated with use of these products (Refs. 2, 4). It was at
this time and within the context of addressing these concerns that the
application holder for SUBUTEX and SUBOXONE proposed changes to the
``Dosage and Administration'' section of the approved labeling. For
SUBOXONE, FDA approved the following language related to the
maintenance dosage in the ``Dosage and Administration'' section of the
labeling (SUBUTEX shares similar language in its labeling (Ref. 5)):
SUBOXONE sublingual tablet is indicated for maintenance
treatment.
The recommended target dosage of SUBOXONE sublingual
tablet is 16 mg/4 mg buprenorphine/naloxone/day as a single daily dose.
The dosage of SUBOXONE sublingual tablet should be
progressively adjusted in increments/decrements of 2 mg/0.5 mg or 4 mg/
1 mg buprenorphine/naloxone to a level that holds the patient in
treatment and suppresses opioid withdrawal signs and symptoms.
The maintenance dose of SUBOXONE sublingual tablet is
generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6
mg buprenorphine/naloxone per day depending on the individual patient.
Dosages higher than this have not been
[[Page 105614]]
demonstrated to provide any clinical advantage.
Relevant to this notice is the inclusion of the statement,
``Dosages higher than [24 mg/6 mg buprenorphine/naloxone per day] have
not been demonstrated to provide any clinical advantage'' in the BTOD
labeling (Ref. 5). This language is consistent with 21 CFR
201.57(c)(3)(i)(B) and conveys, in part, that clinical trial data
support the safety and effectiveness of buprenorphine dosages up to 24
mg once daily. Although clinical trial data support the effectiveness
of buprenorphine dosages ranging from 4 mg to 24 mg once daily for
maintenance treatment, this statement may be misconstrued by some as
imposing a maximum dosage beyond which buprenorphine may not be
prescribed. Further, although the labeling for SUBUTEX and SUBOXONE has
always referred to the 16 mg buprenorphine dosage and 16 mg/4 mg
buprenorphine and naloxone dosage, respectively, as the ``target''
dosage, we understand that this too may be misinterpreted as a maximum
dosage.
The labeling for these products has changed since the inclusion of
the 2011 statement, but the maintenance dosage recommendations in the
``Dosage and Administration'' section of the SUBUTEX and SUBOXONE
labeling have largely remained the same (Refs. 6, 7). Additionally,
labeling for other BTODs includes similar language as the labeling for
SUBUTEX and SUBOXONE regarding maintenance dosage and treatment (Refs.
8, 9).
B. Perceived Dosage Maximums for BTODs
In recent years, a number of interested parties have raised
concerns that the labeling for BTODs, in particular the maintenance
dosage recommendations in the ``Dosage and Administration'' section,
may be adversely impacting patient access to this OUD treatment. In
August 2022, FDA received a citizen petition submitted by the Colorado
Society of Addiction Medicine, in which the petitioner raised concerns
that the current labeling for BTODs may be perceived as a barrier to
prescribing buprenorphine dosages higher than 24 mg once daily \4\ for
certain patients, and even dosages higher than 16 mg once daily, and
that the language in the labeling may have other implications, such as
being used to limit insurance coverage for higher dosages (Ref. 10).\5\
The citizen petition specifically cited the maintenance dosage
recommendations in the ``Dosage and Administration'' section of the
SUBOXONE labeling and asserted that these recommendations do not
recognize the needs of certain patients for buprenorphine dosages
higher than 24 mg once daily (Ref. 10). In May 2023, the Reagan-Udall
Foundation hosted a 2-day public meeting with FDA and the Substance
Abuse and Mental Health Services Administration (SAMHSA), entitled
``Considerations for Buprenorphine Initiation and Maintenance Care''
(Ref. 11). Some interested parties attending the public meeting
expressed concerns similar to those raised in the citizen petition
about perceived buprenorphine maximum dosages (Refs. 12, 13).
Additionally, on December 11, 2023, SAMHSA, FDA, and the National
Institute on Drug Abuse, hosted a listening session to discuss the
medical need, emerging data, and barriers to accessing higher doses of
buprenorphine in the context of high potency synthetic opioid exposure
and concerns were raised about a perceived dosage ``cap at 24 mg/day''
that is ``set to the FDA label'' for BTODs (Ref. 14).
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\4\ The dosages of buprenorphine listed herein are based on the
bioavailability of SUBUTEX and SUBOXONE sublingual tablets. Some
fixed combination products containing buprenorphine and naloxone may
provide equivalent buprenorphine exposure at alternate dosages due
to differences in formulation. Refer to the product labeling for
these products, as appropriate, for equivalent dosing to SUBOXONE.
\5\ Issues concerning insurance coverage and reimbursement are
outside FDA's regulatory purview.
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The reported reluctance of some healthcare practitioners to
prescribe buprenorphine daily dosages of 24 mg or higher, and even 16
mg in some instances, may be based on a misinterpretation of the
labeling that 16 mg or 24 mg once daily dosages are a required ``dosage
limit.'' Some publications have incorrectly interpreted BTOD labeling
as imposing ``dosage limits'' or ``dose limits'' of 16 mg or 24 mg once
daily (Ref. 15). Moreover, the Agency is aware that some States'
Medicaid plans require prior authorization as a condition of
reimbursement, to include such requirements as documentation of medical
necessity for buprenorphine daily dosages of 16 mg or 24 mg and higher,
before buprenorphine is dispensed to the patient (Ref. 16).
Additionally, we understand that some States impose additional
requirements on healthcare practitioners who prescribe buprenorphine
dosages higher than 16 mg/day.\6\ States have authority to regulate the
activities of doctors and pharmacists within their jurisdictions.
However, we want to minimize the possibility that the approved labeling
for BTODs is misinterpreted in a way that results in stakeholders
believing that such labeling recommendations reflect dosage
limitations. The labeling, which states that dosages higher than 24 mg
daily ``have not been demonstrated to provide any clinical advantage,''
or that 16 mg/day is the ``recommended target dose,'' are not
buprenorphine dosage caps.
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\6\ See Tennessee Code Annotated section 53-11-311 (d)
(requiring the healthcare provider to document rationale for
prescribing higher than 16 mg/day); Ohio Administrative Code 4731-
33-03 (same).
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The inclusion of a buprenorphine ``target'' dosage in BTOD labeling
reflects the need to move quickly from the very low dosages recommended
for treatment initiation (to reduce the risk of precipitation of opioid
withdrawal) to dosages that are effective for the treatment of opioid
dependence. BTOD labeling recommends a ``target'' buprenorphine daily
dosage of 16 mg, which is not a maximum dosage. The labeling for these
products recommends that the buprenorphine dosage should be
progressively adjusted in increments or decrements to a level that
holds the patient in treatment and suppresses opioid withdrawal. The
labeling further provides a general range of daily maintenance
buprenorphine dosages of 4 mg to 24 mg per day, depending on the
individual patient and clinical response.
The labeling also includes the statement ``Dosages higher than 24
mg/day have not been demonstrated to provide a clinical advantage.''
This statement informs healthcare practitioners regarding the
limitations of data available at the time of approval of the
application from adequate and well-controlled studies evaluating safety
and efficacy beyond a buprenorphine dosage of 24 mg/day. In other
words, higher daily dosages have not been subjected to evaluation in
randomized trials; it does not mean that daily dosages higher than 24
mg have been shown to be ineffective or that 24 mg/day is a maximum
dosage. The labeling does not include any recommended maximum daily
buprenorphine dosage.
II. Proposed Revisions to the Labeling for BTODs
A. Ways in Which Labeling May Be Revised
Labeling, including the Prescribing Information (PI), must be
updated when new information becomes available that causes the labeling
to become inaccurate, false, or misleading (21 CFR 201.56(a)(2)). An
applicant may, on its own initiative, submit a supplemental NDA
(labeling supplement) to propose
[[Page 105615]]
changes to the PI based on new information to satisfy this requirement.
FDA may also ask applicants to voluntarily update the PI with
information, such as safety information or how to safely use the
medication, by sending applicants a letter requesting them to submit a
labeling supplement. FDA can also require applicants make safety
labeling changes if FDA becomes aware of new safety information or
information related to reduced effectiveness (pursuant to section
505(o)(4) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
355(o)(4))) that it determines should be included in the labeling of
the drug. Less commonly, FDA has encouraged application holders to
submit labeling supplements to modify the approved labeling of drug
products by announcing recommended changes to the labeling through a
Federal Register notice.\7\ We are issuing this notice today because we
believe that the recommended clarifications to BTOD labeling would
benefit the public health by providing clearer dosage and
administration recommendations for these important OUD treatments.
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\7\ See 78 FR 19718 (April 2, 2013), 66 FR 55679 (November 2,
2001).
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B. Recommended Changes to the Maintenance Dosage Recommendations in the
``Dosage and Administration'' Section of the Labeling
The ``Dosage and Administration'' section of the most recently
approved labeling for BTODs contains the following: (1) ``Dosages
higher than 24 mg daily have not been demonstrated to provide a
clinical advantage;'' and (2) reference to dosage of 16 mg as a
``target'' dosage.
As stated previously, the statement ``Dosages higher than 24 mg
daily have not been demonstrated to provide a clinical advantage'' was
added to the labeling to convey, in part, that clinical trial data
support the safety and effectiveness of buprenorphine daily dosages up
to 24 mg. However, this statement should not be construed as a
buprenorphine maximum dosage, and its inclusion is not a recommendation
against healthcare practitioners prescribing buprenorphine daily
dosages higher than 24 mg.
Regarding the reference in the labeling to a buprenorphine daily
dosage of 16 mg as a ``target'' dosage, the ``target'' dosage is to
emphasize the need to move quickly from the very low dosages
recommended for treatment initiation (to reduce the risk of
precipitation of opioid withdrawal) to the dosages that are effective
for the treatment of opioid dependence. For example, patients generally
begin at a low buprenorphine dosage and titrate upward, which allows
the healthcare practitioner to monitor for effectiveness and adverse
reactions, such as precipitated opioid withdrawal. During this time of
titration, the ``target'' buprenorphine dosage provides healthcare
practitioners with a dosage to aim for because most patients can be
stabilized at around 16 mg/day, while also recognizing that further
upward titration may be necessary. Due to patient variability in
response, daily dosages higher or lower than 16 mg/day may be needed,
and each patient should be dosed to clinical effect. The ``target''
dosage is not a maximum daily maintenance dosage.
Accordingly, we are announcing that the statements in the labeling
that dosages higher than 24 mg daily have not been demonstrated to
provide a clinical advantage and the reference to the dosage of 16 mg
as a ``target'' dosage can be modified. FDA recommends the following
specific changes to the maintenance dosage recommendations in the
``Dosage and Administration'' section of the most recent approved BTOD
labeling: \8\
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\8\ Some BTOD products contain buprenorphine only and others are
fixed combination products containing buprenorphine and naloxone.
Further, as discussed in footnote 2, some products containing
buprenorphine may provide equivalent buprenorphine exposure at
alternate doses (e.g., equivalent to 16 mg or equivalent to 24 mg
buprenorphine in SUBUTEX and SUBOXONE) due to differences in
formulation. Accordingly, where this notice recommends changes to
the labeling, application holders of these BTOD products should
update the labeling with appropriate product-specific information,
including the appropriate dose(s) specific to their products.
After treatment induction to the recommended dose of [equivalent
16 mg buprenorphine OR equivalent 16 mg/4 mg buprenorphine/naloxone]
per day, dosing should be further adjusted based on the individual
patient and clinical response. The maintenance dose of [DRUG NAME]
is generally in the range of [equivalent 4 mg buprenorphine OR
equivalent 4 mg/1 mg buprenorphine/naloxone] to [equivalent 24 mg
buprenorphine OR equivalent 24 mg/6 mg buprenorphine/naloxone] per
day. Dosages higher than [equivalent 24 mg buprenorphine OR
equivalent 24 mg/6 mg buprenorphine/naloxone] daily have not been
investigated in randomized clinical trials but may be appropriate
for some patients.
C. Recommended Changes to the ``Pregnancy'' Subsection of the ``Use in
Specific Populations'' Section of the Labeling
The ``Pregnancy'' subsection of the ``Use in Specific Populations''
section of the most recently approved BTOD labeling contains the
statements ``Dosage adjustments of buprenorphine may be required during
pregnancy, even if the patient was maintained on a stable dose prior to
pregnancy. Withdrawal signs and symptoms should be monitored closely,
and the dose adjusted as necessary'' (Refs. 6, 7). To better align with
the changes that the Agency is recommending for the maintenance dosage
recommendations in the ``Dosage and Administration'' section of BTOD
labeling, the Agency further recommends that ``dosage adjustments'' be
revised in the ``Pregnancy'' subsection of BTOD labeling to qualify
that the adjustment is most often a dosage increase. For example, the
labeling would read, ``Dosage adjustments of buprenorphine, such as
using higher doses, may be required . . . .''
FDA recommends these changes given the concerns raised regarding
the maintenance dosage recommendations in the ``Dosage and
Administration'' section of BTOD labeling. Specifically, it may not be
clear from the most recent approved labeling that certain populations,
including pregnant females,\9\ may need a higher dosage of
buprenorphine. For example, the ``Pregnancy'' subsection of the ``Use
in Specific Populations'' section of the labeling discusses the
possible need for ``dosage adjustments'' for pregnant females but does
not specifically highlight the potential need for higher dosages (Refs.
17, 18, 19, 20). We believe it is important that the labeling clearly
communicate that this population may require a higher dosage.
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\9\ For purposes of this notice, ``sex'' is a biological
construct based on anatomical, physiological, hormonal, and genetic
(chromosomal) traits, and is generally assigned based on anatomy at
birth typically categorized as male or female, but variations occur.
Variations of sex refers to differences in sex development or
intersex traits. See Measuring Sex, Gender Identity, and Sexual
Orientation (2022). National Academies of Science, Engineering, and
Medicine. Washington, DC: The National Academies Press. FDA
recognizes that sex and gender are distinct terms, with sex defined
as a biological construct and gender as a social construct. For more
information, see the guidance for industry Enhancing the Diversity
of Clinical Trial Populations--Eligibility Criteria, Enrollment
Practices, and Trial Designs (November 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enhancing-diversity-clinical-trial-populations-eligibility-criteria-enrollment-practices-and-trial.
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Further, these changes are consistent with the data submitted to
support the initial inclusion of the ``dosage adjustment'' statement to
the ``Pregnancy'' subsection of BTOD labeling (Ref. 21). When the
statement on ``dosage adjustments'' for pregnant females was first
added to BTOD labeling, FDA reviewed data showing that this population
may need higher
[[Page 105616]]
dosages. This labeling statement was supported, in part, by a
retrospective case review of buprenorphine dosage adjustments for 45
adult females maintained on buprenorphine during pregnancy, in which 89
percent of all patients required an increase of buprenorphine dosage
during pregnancy (Ref. 17). Pharmacokinetic data submitted at the time
the ``dosage adjustment'' statement was added to the ``Pregnancy''
subsection is also consistent with the changes that are being proposed
in this notice. A study of nine pregnant females, where pharmacokinetic
data were collected on three subjects, reported a trend suggesting a
lower buprenorphine and norbuprenorphine (major metabolite) maximum
plasma concentration (Cmax) and area under the plasma
concentration-time curve (AUC0-24hrs) over the last 24-hour
dosing interval during the third trimester of pregnancy than after
delivery (Ref. 22). The magnitude of this exposure reduction was highly
variable; however, the study authors found that lower Cmax
and AUC0-24hrs suggest ``pregnant opioid-dependent women may
require increased [buprenorphine] dose during gestation and decreased
dose postpartum'' (Ref. 22).
Accordingly, we are announcing that the statement in BTOD labeling
regarding the potential need for dosage adjustments during pregnancy
can be modified as described below. FDA recommends the following
specific change under the ``Dose Adjustment during Pregnancy and the
Postpartum Period'' subheading under the ``Clinical Considerations''
heading in the ``Pregnancy'' subsection of the ``Use in Specific
Populations'' section in BTOD labeling:
Dosage adjustments of buprenorphine, such as using higher doses,
may be required during pregnancy, even if the patient was maintained
on a stable dose prior to pregnancy. Dosing should be based on
individual response, and withdrawal signs and symptoms should be
monitored closely and the dose adjusted as necessary.
D. Summary of Proposed Labeling Revisions
To clarify that the recommendations in the current BTOD labeling do
not reflect a maximum buprenorphine dosage of 16 mg or 24 mg once
daily, FDA recommends changes to the maintenance dosage recommendations
in the ``Dosage and Administration'' section of BTOD labeling as noted
in table 1.
Table 1--Recommended Changes to Maintenance Dosage Recommendations in
the ``Dosage and Administration'' Section of BTOD Labeling
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Most recently approved labeling Proposed labeling
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2 DOSAGE AND ADMINISTRATION 2 DOSAGE AND ADMINISTRATION
. . . . . .
After treatment induction and After treatment induction to
stabilization, the maintenance the recommended dose of
dose of [DRUG NAME] is generally [equivalent 16 mg
in the range of [equivalent 4 mg buprenorphine OR equivalent
buprenorphine OR equivalent 4 mg/1 16 mg/4 mg buprenorphine/
mg buprenorphine/naloxone] to naloxone] per day, dosing
[equivalent 24 mg buprenorphine OR should be further adjusted
equivalent 24 mg/6 mg based on the individual
buprenorphine/naloxone] per day patient and clinical
depending on the individual response. The maintenance
patient. The recommended target dose of [DRUG NAME] is
dosage of [DRUG NAME] is generally in the range of
[equivalent 16 mg buprenorphine OR [equivalent 4 mg
equivalent 16 mg/4 mg buprenorphine OR 4 mg/1 mg
buprenorphine/naloxone] as a buprenorphine/naloxone] to
single daily dose. Dosages higher [equivalent 24 mg
than [equivalent 24 mg buprenorphine OR equivalent
buprenorphine OR 24 mg/6 mg 24 mg/6 mg buprenorphine/
buprenorphine/naloxone] have not naloxone] per day. Dosages
been demonstrated to provide any higher than [equivalent 24
clinical advantage. mg buprenorphine OR
equivalent 24 mg/6 mg
buprenorphine/naloxone] mg
daily have not been
investigated in randomized
clinical trials but may be
appropriate for some
patients.
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Additionally, to align with the changes that the Agency is
recommending for the maintenance information in the ``Dosage and
Administration'' section of BTOD labeling, FDA recommends changes to
the ``Dose Adjustment during Pregnancy and the Postpartum Period''
subheading under the ``Clinical Considerations'' heading in the
``Pregnancy'' subsection of the ``Use in Specific Populations'' section
of BTOD labeling as noted in table 2.
Table 2--Recommended Changes to the ``Pregnancy'' Subsection of the
``Use in Special Populations'' Section of BTOD Labeling
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Most recently approved labeling Proposed labeling
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8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy 8.1 Pregnancy
Clinical Considerations Clinical Considerations
. . . . . .
Dose Adjustment during Pregnancy and Dose Adjustment during
the Postpartum Period. Pregnancy and the Postpartum
Period.
Dosage adjustments of buprenorphine Dosage adjustments of
may be required during pregnancy, buprenorphine, such as
even if the patient was maintained using higher doses, may be
on a stable dose prior to required during pregnancy,
pregnancy. Withdrawal signs and even if the patient was
symptoms should be monitored maintained on a stable dose
closely and the dose adjusted as prior to pregnancy. Dosing
necessary. should be based on
individual response, and
withdrawal signs and
symptoms should be
monitored closely and the
dose adjusted as necessary.
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We have determined that these labeling revisions may be addressed
through a supplement submitted under 21 CFR 314.70(c)(6). Any labeling
revisions submitted pursuant to this notice should reflect changes to
all of
[[Page 105617]]
the relevant sections of the labeling identified in this notice, which
include the ``Dosage and Administration'' and ``Use in Specific
Populations'' sections of BTOD labeling.
III. Electronic Submissions
Submit any draft labeling as a prior approval supplement to your
NDA. Any labeling supplement must be submitted in the electronic common
technical document (eCTD) standard format. The eCTD is the standard
format for electronic regulatory submissions to FDA's Center for Drug
Evaluation and Research. The FDA Electronic Submissions Gateway
(available at: https://www.fda.gov/industry/electronic-submissions-gateway) is the central transmission point for sending information
electronically to FDA and enables the secure submission of regulatory
information for review.
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. Although FDA verified the website addresses
in this document, please note that websites are subject to change over
time.
1. * Labeling for SUBUTEX (buprenorphine HCl) (NDA 020732) and
SUBOXONE (buprenorphine HCl and naloxone HCl) (NDA 020733)
sublingual tablets, Oct. 8, 2002, available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20732,20733lbl.pdf.
2. * Supplement Approval for SUBUTEX (buprenorphine HCl) sublingual
tablets (NDA 020732), Dec. 22, 2011, available at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/020732s006,s007ltr.pdf.
3. * Labeling for SUBUTEX (buprenorphine HCl) sublingual tablets
(NDA 020732), Dec. 22, 2011, available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020732s006s007lbl.pdf.
4. * Supplement Approval for SUBOXONE (buprenorphine HCl and
naloxone HCl) sublingual tablets (NDA 020733), Dec. 22, 2011,
available at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/020733s007,s008ltr.pdf.
* 5. Labeling for SUBOXONE (buprenorphine HCl and naloxone HCl)
sublingual tablets (NDA 020733), Dec. 22, 2011, available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020733s007s008lbl.pdf.
* 6. Labeling for SUBUTEX (buprenorphine HCl) sublingual tablets
(NDA 020732), June 17, 2022, available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020732s027s028lbl.pdf.
* 7. Labeling for SUBOXONE (buprenorphine HCl and naloxone HCl)
sublingual tablets (NDA 020733), June 17, 2022, available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020733s031s032lbl.pdf.
* 8. ZUBSOLV (buprenorphine HCl and naloxone HCl) sublingual tablets
(NDA 204242), Dec. 15, 2023, available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/204242s027lbl.pdf.
* 9. BUNAVAIL (buprenorphine HCl and naloxone HCl) buccal film (NDA
205637), June 17, 2022, available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/205637s023s024lbl.pdf.
* 10. Citizen petition submitted by the Colorado Society of
Addiction Medicine (FDA-2022-P-1863), posted Aug. 10, 2022,
available at: https://www.regulations.gov/docket/FDA-2022-P-1863.
11. Reagan-Udall Foundation, virtual public meeting entitled
``Considerations for Buprenorphine Initiation and Maintenance
Care,'' May 10-11, 2023, meeting materials and transcripts available
at: https://reaganudall.org/news-and-events/events/considerations-buprenorphine-initiation-and-maintenance-care.
12. Reagan-Udall Foundation, Meeting Transcript, ``Considerations
for Buprenorphine Initiation and Maintenance Care--Day One,'' May
10, 2023, available at: https://reaganudall.org/sites/default/files/2023-07/Transcript%20-%20Buprenorphine%20Initiation%20-%20Day%201%20-%20REVISED%20FINAL.pdf.
13. Reagan-Udall Foundation, Meeting Transcript, ``Considerations
for Buprenorphine Initiation and Maintenance Care--Day Two,'' May
11, 2023, available at: https://reaganudall.org/sites/default/files/2023-05/Transcript%20-%20Buprenorphine%20Initiation%20-%20Day%202%20-%20final.pdf.
* 14. SAMHSA, Meeting Summary, ``Listening Session: Use of High Dose
Buprenorphine for the Treatment of Opioid Use Disorder,'' December
11, 2023, available at: https://store.samhsa.gov/sites/default/files/high-dose-buprenorphine-report-pep24-02-013.pdf.
15. Grande, LA, D Cundiff, MK Greenwald, et al., 2023, ``Evidence on
Buprenorphine Dose Limits: A Review,'' J Addict Med, 17(5): 509-516.
16. Tiako, MJN, A Dolan, M Abrams, et al., 2023, ``Thematic Analysis
of State Medicaid Buprenorphine Prior Authorization Requirements,''
JAMA Netw Open, 6(6):e2318487.
17. Bakaysa, S, S Heil, and M Meyer, 2009, ``833: Buprenorphine Dose
Changes During Gestation,'' Am J Obstet Gynecol, 201(6):S297-S298.
18. Martin, CE, C Shadowen, B Thakkar, et al., 2020, ``Buprenorphine
Dosing for the Treatment of Opioid Use Disorder Through Pregnancy
and Postpartum,'' Curr Treat Options Psychiatry, 7(3): 375-399.
19. The American College of Obstetricians and Gynecologists,
``Opioid Use and Opioid Use Disorder in Pregnancy,'' Committee
Opinion Number 711, August 2017, available at: https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/08/opioid-use-and-opioid-use-disorder-in-pregnancy.
* 20. Substance Abuse and Mental Health Services Administration
(SAMHSA) Advisory, ``Evidence-Based, Whole-Person Care for Pregnant
People Who Have Opioid Use Disorder,'' March 2024, available at:
https://store.samhsa.gov/sites/default/files/whole-person-care-pregnant-people-oud-pep23-02-01-002.pdf.
* 21. Supplement Approval for SUBOXONE (buprenorphine HCl and
naloxone HCl) sublingual film (NDA 022410), Feb. 13, 2017, available
at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/022410Orig1s023ltr.pdf.
22. Concheiro, M, HE Jones, RE Johnson, et al., 2011, ``Preliminary
Buprenorphine Sublingual Tablet Pharmacokinetic Data in Plasma, Oral
Fluid and Sweat During Treatment of Opioid-Dependent Pregnant
Women,'' The Drug Monit, 33(5):619-626.
Dated: December 18, 2024.
P. Ritu Nalubola,
Associate Commissioner for Policy.
[FR Doc. 2024-30776 Filed 12-26-24; 8:45 am]
BILLING CODE 4164-01-P