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[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
------------------------------------------------------------------------
    Most recently approved labeling             Proposed labeling
------------------------------------------------------------------------
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.
------------------------------------------------------------------------

    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
------------------------------------------------------------------------
    Most recently approved labeling             Proposed labeling
------------------------------------------------------------------------
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.
------------------------------------------------------------------------

    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
```