Federal Register / Vol. 89, No. 248 / Friday, December 27, 2024 / Notices 105613 

1For the purposes of this notice, the terms opioid 

dependence and opioid use disorder are used 

interchangeably. 

2 21 CFR 1308.13(e). 

3Approvals of Subutex and Suboxone sublingual 

tablets were withdrawn on September 15, 2022 (87 

FR 50337, August 16, 2022). 

or other forms of information 

technology. Consideration will be given 

to comments and suggestions submitted 

within 60 days of this publication. 

Authority: 6 U.S.C. 279; 8 U.S.C. 

1232; 45 CFR 410; 45 CFR 411. 

Mary C. Jones, 

ACF/OPRE Certifying Officer. 

[FR Doc. 2024–30851 Filed 12–26–24; 8:45 am] 

BILLING CODE 4184–45–P 

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. 

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, kimberly.compton@

fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

A. FDA-Approved BTODs 

Buprenorphine is a mu-opioid 

receptor partial agonist and a kappaopioid 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. 

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 doubleblind, 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: 

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 


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105614 Federal Register / Vol. 89, No. 248 / Friday, December 27, 2024 / Notices 

4The 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. 

6See 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). 

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). 

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. 

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 wellcontrolled 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 


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7See 78 FR 19718 (April 2, 2013), 66 FR 55679 

(November 2, 2001). 

8Some 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 productspecific information, including the appropriate 

dose(s) specific to their products. 

9For 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/regulatoryinformation/search-fda-guidance-documents/ 

enhancing-diversity-clinical-trial-populationseligibility-criteria-enrollment-practices-and-trial. 

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. 

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

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. 

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 


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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 opioiddependent 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 stabilization, 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 depending on the individual patient. The recommended target dosage of [DRUG 

NAME] is [equivalent 16 mg buprenorphine OR equivalent 16 

mg/4 mg buprenorphine/naloxone] as a single daily dose. Dosages higher than [equivalent 24 mg buprenorphine OR 24 mg/6 

mg buprenorphine/naloxone] have not been demonstrated to 

provide any clinical advantage. 

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 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] 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 the Postpartum Period. Dose Adjustment during Pregnancy and the Postpartum Period. 

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. 

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. 

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 


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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/considerationsbuprenorphine-initiation-andmaintenance-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-%20Bupre

norphine%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/highdose-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/committeeopinion/articles/2017/08/opioid-useand-opioid-use-disorder-in-pregnancy. 

* 20. Substance Abuse and Mental Health 

Services Administration (SAMHSA) 

Advisory, ‘‘Evidence-Based, WholePerson Care for Pregnant People Who 

Have Opioid Use Disorder,’’ March 2024, 

available at: https://store.samhsa.gov/ 

sites/default/files/whole-person-carepregnant-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] 

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