8088 Federal Register / Vol. 80, No. 30 / Friday, February 13, 2015 / Notices 

1On September 27, 2012, after Reckitt publicly 

announced that it was planning to discontinue the 

product, Lachman Consultant Services Inc. 

(Lachman) submitted a citizen petition requesting 

that the Agency determine whether SUBOXONE 

Sublingual Tablets were withdrawn from sale for 

reasons of safety or effectiveness (Docket No. FDA– 

2012–P–1034). After considering Lachman’s citizen 

petition and reviewing our records, including the 

analysis that the Agency prepared in connection 

with Reckitt’s citizen petition (Docket No. FDA– 

2012–P–1028), FDA determined that SUBOXONE 

Sublingual Tablets was not discontinued for 

reasons of safety or effectiveness (78 FR 34108). 

2On September 25, 2012, Reckitt submitted a 

citizen petition requesting that FDA not approve 

any new drug application or abbreviated new drug 

application (ANDA) for a buprenorphine product 

for treatment of opioid dependence unless the 

applications and products met certain criteria. On 

February 22, 2013, FDA denied Reckitt’s petition 

(Docket No. FDA–2012–P–1028). 

TABLE 2—ESTIMATED ANNUAL REPORTING BURDEN 1

FDA center Number of 

respondents 

Number of 

responses 

per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

Total hours 

Center for Biologics Evaluation and Research ........................................ 2,114 1 2,114 1 2,114 

Center for Devices and Radiological Health ........................................... 10,528 1 10,528 2 21,056 

Center for Veterinary Medicine ................................................................ 1,848 1 1,848 1 1,848 

Total .................................................................................................. .................... .................... .................... .................... 25,018 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

Dated: February 9, 2015. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2015–03005 Filed 2–12–15; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2013–P–1055] 

Determination That SUBUTEX 

(Buprenorphine Hydrochloride) 

Sublingual Tablets, Equivalent 2 

Milligrams Base and Equivalent 8 

Milligrams Base, Were Not Withdrawn 

From Sale for Reasons of Safety or 

Effectiveness 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice. 

SUMMARY: The Food and Drug 

Administration (FDA) has determined 

that SUBUTEX (buprenorphine 

hydrochloride (HCl)) Sublingual 

Tablets, Equivalent (Eq) 2 milligrams 

(mg) base and Eq 8 mg base, were not 

withdrawn from sale for reasons of 

safety or effectiveness. This 

determination means that FDA will not 

begin procedures to withdraw approval 

of abbreviated new drug applications 

(ANDAs) that refer to SUBUTEX, and it 

will allow FDA to continue to approve 

ANDAs that refer to SUBUTEX as long 

as they meet relevant legal and 

regulatory requirements. 

FOR FURTHER INFORMATION CONTACT: 

Ayako Sato, Center for Drug Evaluation 

and Research, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 51, Rm. 6228, Silver Spring, 

MD 20993–0002, 240–402–4191. 

SUPPLEMENTARY INFORMATION: In 1984, 

Congress enacted the Drug Price 

Competition and Patent Term 

Restoration Act of 1984 (Pub. L. 98–417) 

(the 1984 amendments), which 

authorized the approval of duplicate 

versions of drug products under an 

ANDA procedure. ANDA sponsors 

must, with certain exceptions, show that 

the drug for which they are seeking 

approval contains the same active 

ingredient in the same strength and 

dosage form as the ‘‘listed drug,’’ which 

is a version of the drug that was 

previously approved. Sponsors of 

ANDAs do not have to repeat the 

extensive clinical testing otherwise 

necessary to gain approval of a new 

drug application (NDA). 

The 1984 amendments include what 

is now section 505(j)(7) of the Federal 

Food, Drug, and Cosmetic Act (21 U.S.C. 

355(j)(7)), which requires FDA to 

publish a list of all approved drugs. 

FDA publishes this list as part of the 

‘‘Approved Drug Products with 

Therapeutic Equivalence Evaluations,’’ 

which is known generally as the 

‘‘Orange Book.’’ Under FDA regulations, 

a drug is removed from the list if the 

Agency withdraws or suspends 

approval of the drug’s NDA or ANDA 

for reasons of safety or effectiveness or 

if FDA determines that the listed drug 

was withdrawn from sale for reasons of 

safety or effectiveness (21 CFR 314.162). 

Under § 314.161(a) (21 CFR 

314.161(a)), the Agency must determine 

whether a listed drug was withdrawn 

from sale for reasons of safety or 

effectiveness: (1) Before an ANDA that 

refers to that listed drug may be 

approved, (2) whenever a listed drug is 

voluntarily withdrawn from sale and 

ANDAs that refer to the listed drug have 

been approved, and (3) when a person 

petitions for such a determination under 

21 CFR 10.25(a) and 10.30. 

SUBUTEX (buprenorphine HCl) 

Sublingual Tablets is the subject of NDA 

20–732, held by Reckitt Benckiser 

Pharmaceuticals, Inc. (Reckitt). It was 

approved on October 8, 2002. After 

Reckitt discontinued marketing 

SUBUTEX in 2011, FDA moved 

SUBUTEX to the ‘‘Discontinued Drug 

Product List’’ section of the Orange 

Book. Another buprenorphinecontaining product, SUBOXONE 

(buprenorphine HCl and naloxone HCl) 

Sublingual Tablets, is the subject of 

NDA 20–733, also held by Reckitt. It 

was originally approved on October 8, 

2002, and later approved in another 

dosage form (sublingual film) on August 

30, 2010, under NDA 22–410. In March 

2013, Reckitt discontinued marketing 

the sublingual tablet dosage form of 

SUBOXONE.1 All three products are 

approved for treatment of opioid 

dependence.2

Actavis Elizabeth LLC submitted a 

citizen petition dated August 16, 2013 

(Docket No. FDA–2013–P–1055), under 

21 CFR 10.30, requesting that FDA 

determine whether SUBUTEX was 

withdrawn from sale for reasons of 

safety or effectiveness. The petition 

contains no data or other information 

suggesting that SUBUTEX was 

withdrawn for reasons of safety or 

effectiveness. 

We have carefully reviewed our 

records concerning the withdrawal of 

SUBUTEX from sale. Based on the 

information we have at this time, FDA 

has determined under § 314.161 that 

SUBUTEX was not withdrawn for 

reasons of safety or effectiveness. 

The buprenorphine in both SUBUTEX 

and SUBOXONE is a mu opioid partial 

agonist that can precipitate withdrawal 

in patients physically dependent on full 

opioid agonists. That is, the relative 

reduction in activity at the mu receptor 

when buprenorphine replaces a full 

opioid agonist can cause symptoms of 

opioid withdrawal. SUBOXONE also 

contains naloxone. Naloxone is a potent 


tkelley on DSK3SPTVN1PROD with NOTICES
Federal Register / Vol. 80, No. 30 / Friday, February 13, 2015 / Notices 8089 

opioid antagonist with high affinity for 

the mu opioid receptor. The naloxone is 

intended to be inactive when 

SUBOXONE is used appropriately, but 

to precipitate more severe withdrawal 

symptoms if the product is crushed and 

injected by an individual dependent on 

full opioid agonists. A variety of factors 

such as degree of opioid dependence, 

relative amount of buprenorphine 

exposure, and route of administration 

influence the antagonist effect of 

naloxone. As a result, buprenorphine/ 

naloxone combination products may not 

have the same effect on non-dependent 

opioid abusers or abusers of 

buprenorphine. As stated in the 

approved SUBOXONE labeling in 

section 12.2, ‘‘naloxone in 

buprenorphine/naloxone tablets may 

deter injection of buprenorphine/ 

naloxone tablets by persons with active 

substantial heroin or other full muopioid dependence,’’ but ‘‘some opioiddependent persons, particularly those 

with a low level of full mu-opioid 

physical dependence or those whose 

opioid physical dependence is 

predominantly to buprenorphine, abuse 

buprenorphine/naloxone combinations 

by the intravenous or intranasal route.’’ 

SUBUTEX has important therapeutic 

benefits for certain patient populations 

that may not tolerate or should not be 

exposed to the naloxone in SUBOXONE. 

Specifically, as explained in section 

5.11 of the approved labeling for 

SUBOXONE, ‘‘[b]uprenorphine/ 

naloxone products are not 

recommended in patients with severe 

hepatic [liver] impairment and may not 

be appropriate for patients with 

moderate hepatic impairment.’’ Section 

5.11 further states that ‘‘hepatic 

impairment results in a reduced 

clearance of naloxone to a much greater 

extent than buprenorphine,’’ and thus, 

‘‘patients with severe hepatic 

impairment will be exposed to 

substantially higher levels of naloxone 

than patients with normal hepatic 

function.’’ SUBUTEX also is preferred to 

SUBOXONE for patients transitioning 

from treatment with methadone or other 

long-acting opioid products because 

they are at higher risk for precipitated 

and prolonged withdrawal, and the 

naloxone in buprenorphine/naloxone 

combination products may cause worse 

withdrawal in this population. 

Although Reckitt has publicly stated 

that SUBUTEX ‘‘creates a greater risk of 

misuse, abuse, and diversion’’ than 

SUBOXONE (please refer to letter from 

Reckitt to Health Care Providers, 

available at http:// 

buprenorphine.samhsa.gov/ 

SubutexDiscontinuation9-16-11.pdf), 

Reckitt has not submitted any data, 

information, or analysis to support this 

claim. Based on our independent review 

of the available data and the published 

studies on the relative abuse liability of 

SUBUTEX and SUBOXONE, we do not 

have sufficient information at this time 

to determine that SUBUTEX poses an 

increased potential for abuse or misuse 

relative to SUBOXONE. Furthermore, as 

discussed previously, SUBUTEX has 

important therapeutic benefits for 

certain patient populations that may not 

tolerate or should not be exposed to the 

naloxone in SUBOXONE. 

For these reasons, based on the data 

and information available to the Agency 

at this time, we find that the benefits of 

SUBUTEX continue to outweigh the 

risks. Therefore, we conclude that 

SUBUTEX was not withdrawn from sale 

for reasons of safety or effectiveness. 

Accordingly, the Agency will 

continue to list SUBUTEX in the 

‘‘Discontinued Drug Product List’’ 

section of the Orange Book. The 

‘‘Discontinued Drug Product List’’ 

delineates, among other items, drug 

products that have been discontinued 

from marketing for reasons other than 

safety or effectiveness. FDA will not 

begin procedures to withdraw approval 

of ANDAs that refer to SUBUTEX. Such 

ANDAs may continue to be approved by 

the Agency as long as they meet all 

other legal and regulatory requirements 

for the approval of ANDAs. 

Dated: February 9, 2015. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2015–03001 Filed 2–12–15; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2014–N–2187] 

Identifying Potential Biomarkers for 

Qualification and Describing Contexts 

of Use To Address Areas Important to 

Drug Development; Request for 

Comments 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice; request for comments. 

SUMMARY: The Food and Drug 

Administration (FDA or Agency) is 

seeking information to facilitate 

development and qualification of 

biomarkers in areas related to human 

drug therapeutics. Towards this goal, 

FDA is encouraging interested groups 

and individuals to submit information 

on specific medical and biological areas 

where novel biomarkers can be 

identified that would meaningfully 

advance drug development. FDA 

encourages respondents to describe 

evidentiary considerations that are 

important to qualify these biomarkers 

for a specific context of use. Details of 

information that should be provided to 

the Agency are described in the survey. 

DATES: Submit either electronic or 

written comments by April 14, 2015. 

ADDRESSES: You may submit comments 

by any of the following methods: 

Electronic Submissions 

Submit electronic comments in either 

of the following ways: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

• SurveyMonkey Link: https://

www.surveymonkey.com/s/RHJLHS7. 

This survey may be used to provide 

feedback on answers to questions 

regarding potential biomarkers for 

qualification and to describe contexts of 

use to address areas important to drug 

development. 

Written Submissions 

Submit written submissions in the 

following ways: 

• Mail/Hand delivery/Courier (for 

paper submissions): Division of Dockets 

Management (HFA–305), Food and Drug 

Administration, 5630 Fishers Lane, Rm. 

1061, Rockville, MD 20852. 

Instructions: All submissions received 

must include the Docket No. FDA– 

2014–N–2187 for this document. All 

comments received may be posted 

without change to http://

www.regulations.gov, including any 

personal information provided. It is 

only necessary to send one set of 

comments. For additional information 

on submitting comments, see the 

‘‘Request for Information’’ heading of 

the SUPPLEMENTARY INFORMATION section 

of this document. 

Docket: For access to the docket to 

read background documents or 

comments received, go to http://

www.regulations.gov and insert the 

docket number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Division of Dockets 

Management, 5630 Fishers Lane, Rm. 

1061, Rockville, MD 20852, between 9 

a.m. and 4 p.m., Monday through 

Friday. 

FOR FURTHER INFORMATION CONTACT: 

Marianne Noone, Center for Devices and 

Radiological Health, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 21, Rm. 4528, Silver Spring, 

MD 20993–0002, 301–796–7495. 


tkelley on DSK3SPTVN1PROD with NOTICES