80_FR_8118 80 FR 8088 - 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Hydrochloride) Sublingual Tablets, Equivalent 2 Milligrams Base and Equivalent 8 Milligrams Base, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness

80 FR 8088 - 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Hydrochloride) Sublingual Tablets, Equivalent 2 Milligrams Base and Equivalent 8 Milligrams Base, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 80, Issue 30 (February 13, 2015)

Page Range8088-8089
FR Document2015-03001

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hydrochloride (HCl)) Sublingual Tablets, Equivalent (Eq) 2 milligrams (mg) base and Eq 8 mg base, were not withdrawn from sale for reasons of safety or effectiveness.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.

Federal Register, Volume 80 Issue 30 (Friday, February 13, 2015) 
[Federal Register Volume 80, Number 30 (Friday, February 13, 2015)]
[Notices]
[Pages 8088-8089]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2015-03001]


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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Milligrams Base, Were Not Withdrawn From Sale for Reasons of Safety or 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.

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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withdrawn from sale for reasons of safety or effectiveness.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 Sec.  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 buprenorphine-
containing 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\
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    \1\ On 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).
    \2\ On 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).
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    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 Sec.  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

[[Page 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 mu-opioid dependence,'' but ``some opioid-
dependent 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

8088 Federal Register / Vol. 80, No. 30 / Friday, February 13, 2015 / Notices TABLE 2—ESTIMATED ANNUAL REPORTING BURDEN 1 Number of Average Number of responses Total annual FDA center burden per Total hours respondents per responses response respondent 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 1 There are no capital costs or operating and maintenance costs associated with this collection of information. Dated: February 9, 2015. must, with certain exceptions, show that 2002, and later approved in another Leslie Kux, the drug for which they are seeking dosage form (sublingual film) on August Associate Commissioner for Policy. approval contains the same active 30, 2010, under NDA 22–410. In March [FR Doc. 2015–03005 Filed 2–12–15; 8:45 am] ingredient in the same strength and 2013, Reckitt discontinued marketing BILLING CODE 4164–01–P dosage form as the ‘‘listed drug,’’ which the sublingual tablet dosage form of is a version of the drug that was SUBOXONE.1 All three products are previously approved. Sponsors of approved for treatment of opioid DEPARTMENT OF HEALTH AND ANDAs do not have to repeat the dependence.2 HUMAN SERVICES extensive clinical testing otherwise Actavis Elizabeth LLC submitted a necessary to gain approval of a new citizen petition dated August 16, 2013 Food and Drug Administration drug application (NDA). (Docket No. FDA–2013–P–1055), under [Docket No. FDA–2013–P–1055] The 1984 amendments include what 21 CFR 10.30, requesting that FDA is now section 505(j)(7) of the Federal determine whether SUBUTEX was Determination That SUBUTEX Food, Drug, and Cosmetic Act (21 U.S.C. withdrawn from sale for reasons of (Buprenorphine Hydrochloride) 355(j)(7)), which requires FDA to safety or effectiveness. The petition Sublingual Tablets, Equivalent 2 publish a list of all approved drugs. contains no data or other information Milligrams Base and Equivalent 8 FDA publishes this list as part of the suggesting that SUBUTEX was Milligrams Base, Were Not Withdrawn ‘‘Approved Drug Products with withdrawn for reasons of safety or From Sale for Reasons of Safety or Therapeutic Equivalence Evaluations,’’ effectiveness. Effectiveness which is known generally as the We have carefully reviewed our ‘‘Orange Book.’’ Under FDA regulations, records concerning the withdrawal of AGENCY: Food and Drug Administration, a drug is removed from the list if the SUBUTEX from sale. Based on the HHS. Agency withdraws or suspends information we have at this time, FDA ACTION: Notice. approval of the drug’s NDA or ANDA has determined under § 314.161 that for reasons of safety or effectiveness or SUBUTEX was not withdrawn for SUMMARY: The Food and Drug if FDA determines that the listed drug reasons of safety or effectiveness. Administration (FDA) has determined was withdrawn from sale for reasons of The buprenorphine in both SUBUTEX that SUBUTEX (buprenorphine safety or effectiveness (21 CFR 314.162). and SUBOXONE is a mu opioid partial hydrochloride (HCl)) Sublingual Under § 314.161(a) (21 CFR agonist that can precipitate withdrawal Tablets, Equivalent (Eq) 2 milligrams 314.161(a)), the Agency must determine in patients physically dependent on full (mg) base and Eq 8 mg base, were not whether a listed drug was withdrawn opioid agonists. That is, the relative withdrawn from sale for reasons of from sale for reasons of safety or reduction in activity at the mu receptor safety or effectiveness. This effectiveness: (1) Before an ANDA that when buprenorphine replaces a full determination means that FDA will not refers to that listed drug may be opioid agonist can cause symptoms of begin procedures to withdraw approval approved, (2) whenever a listed drug is opioid withdrawal. SUBOXONE also of abbreviated new drug applications voluntarily withdrawn from sale and contains naloxone. Naloxone is a potent (ANDAs) that refer to SUBUTEX, and it ANDAs that refer to the listed drug have will allow FDA to continue to approve been approved, and (3) when a person 1 On September 27, 2012, after Reckitt publicly ANDAs that refer to SUBUTEX as long petitions for such a determination under announced that it was planning to discontinue the as they meet relevant legal and 21 CFR 10.25(a) and 10.30. product, Lachman Consultant Services Inc. regulatory requirements. (Lachman) submitted a citizen petition requesting SUBUTEX (buprenorphine HCl) that the Agency determine whether SUBOXONE FOR FURTHER INFORMATION CONTACT: Sublingual Tablets is the subject of NDA Sublingual Tablets were withdrawn from sale for Ayako Sato, Center for Drug Evaluation 20–732, held by Reckitt Benckiser reasons of safety or effectiveness (Docket No. FDA– and Research, Food and Drug Pharmaceuticals, Inc. (Reckitt). It was 2012–P–1034). After considering Lachman’s citizen petition and reviewing our records, including the Administration, 10903 New Hampshire approved on October 8, 2002. After analysis that the Agency prepared in connection Ave., Bldg. 51, Rm. 6228, Silver Spring, Reckitt discontinued marketing with Reckitt’s citizen petition (Docket No. FDA– MD 20993–0002, 240–402–4191. SUBUTEX in 2011, FDA moved 2012–P–1028), FDA determined that SUBOXONE SUPPLEMENTARY INFORMATION: In 1984, SUBUTEX to the ‘‘Discontinued Drug Sublingual Tablets was not discontinued for reasons of safety or effectiveness (78 FR 34108). tkelley on DSK3SPTVN1PROD with NOTICES Congress enacted the Drug Price Product List’’ section of the Orange 2 On September 25, 2012, Reckitt submitted a Competition and Patent Term Book. Another buprenorphine- citizen petition requesting that FDA not approve Restoration Act of 1984 (Pub. L. 98–417) containing product, SUBOXONE any new drug application or abbreviated new drug (the 1984 amendments), which (buprenorphine HCl and naloxone HCl) application (ANDA) for a buprenorphine product for treatment of opioid dependence unless the authorized the approval of duplicate Sublingual Tablets, is the subject of applications and products met certain criteria. On versions of drug products under an NDA 20–733, also held by Reckitt. It February 22, 2013, FDA denied Reckitt’s petition ANDA procedure. ANDA sponsors was originally approved on October 8, (Docket No. FDA–2012–P–1028). VerDate Sep<11>2014 21:56 Feb 12, 2015 Jkt 235001 PO 00000 Frm 00034 Fmt 4703 Sfmt 4703 E:\FR\FM\13FEN1.SGM 13FEN1

Federal Register / Vol. 80, No. 30 / Friday, February 13, 2015 / Notices 8089 opioid antagonist with high affinity for information, or analysis to support this where novel biomarkers can be the mu opioid receptor. The naloxone is claim. Based on our independent review identified that would meaningfully intended to be inactive when of the available data and the published advance drug development. FDA SUBOXONE is used appropriately, but studies on the relative abuse liability of encourages respondents to describe to precipitate more severe withdrawal SUBUTEX and SUBOXONE, we do not evidentiary considerations that are symptoms if the product is crushed and have sufficient information at this time important to qualify these biomarkers injected by an individual dependent on to determine that SUBUTEX poses an for a specific context of use. Details of full opioid agonists. A variety of factors increased potential for abuse or misuse information that should be provided to such as degree of opioid dependence, relative to SUBOXONE. Furthermore, as the Agency are described in the survey. relative amount of buprenorphine discussed previously, SUBUTEX has DATES: Submit either electronic or exposure, and route of administration important therapeutic benefits for written comments by April 14, 2015. influence the antagonist effect of certain patient populations that may not ADDRESSES: You may submit comments naloxone. As a result, buprenorphine/ tolerate or should not be exposed to the by any of the following methods: naloxone combination products may not naloxone in SUBOXONE. have the same effect on non-dependent For these reasons, based on the data Electronic Submissions opioid abusers or abusers of and information available to the Agency Submit electronic comments in either buprenorphine. As stated in the at this time, we find that the benefits of of the following ways: approved SUBOXONE labeling in SUBUTEX continue to outweigh the • Federal eRulemaking Portal: http:// section 12.2, ‘‘naloxone in risks. Therefore, we conclude that www.regulations.gov. Follow the buprenorphine/naloxone tablets may SUBUTEX was not withdrawn from sale instructions for submitting comments. deter injection of buprenorphine/ for reasons of safety or effectiveness. • SurveyMonkey Link: https:// naloxone tablets by persons with active Accordingly, the Agency will www.surveymonkey.com/s/RHJLHS7. substantial heroin or other full mu- continue to list SUBUTEX in the This survey may be used to provide opioid dependence,’’ but ‘‘some opioid- ‘‘Discontinued Drug Product List’’ feedback on answers to questions dependent persons, particularly those section of the Orange Book. The regarding potential biomarkers for with a low level of full mu-opioid ‘‘Discontinued Drug Product List’’ qualification and to describe contexts of physical dependence or those whose delineates, among other items, drug use to address areas important to drug opioid physical dependence is products that have been discontinued development. predominantly to buprenorphine, abuse from marketing for reasons other than buprenorphine/naloxone combinations safety or effectiveness. FDA will not Written Submissions by the intravenous or intranasal route.’’ begin procedures to withdraw approval Submit written submissions in the SUBUTEX has important therapeutic of ANDAs that refer to SUBUTEX. Such following ways: benefits for certain patient populations ANDAs may continue to be approved by • Mail/Hand delivery/Courier (for that may not tolerate or should not be the Agency as long as they meet all paper submissions): Division of Dockets exposed to the naloxone in SUBOXONE. other legal and regulatory requirements Management (HFA–305), Food and Drug Specifically, as explained in section for the approval of ANDAs. Administration, 5630 Fishers Lane, Rm. 5.11 of the approved labeling for 1061, Rockville, MD 20852. SUBOXONE, ‘‘[b]uprenorphine/ Dated: February 9, 2015. Instructions: All submissions received naloxone products are not Leslie Kux, must include the Docket No. FDA– recommended in patients with severe Associate Commissioner for Policy. 2014–N–2187 for this document. All hepatic [liver] impairment and may not [FR Doc. 2015–03001 Filed 2–12–15; 8:45 am] comments received may be posted be appropriate for patients with BILLING CODE 4164–01–P without change to http:// moderate hepatic impairment.’’ Section www.regulations.gov, including any 5.11 further states that ‘‘hepatic personal information provided. It is impairment results in a reduced DEPARTMENT OF HEALTH AND only necessary to send one set of clearance of naloxone to a much greater HUMAN SERVICES comments. For additional information extent than buprenorphine,’’ and thus, on submitting comments, see the ‘‘patients with severe hepatic Food and Drug Administration ‘‘Request for Information’’ heading of impairment will be exposed to [Docket No. FDA–2014–N–2187] the SUPPLEMENTARY INFORMATION section substantially higher levels of naloxone of this document. than patients with normal hepatic Identifying Potential Biomarkers for Docket: For access to the docket to function.’’ SUBUTEX also is preferred to Qualification and Describing Contexts read background documents or SUBOXONE for patients transitioning of Use To Address Areas Important to comments received, go to http:// from treatment with methadone or other Drug Development; Request for www.regulations.gov and insert the long-acting opioid products because Comments docket number, found in brackets in the they are at higher risk for precipitated AGENCY: Food and Drug Administration, heading of this document, into the and prolonged withdrawal, and the HHS. ‘‘Search’’ box and follow the prompts naloxone in buprenorphine/naloxone and/or go to the Division of Dockets combination products may cause worse ACTION: Notice; request for comments. Management, 5630 Fishers Lane, Rm. withdrawal in this population. Although Reckitt has publicly stated SUMMARY: The Food and Drug 1061, Rockville, MD 20852, between 9 that SUBUTEX ‘‘creates a greater risk of Administration (FDA or Agency) is a.m. and 4 p.m., Monday through Friday. tkelley on DSK3SPTVN1PROD with NOTICES misuse, abuse, and diversion’’ than seeking information to facilitate SUBOXONE (please refer to letter from development and qualification of FOR FURTHER INFORMATION CONTACT: Reckitt to Health Care Providers, biomarkers in areas related to human Marianne Noone, Center for Devices and available at http:// drug therapeutics. Towards this goal, Radiological Health, Food and Drug buprenorphine.samhsa.gov/ FDA is encouraging interested groups Administration, 10903 New Hampshire SubutexDiscontinuation9-16-11.pdf), and individuals to submit information Ave., Bldg. 21, Rm. 4528, Silver Spring, Reckitt has not submitted any data, on specific medical and biological areas MD 20993–0002, 301–796–7495. VerDate Sep<11>2014 21:56 Feb 12, 2015 Jkt 235001 PO 00000 Frm 00035 Fmt 4703 Sfmt 4703 E:\FR\FM\13FEN1.SGM 13FEN1


Document Created: 2015-12-18 13:17:50
Document Modified: 2015-12-18 13:17:50
CategoryRegulatory Information
CollectionFederal Register
sudoc ClassAE 2.7:
GS 4.107:
AE 2.106:
PublisherOffice of the Federal Register, National Archives and Records Administration
SectionNotices
ActionNotice.
ContactAyako 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.
FR Citation80 FR 8088 
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