[Federal Register Volume 80, Number 30 (Friday, February 13, 2015)]
[Notices]
[Pages 8088-8089]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-03001]


-----------------------------------------------------------------------

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Milligrams Base, Were Not Withdrawn From Sale for Reasons of Safety or 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withdrawn from sale for reasons of safety or effectiveness.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 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\
---------------------------------------------------------------------------

    \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).
---------------------------------------------------------------------------

    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