81_FR_22686 81 FR 22612 - AbbVie Inc. et al; Withdrawal of Approval of Indications Related to the Coadministration With Statins in Applications for Niacin Extended-Release Tablets and Fenofibric Acid Delayed-Release Capsules

81 FR 22612 - AbbVie Inc. et al; Withdrawal of Approval of Indications Related to the Coadministration With Statins in Applications for Niacin Extended-Release Tablets and Fenofibric Acid Delayed-Release Capsules

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 81, Issue 74 (April 18, 2016)

Page Range22612-22613
FR Document2016-08887

The Food and Drug Administration (FDA or Agency) is withdrawing approval of the indications related to the coadministration with a statin for niacin extended-release (ER) tablets and fenofibric acid delayed-release (DR) capsules. Affected applications include one new drug application (NDA) and seven abbreviated new drug applications (ANDAs) for niacin ER tablets, and one NDA and three ANDAs for fenofibric acid DR capsules. The holders of these applications have requested that FDA withdraw approval of the indications and have waived their opportunities for a hearing.

Federal Register, Volume 81 Issue 74 (Monday, April 18, 2016) 
[Federal Register Volume 81, Number 74 (Monday, April 18, 2016)]
[Notices]
[Pages 22612-22613]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2016-08887]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-N-1127]


AbbVie Inc. et al; Withdrawal of Approval of Indications Related 
to the Coadministration With Statins in Applications for Niacin 
Extended-Release Tablets and Fenofibric Acid Delayed-Release Capsules

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

SUMMARY: The Food and Drug Administration (FDA or Agency) is 
withdrawing approval of the indications related to the coadministration 
with a statin for niacin extended-release (ER) tablets and fenofibric 
acid delayed-release (DR) capsules. Affected applications include one 
new drug application (NDA) and seven abbreviated new drug applications 
(ANDAs) for niacin ER tablets, and one NDA and three ANDAs for 
fenofibric acid DR capsules. The holders of these applications have 
requested that FDA withdraw approval of the indications and have waived 
their opportunities for a hearing.

DATES: The effective date is April 18, 2016.

ADDRESSES: For access to the docket to read background documents, 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 
(HFA-305), 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Jay Sitlani, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6282, Silver Spring, MD 20993-0002, 301-
796-5202.

SUPPLEMENTARY INFORMATION:

I. Background

A. Applications for Niacin ER Tablets

    FDA first approved NDA 020381 for Niaspan (niacin extended-release) 
tablets for several indications on July 28, 1997. On March 26, 2009, 
FDA approved a revised indication that read as follows:
     Niaspan in combination with simvastatin or lovastatin is 
indicated for the treatment of primary hyperlipidemia (heterozygous 
familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa 
and IIb) when treatment with Niaspan, simvastatin, or lovastatin 
monotherapy is considered inadequate.
    In addition, the following Limitation of Use was added to the 
Indications and Usage section of the labeling:
     No incremental benefit of Niaspan coadministered with 
simvastatin or lovastatin on cardiovascular morbidity and mortality 
over and above that demonstrated for niacin, simvastatin, or lovastatin 
monotherapy has been established. Niaspan has not been studied in 
Fredrickson Type I and III dyslipidemias.
    This indication was revised between March 26, 2009, and April 27, 
2015, at which time it was removed from the approved labeling. The 
Limitation of Use currently reads:
     Addition of Niaspan did not reduce cardiovascular 
morbidity or mortality among patients treated with simvastatin in a 
large, randomized controlled trial (AIM-HIGH).
    There are seven approved ANDAs that cited Niaspan as the reference 
listed drug (RLD) and that are approved for the same indications as 
Niaspan (see table 1).

[[Page 22613]]



                                        Table 1--Affected Niacin Products
----------------------------------------------------------------------------------------------------------------
            Application No.                        Drug                          Application holder
----------------------------------------------------------------------------------------------------------------
NDA 020381............................  Niaspan (niacin extended-   AbbVie.
                                         release) tablets.
ANDA 076250...........................  Niacin extended-release     Barr.
                                         tablets.
ANDA 076378...........................  Niacin extended-release     Barr.
                                         tablets.
ANDA 090446...........................  Niacin extended-release     Lupin Ltd.
                                         tablets.
ANDA 090860...........................  Niacin extended-release     Lupin Ltd.
                                         tablets.
ANDA 090892...........................  Niacin extended-release     Lupin Ltd.
                                         tablets.
ANDA 200484...........................  Niacin extended-release     Sun Pharma Global.
                                         tablets.
ANDA 201273...........................  Niacin extended-release     Sun Pharma Global.
                                         tablets.
----------------------------------------------------------------------------------------------------------------

B. Applications for Fenofibric Acid DR Capsules

    FDA approved NDA 022224 for Trilipix (fenofibric acid) DR capsules 
on December 15, 2008, for several indications, including the following:
     Trilipix is indicated as an adjunct to diet in combination 
with a statin to reduce TG and increase HDL-C in patients with mixed 
dyslipidemia and CHD (coronary heart disease) or a CHD risk equivalent 
who are on optimal statin therapy to achieve their LDL-C goal.
    CHD risk equivalents comprise:
    [cir] Other clinical forms of atherosclerotic disease (peripheral 
arterial disease, abdominal aortic aneurysm, and symptomatic carotid 
artery disease);
    [cir] Diabetes; and
    [cir] Multiple risk factors that confer a 10-year risk for CHD >20 
percent.
    The following Limitation of Use was included in the Indications and 
Usage section of the labeling:
     No incremental benefit of Trilipix on cardiovascular 
morbidity and mortality over and above that demonstrated for statin 
monotherapy has been established.
    Both this indication and the Limitation of Use were removed from 
the labeling on April 27, 2015.
    There are three approved ANDAs that cited Trilipix as the RLD and 
that are approved for the same indications as Trilipix (see table 2).

                                   Table 2--Affected Fenofibric Acid Products
----------------------------------------------------------------------------------------------------------------
            Application No.                        Drug                          Application holder
----------------------------------------------------------------------------------------------------------------
NDA 022224............................  Trilipix (fenofibric acid)  AbbVie.
                                         delayed-release capsules.
ANDA 201573...........................  Fenofibric acid delayed-    Anchen Pharmaceuticals.
                                         release capsules.
ANDA 200750...........................  Fenofibric acid delayed-    Lupin Ltd.
                                         release capsules.
ANDA 200913...........................  Fenofibric acid delayed-    Mylan Pharmaceuticals Inc.
                                         release capsules.
----------------------------------------------------------------------------------------------------------------

II. Withdrawal Under Section 505(e) of the FD&C Act

    Based on the collective evidence from several large cardiovascular 
outcome trials (Refs. 1-3), the Agency has concluded that the totality 
of the scientific evidence no longer supports the conclusion that a 
drug-induced reduction in triglyceride levels and/or increase in HDL-
cholesterol levels in statin-treated patients results in a reduction in 
the risk of cardiovascular events. Consistent with this conclusion, FDA 
has determined that the benefits of niacin ER tablets and fenofibric 
acid DR capsules for coadministration with statins no longer outweigh 
the risks, and the approvals for this indication should be withdrawn.
    FDA requested that the application holders voluntarily discontinue 
marketing of niacin ER tablets and fenofibric acid DR capsules for 
these indications. The NDA and ANDA holders identified above have 
requested in writing that FDA withdraw approval of these indications 
and waived their opportunity for a hearing.
    Therefore, under section 505(e) of the FD&C Act and under authority 
delegated to the Director of the Center for Drug Evaluation and 
Research by the Commissioner of Food and Drugs, the approvals of the 
indications related to coadministration with statins for the 
applications listed in tables 1 and 2 are withdrawn. Introduction or 
delivery for introduction of these products with these indications in 
interstate commerce without an approved application is illegal and 
subject to regulatory action (see sections 505(a) and 301(d) of the 
FD&C Act (21 U.S.C. 355(a) and 331(d)).

III. References

    The following references are on display in the Division of Dockets 
Management (HFA 305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, and are available for viewing by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday; 
they are also available electronically at http://www.regulations.gov. 
FDA has verified the Web site addresses, as of the date this document 
publishes in the Federal Register, but Web sites are subject to change 
over time.

    1. The ACCORD Study Group, ``Effects of Combination Lipid 
Therapy in Type 2 Diabetes Mellitus,'' New England Journal of 
Medicine, vol. 362, pp. 1563-1574, 2010 (http://www.nejm.org/doi/pdf/10.1056/NEJMoa1001282).
    2. The AIM-HIGH Investigators, ``Niacin in Patients with Low HDL 
Cholesterol Levels Receiving Intensive Statin Therapy,'' New England 
Journal of Medicine, vol. 365, pp. 2255-2267, 2011 (http://www.nejm.org/doi/pdf/10.1056/NEJMoa1107579).
    3. The HPS2-THRIVE Collaborative Group, ``Effects of Extended-
Release Niacin with Laropiprant in High-Risk Patients,'' New England 
Journal of Medicine, vol. 371(3), pp. 203-212, 2014 (http://www.nejm.org/doi/pdf/10.1056/NEJMoa1300955).

    Dated: April 13, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-08887 Filed 4-15-16; 8:45 am]
 BILLING CODE 4164-01-P

22612 Federal Register / Vol. 81, No. 74 / Monday, April 18, 2016 / Notices and Research, Food and Drug This draft guidance is being issued DATES: The effective date is April 18, Administration, 10903 New Hampshire consistent with FDA’s good guidance 2016. Ave., Bldg. 51, Rm. 5197, Silver Spring, practices regulation (21 CFR 10.115). ADDRESSES: For access to the docket to MD 20993, 301–796–3110. The draft guidance, when finalized, will read background documents, go to SUPPLEMENTARY INFORMATION: represent the current thinking of FDA http://www.regulations.gov and insert on the meaning of the term ‘‘facility at the docket number, found in brackets in I. Background one geographic location or address’’ the heading of this document, into the FDA is announcing the availability of under section 503B of the FD&C Act. It ‘‘Search’’ box and follow the prompts a draft guidance for industry entitled does not establish any rights for any and/or go to the Division of Dockets ‘‘Facility Definition Under Section 503B person and is not binding on FDA or the Management (HFA–305), 5630 Fishers of the Federal Food, Drug, and Cosmetic public. You can use an alternative Lane, Rm. 1061, Rockville, MD 20852. Act.’’ approach if it satisfies the requirements Section 503B, added to the Federal of the applicable statutes and FOR FURTHER INFORMATION CONTACT: Jay Food, Drug, and Cosmetic Act (the regulations. Sitlani, Center for Drug Evaluation and FD&C Act) by the Drug Quality and Research, Food and Drug Security Act in 2013, created a new II. Electronic Access Administration, 10903 New Hampshire category of compounders called Persons with access to the Internet Ave., Bldg. 51, Rm. 6282, Silver Spring, outsourcing facilities. Section 503B may obtain the draft guidance at either MD 20993–0002, 301–796–5202. describes the conditions that must be http://www.fda.gov/Drugs/Guidance SUPPLEMENTARY INFORMATION: satisfied for human drug products ComplianceRegulatoryInformation/ I. Background compounded by or under the direct Guidances/default.htm or http:// supervision of a licensed pharmacist in www.regulations.gov. A. Applications for Niacin ER Tablets an outsourcing facility to qualify for Dated: April 12, 2016. FDA first approved NDA 020381 for exemptions from three sections of the Leslie Kux, Niaspan (niacin extended-release) FD&C Act: Associate Commissioner for Policy. tablets for several indications on July • Section 502(f)(1) (concerning [FR Doc. 2016–08878 Filed 4–15–16; 8:45 am] 28, 1997. On March 26, 2009, FDA labeling requirements); • Section 505 (concerning drug BILLING CODE 4164–01–P approved a revised indication that read approval requirements); and as follows: • Section 582 (concerning Drug • Niaspan in combination with Supply Chain Security Act DEPARTMENT OF HEALTH AND simvastatin or lovastatin is indicated for requirements). HUMAN SERVICES the treatment of primary hyperlipidemia Section 503B(d)(4) of the FD&C Act (heterozygous familial and nonfamilial) defines an outsourcing facility as a Food and Drug Administration and mixed dyslipidemia (Fredrickson facility at one geographic location or Types IIa and IIb) when treatment with address that: (1) Is engaged in the [Docket No. FDA–2016–N–1127] Niaspan, simvastatin, or lovastatin compounding of sterile drugs; (2) has monotherapy is considered inadequate. AbbVie Inc. et al; Withdrawal of In addition, the following Limitation elected to register as an outsourcing Approval of Indications Related to the facility; and (3) complies with all of the of Use was added to the Indications and Coadministration With Statins in Usage section of the labeling: requirements of this section. In Applications for Niacin Extended- addition, an outsourcing facility is not • No incremental benefit of Niaspan Release Tablets and Fenofibric Acid coadministered with simvastatin or required to be a licensed pharmacy, and Delayed-Release Capsules it may or may not obtain prescriptions lovastatin on cardiovascular morbidity for identified individual patients. AGENCY: Food and Drug Administration, and mortality over and above that Because drugs compounded by HHS. demonstrated for niacin, simvastatin, or outsourcing facilities are not exempt ACTION: Notice. lovastatin monotherapy has been from section 501(a)(2)(B) of the FD&C established. Niaspan has not been Act, outsourcing facilities are subject to SUMMARY: The Food and Drug studied in Fredrickson Type I and III current good manufacturing practice Administration (FDA or Agency) is dyslipidemias. (CGMP) requirements. withdrawing approval of the indications This indication was revised between FDA has received questions from related to the coadministration with a March 26, 2009, and April 27, 2015, at outsourcing facilities and other statin for niacin extended-release (ER) which time it was removed from the stakeholders about the meaning of the tablets and fenofibric acid delayed- approved labeling. The Limitation of term ‘‘facility at one geographic location release (DR) capsules. Affected Use currently reads: or address,’’ such as whether multiple applications include one new drug • Addition of Niaspan did not reduce suites used for compounding human application (NDA) and seven cardiovascular morbidity or mortality drugs at a single street address abbreviated new drug applications among patients treated with simvastatin constitute one or multiple facilities, or (ANDAs) for niacin ER tablets, and one in a large, randomized controlled trial whether a single location where human NDA and three ANDAs for fenofibric (AIM–HIGH). drugs are compounded can be acid DR capsules. The holders of these There are seven approved ANDAs that subdivided into separate operations applications have requested that FDA cited Niaspan as the reference listed mstockstill on DSK4VPTVN1PROD with NOTICES compounding under different standards. withdraw approval of the indications drug (RLD) and that are approved for the FDA is issuing this draft guidance to and have waived their opportunities for same indications as Niaspan (see table answer these questions. a hearing. 1). VerDate Sep<11>2014 17:54 Apr 15, 2016 Jkt 238001 PO 00000 Frm 00046 Fmt 4703 Sfmt 4703 E:\FR\FM\18APN1.SGM 18APN1

Federal Register / Vol. 81, No. 74 / Monday, April 18, 2016 / Notices 22613 TABLE 1—AFFECTED NIACIN PRODUCTS Application No. Drug Application holder NDA 020381 .............. Niaspan (niacin extended-release) tablets ............................................................................. AbbVie. ANDA 076250 ............ Niacin extended-release tablets ............................................................................................. Barr. ANDA 076378 ............ Niacin extended-release tablets ............................................................................................. Barr. ANDA 090446 ............ Niacin extended-release tablets ............................................................................................. Lupin Ltd. ANDA 090860 ............ Niacin extended-release tablets ............................................................................................. Lupin Ltd. ANDA 090892 ............ Niacin extended-release tablets ............................................................................................. Lupin Ltd. ANDA 200484 ............ Niacin extended-release tablets ............................................................................................. Sun Pharma Global. ANDA 201273 ............ Niacin extended-release tablets ............................................................................................. Sun Pharma Global. B. Applications for Fenofibric Acid DR statin therapy to achieve their LDL–C • No incremental benefit of Trilipix Capsules goal. on cardiovascular morbidity and CHD risk equivalents comprise: mortality over and above that FDA approved NDA 022224 for Æ Other clinical forms of demonstrated for statin monotherapy Trilipix (fenofibric acid) DR capsules on atherosclerotic disease (peripheral has been established. December 15, 2008, for several arterial disease, abdominal aortic indications, including the following: aneurysm, and symptomatic carotid Both this indication and the artery disease); Limitation of Use were removed from • Trilipix is indicated as an adjunct the labeling on April 27, 2015. Æ Diabetes; and to diet in combination with a statin to Æ Multiple risk factors that confer a reduce TG and increase HDL–C in There are three approved ANDAs that 10-year risk for CHD >20 percent. cited Trilipix as the RLD and that are patients with mixed dyslipidemia and The following Limitation of Use was CHD (coronary heart disease) or a CHD approved for the same indications as included in the Indications and Usage Trilipix (see table 2). risk equivalent who are on optimal section of the labeling: TABLE 2—AFFECTED FENOFIBRIC ACID PRODUCTS Application Application No. Drug holder NDA 022224 .............. Trilipix (fenofibric acid) delayed-release capsules ................................................................. AbbVie. ANDA 201573 ............ Fenofibric acid delayed-release capsules .............................................................................. Anchen Pharmaceuticals. ANDA 200750 ............ Fenofibric acid delayed-release capsules .............................................................................. Lupin Ltd. ANDA 200913 ............ Fenofibric acid delayed-release capsules .............................................................................. Mylan Pharmaceuticals Inc. II. Withdrawal Under Section 505(e) of delegated to the Director of the Center 1. The ACCORD Study Group, ‘‘Effects of the FD&C Act for Drug Evaluation and Research by the Combination Lipid Therapy in Type 2 Commissioner of Food and Drugs, the Diabetes Mellitus,’’ New England Journal of Based on the collective evidence from approvals of the indications related to Medicine, vol. 362, pp. 1563–1574, 2010 several large cardiovascular outcome coadministration with statins for the (http://www.nejm.org/doi/pdf/10.1056/ trials (Refs. 1–3), the Agency has NEJMoa1001282). concluded that the totality of the applications listed in tables 1 and 2 are 2. The AIM–HIGH Investigators, ‘‘Niacin in scientific evidence no longer supports withdrawn. Introduction or delivery for Patients with Low HDL Cholesterol Levels the conclusion that a drug-induced introduction of these products with Receiving Intensive Statin Therapy,’’ New reduction in triglyceride levels and/or these indications in interstate commerce England Journal of Medicine, vol. 365, pp. increase in HDL-cholesterol levels in without an approved application is 2255–2267, 2011 (http://www.nejm.org/doi/ statin-treated patients results in a illegal and subject to regulatory action pdf/10.1056/NEJMoa1107579). reduction in the risk of cardiovascular (see sections 505(a) and 301(d) of the 3. The HPS2–THRIVE Collaborative Group, events. Consistent with this conclusion, FD&C Act (21 U.S.C. 355(a) and 331(d)). ‘‘Effects of Extended-Release Niacin with FDA has determined that the benefits of Laropiprant in High-Risk Patients,’’ New niacin ER tablets and fenofibric acid DR III. References England Journal of Medicine, vol. 371(3), pp. capsules for coadministration with The following references are on 203–212, 2014 (http://www.nejm.org/doi/pdf/ statins no longer outweigh the risks, and 10.1056/NEJMoa1300955). display in the Division of Dockets the approvals for this indication should Management (HFA 305), Food and Drug Dated: April 13, 2016. be withdrawn. FDA requested that the application Administration, 5630 Fishers Lane, Rm. Leslie Kux, holders voluntarily discontinue 1061, Rockville, MD 20852, and are Associate Commissioner for Policy. marketing of niacin ER tablets and available for viewing by interested [FR Doc. 2016–08887 Filed 4–15–16; 8:45 am] persons between 9 a.m. and 4 p.m., mstockstill on DSK4VPTVN1PROD with NOTICES fenofibric acid DR capsules for these BILLING CODE 4164–01–P indications. The NDA and ANDA Monday through Friday; they are also holders identified above have requested available electronically at http:// in writing that FDA withdraw approval www.regulations.gov. FDA has verified of these indications and waived their the Web site addresses, as of the date opportunity for a hearing. this document publishes in the Federal Therefore, under section 505(e) of the Register, but Web sites are subject to FD&C Act and under authority change over time. VerDate Sep<11>2014 17:54 Apr 15, 2016 Jkt 238001 PO 00000 Frm 00047 Fmt 4703 Sfmt 9990 E:\FR\FM\18APN1.SGM 18APN1


Document Created: 2016-04-16 01:45:31
Document Modified: 2016-04-16 01:45:31
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.
DatesThe effective date is April 18, 2016.
ContactJay Sitlani, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 6282, Silver Spring, MD 20993-0002, 301- 796-5202.
FR Citation81 FR 22612 
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