83_FR_42677 83 FR 42514 - Determination That DANOCRINE (Danazol) Capsules, 50 Milligrams, 100 Milligrams, and 200 Milligrams, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness Except the Indication of Fibrocystic Breast Disease, Which Was Withdrawn From Sale for Reasons of Safety or Effectiveness

83 FR 42514 - Determination That DANOCRINE (Danazol) Capsules, 50 Milligrams, 100 Milligrams, and 200 Milligrams, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness Except the Indication of Fibrocystic Breast Disease, Which Was Withdrawn From Sale for Reasons of Safety or Effectiveness

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 83, Issue 163 (August 22, 2018)

Page Range42514-42515
FR Document2018-18081

The Food and Drug Administration (FDA or Agency) has determined that DANOCRINE (danazol) Capsules, 50 milligrams (mg), 100 mg, and 200 mg, were not withdrawn from sale for reasons of safety or effectiveness, except with respect to the indication of fibrocystic breast disease that was withdrawn for reasons of safety or effectiveness. This determination means that FDA will not begin procedures to suspend approval of abbreviated new drug applications (ANDAs) that refer to this drug product and have removed the indication for fibrocystic breast disease. This determination also will allow FDA to continue to approve ANDAs that refer to this drug as long as they meet relevant legal and regulatory requirements. However, the Agency will not accept or approve ANDAs for DANOCRINE (danazol) Capsules, 50 mg, 100 mg, and 200 mg that include fibrocystic breast disease as an indication.

Federal Register, Volume 83 Issue 163 (Wednesday, August 22, 2018) 
[Federal Register Volume 83, Number 163 (Wednesday, August 22, 2018)]
[Notices]
[Pages 42514-42515]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2018-18081]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-2999]


Determination That DANOCRINE (Danazol) Capsules, 50 Milligrams, 
100 Milligrams, and 200 Milligrams, Were Not Withdrawn From Sale for 
Reasons of Safety or Effectiveness Except the Indication of Fibrocystic 
Breast Disease, Which Was Withdrawn From Sale for Reasons of Safety or 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 or Agency) has 
determined that DANOCRINE (danazol) Capsules, 50 milligrams (mg), 100 
mg, and 200 mg, were not withdrawn from sale for reasons of safety or 
effectiveness, except with respect to the indication of fibrocystic 
breast disease that was withdrawn for reasons of safety or 
effectiveness. This determination means that FDA will not begin 
procedures to suspend approval of abbreviated new drug applications 
(ANDAs) that refer to this drug product and have removed the indication 
for fibrocystic breast disease. This determination also will allow FDA 
to continue to approve ANDAs that refer to this drug as long as they 
meet relevant legal and regulatory requirements. However, the Agency 
will not accept or approve ANDAs for DANOCRINE (danazol) Capsules, 50 
mg, 100 mg, and 200 mg that include fibrocystic breast disease as an 
indication.

FOR FURTHER INFORMATION CONTACT: Stacy Kane, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 51, Rm. 6236, Silver Spring, MD 20993-0002, 301-796-8363.

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 applicants 
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. ANDA applicants 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, drugs are 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).
    A person may petition the Agency to determine, or the Agency may 
determine on its own initiative, whether a listed drug was withdrawn 
from sale for reasons of safety or effectiveness. This determination 
may be made at any time after the drug has been withdrawn from sale, 
but must be made prior to approving an ANDA that refers to the listed 
drug (Sec.  314.161 (21 CFR 314.161)). FDA may not approve an ANDA that 
does not refer to a listed drug.
    Under Sec.  314.161(a)(2), the Agency must also determine whether a 
listed drug was withdrawn from sale for reasons of safety or 
effectiveness if ANDAs that referred to the listed drug have already 
been approved prior to its market withdrawal. If the Agency determines 
that a listed drug was withdrawn from sale for reasons of safety or 
effectiveness, and there are approved ANDAs that reference that listed 
drug, FDA will initiate a proceeding to determine whether the 
suspension of the ANDAs is also required (Sec.  314.161(d)).
    DANOCRINE (danazol) Capsules, 50 mg, 100 mg, and 200 mg, is the 
subject of NDA 017557 held by Sanofi-Aventis, and initially approved on 
June 21, 1976. DANOCRINE is indicated for the treatment of 
endometriosis amenable to hormonal management, prevention of attacks of 
angioedema of all types (cutaneous, abdominal, and laryngeal) in males 
and females, and fibrocystic breast disease. Specifically, with respect 
to fibrocystic breast disease, the labeling states ``Most cases of 
fibrocystic breast disease may be treated by simple

[[Page 42515]]

measures (e.g., padded brassieres and analgesics). In infrequent 
patients, symptoms of pain and tenderness may be severe enough to 
warrant treatment by suppression of ovarian function. DANOCRINE is 
usually effective in decreasing nodularity, pain, and tenderness. It 
should be stressed to the patient that this treatment is not innocuous 
in that it involves considerable alterations of hormone levels and that 
recurrence of symptoms is very common after cessation of therapy.''
    DANOCRINE (danazol) Capsules, 50 mg, 100 mg, and 200 mg, were 
discontinued from sale in December 2004. FDA moved the product to the 
``Discontinued Drug Product List'' section of the Orange Book at that 
time. In a letter dated October 17, 2011, Sanofi-Aventis requested the 
withdrawal of the DANOCRINE application. On July 19, 2013, the Agency 
issued a Federal Register notice withdrawing NDA 017557, the 
application for DANOCRINE, effective August 19, 2013.
    After reviewing our records and based on the information we have at 
this time, FDA has determined that under Sec.  314.161 DANOCRINE 
(danazol) Capsules, 50 mg, 100 mg, and 200 mg, were not withdrawn from 
sale for reasons of safety or effectiveness, except with respect to the 
indication for fibrocystic breast disease. Fibrocystic breast disease 
refers to mastalgia or breast pain caused by benign proliferative 
breast tissue. The term fibrocystic breast disease is no longer used, 
in part because it is not accurate to describe the condition as a 
disease when it is in fact the result of normal physiologic changes.
    DANOCRINE (danazol) has been associated with two serious adverse 
reactions: hepatocellular injury (i.e., hepatocellular injury, 
hepatocellular jaundice, and hepatic failure) and an increased risk of 
rhabdomyolysis in patients taking danazol and statins. These two 
adverse reactions were not yet recognized when DANOCRINE (danazol) was 
originally approved for fibrocystic breast disease in 1980. Both of 
these adverse reactions were added to the safety labeling for the 
product several years after the product was initially approved. In 
addition, androgenic adverse effects and a contraindication for use in 
women who are pregnant or attempting to become pregnant limit the 
utility of DANOCRINE (danazol) for the fibrocystic breast disease 
indication.
    The Agency conducted a review of the benefit-risk profile for each 
indication of DANOCRINE (danazol). For the treatment of fibrocystic 
breast disease, the Agency concluded that the benefit-risk profile of 
the product is unfavorable given the risk of potentially serious 
adverse reactions and that the condition is a benign, non-disease 
state. In addition, many other treatment options exist for this 
condition, including dietary measures, use of supportive undergarments 
and pain relievers such as acetaminophen or non-steroidal anti-
inflammatory drug products. Many of these treatment options present a 
very low risk of adverse reactions. For the indications of treatment of 
endometriosis amenable to hormone management and prevention of attacks 
of angioedema of all types (cutaneous, abdominal, and laryngeal) in 
males and females, the Agency has determined that DANOCRINE (danazol) 
continues to have a favorable benefit-risk profile.
    Accordingly, the Agency will continue to list DANOCRINE (danazol) 
Capsules, 50 mg, 100 mg, and 200 mg, in the ``Discontinued Drug Product 
List'' section of the Orange Book. All approved ANDAs have removed the 
fibrocystic breast disease indication from their labeling. In addition, 
FDA will continue to approve ANDAs that refer to DANOCRINE (danazol) 
Capsules as long as they meet relevant legal and regulatory 
requirements, but FDA will not accept or approve ANDAs that refer to 
this drug product and propose to include the fibrocystic breast disease 
indication.

    Dated: August 16, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-18081 Filed 8-21-18; 8:45 am]
 BILLING CODE 4164-01-P

42514 Federal Register / Vol. 83, No. 163 / Wednesday, August 22, 2018 / Notices FOR FURTHER INFORMATION CONTACT: ensuring the continued forward progress must, with certain exceptions, show that Claudine Kavanaugh, Food and Drug of FDA’s Nutrition Innovation Strategy. the drug for which they are seeking Administration, Office of Foods and Dated: August 16, 2018. approval contains the same active Veterinary Medicine, 10903 New Leslie Kux, ingredient in the same strength and Hampshire Ave., Bldg. 1, Rm. 3218, dosage form as the ‘‘listed drug,’’ which Associate Commissioner for Policy. Silver Spring, MD 20993, 301–796– is a version of the drug that was [FR Doc. 2018–18072 Filed 8–21–18; 8:45 am] previously approved. ANDA applicants 4647. BILLING CODE 4164–01–P do not have to repeat the extensive SUPPLEMENTARY INFORMATION: In the clinical testing otherwise necessary to Federal Register of June 27, 2018 (83 FR gain approval of a new drug application 30180), FDA announced that it would DEPARTMENT OF HEALTH AND (NDA). hold a public meeting entitled ‘‘FDA’s HUMAN SERVICES The 1984 amendments include what Comprehensive, Multi-Year Nutrition is now section 505(j)(7) of the Federal Innovation Strategy.’’ The public Food and Drug Administration Food, Drug, and Cosmetic Act (21 U.S.C. meeting, which we held on July 26, [Docket No. FDA–2018–N–2999] 355(j)(7)), which requires FDA to 2018, was intended to give interested publish a list of all approved drugs. persons an opportunity to discuss FDA’s Determination That DANOCRINE FDA publishes this list as part of the Nutrition Innovation Strategy and to (Danazol) Capsules, 50 Milligrams, 100 ‘‘Approved Drug Products With provide input on ways to modernize Milligrams, and 200 Milligrams, Were Therapeutic Equivalence Evaluations,’’ FDA’s approach to better protect public Not Withdrawn From Sale for Reasons which is known generally as the health while removing barriers to of Safety or Effectiveness Except the ‘‘Orange Book.’’ Under FDA regulations, industry innovation. We stated that the Indication of Fibrocystic Breast drugs are removed from the list if the topics to be addressed at the meeting Disease, Which Was Withdrawn From Agency withdraws or suspends would include the following: Sale for Reasons of Safety or approval of the drug’s NDA or ANDA • Considering using a standard icon Effectiveness for reasons of safety or effectiveness or to denote the claim ‘‘healthy’’ on food if FDA determines that the listed drug labels. AGENCY: Food and Drug Administration, was withdrawn from sale for reasons of • Creating a more efficient review HHS. safety or effectiveness (21 CFR 314.162). strategy for evaluating qualified health ACTION: Notice. A person may petition the Agency to claims on food labels. determine, or the Agency may • Discussing new or enhanced SUMMARY: The Food and Drug Administration (FDA or Agency) has determine on its own initiative, whether labeling statements or claims that could a listed drug was withdrawn from sale facilitate innovation to produce more determined that DANOCRINE (danazol) Capsules, 50 milligrams (mg), 100 mg, for reasons of safety or effectiveness. healthful foods and more healthful This determination may be made at any consumer food choices. and 200 mg, were not withdrawn from sale for reasons of safety or time after the drug has been withdrawn • Modernizing the standards of from sale, but must be made prior to identity to provide more flexibility for effectiveness, except with respect to the indication of fibrocystic breast disease approving an ANDA that refers to the the development of healthier products, listed drug (§ 314.161 (21 CFR 314.161)). while making sure consumers have that was withdrawn for reasons of safety or effectiveness. This determination FDA may not approve an ANDA that accurate information about these food does not refer to a listed drug. products. means that FDA will not begin Under § 314.161(a)(2), the Agency • Providing opportunities to make procedures to suspend approval of must also determine whether a listed ingredient information more helpful to abbreviated new drug applications drug was withdrawn from sale for consumers. (ANDAs) that refer to this drug product reasons of safety or effectiveness if • FDA’s educational campaign for and have removed the indication for ANDAs that referred to the listed drug consumers about the updated Nutrition fibrocystic breast disease. This have already been approved prior to its Facts label. determination also will allow FDA to market withdrawal. If the Agency See 83 FR 30180 at 30181 to 30182. continue to approve ANDAs that refer to determines that a listed drug was The notice invited interested parties this drug as long as they meet relevant withdrawn from sale for reasons of to provide information on these and legal and regulatory requirements. safety or effectiveness, and there are other topics related to FDA’s Nutrition However, the Agency will not accept or approved ANDAs that reference that Innovation Strategy. We asked that approve ANDAs for DANOCRINE listed drug, FDA will initiate a comments be submitted on or before (danazol) Capsules, 50 mg, 100 mg, and proceeding to determine whether the August 27, 2018. 200 mg that include fibrocystic breast suspension of the ANDAs is also After the public meeting, we received disease as an indication. required (§ 314.161(d)). several requests to extend the comment FOR FURTHER INFORMATION CONTACT: DANOCRINE (danazol) Capsules, 50 period. The requesters asserted that the Stacy Kane, Center for Drug Evaluation mg, 100 mg, and 200 mg, is the subject time period of 32 days was insufficient and Research, Food and Drug of NDA 017557 held by Sanofi-Aventis, to respond fully to FDA’s specific Administration, 10903 New Hampshire and initially approved on June 21, 1976. request for comments and to ensure Ave., Bldg. 51, Rm. 6236, Silver Spring, DANOCRINE is indicated for the comprehensive public input and allow MD 20993–0002, 301–796–8363. treatment of endometriosis amenable to potential respondents to thoroughly SUPPLEMENTARY INFORMATION: In 1984, hormonal management, prevention of amozie on DSK3GDR082PROD with NOTICES1 evaluate and address pertinent issues. Congress enacted the Drug Price attacks of angioedema of all types We have considered the requests and Competition and Patent Term (cutaneous, abdominal, and laryngeal) are extending the comment period for Restoration Act of 1984 (Pub. L. 98–417) in males and females, and fibrocystic another 45 days, until October 11, 2018. (the 1984 amendments), which breast disease. Specifically, with respect We believe that a 45-day extension authorized the approval of duplicate to fibrocystic breast disease, the labeling allows adequate time for interested versions of drug products under an states ‘‘Most cases of fibrocystic breast persons to submit comments while ANDA procedure. ANDA applicants disease may be treated by simple VerDate Sep<11>2014 16:34 Aug 21, 2018 Jkt 244001 PO 00000 Frm 00056 Fmt 4703 Sfmt 4703 E:\FR\FM\22AUN1.SGM 22AUN1

Federal Register / Vol. 83, No. 163 / Wednesday, August 22, 2018 / Notices 42515 measures (e.g., padded brassieres and treatment of fibrocystic breast disease, DATES: September 10, 2018, 9:00 a.m.– analgesics). In infrequent patients, the Agency concluded that the benefit- 5:00 p.m. ET, and September 11, 2018, symptoms of pain and tenderness may risk profile of the product is unfavorable 8:30 a.m.–2:30 p.m. ET. be severe enough to warrant treatment given the risk of potentially serious ADDRESSES: This meeting will be held in by suppression of ovarian function. adverse reactions and that the condition person and offer virtual access through DANOCRINE is usually effective in is a benign, non-disease state. In teleconference and webinar. The decreasing nodularity, pain, and addition, many other treatment options address for the meeting is 5600 Fishers tenderness. It should be stressed to the exist for this condition, including Lane, Rockville, Maryland 20857. patient that this treatment is not dietary measures, use of supportive • Conference call-in number: 1–800– innocuous in that it involves undergarments and pain relievers such 238–9007; Passcode: 532320. considerable alterations of hormone as acetaminophen or non-steroidal anti- • Webinar link: https:// levels and that recurrence of symptoms inflammatory drug products. Many of hrsa.connectsolutions.com/actpcmd. is very common after cessation of these treatment options present a very FOR FURTHER INFORMATION CONTACT: Dr. therapy.’’ low risk of adverse reactions. For the Kennita Carter, Designated Federal DANOCRINE (danazol) Capsules, 50 indications of treatment of Official (DFO), Division of Medicine mg, 100 mg, and 200 mg, were endometriosis amenable to hormone and Dentistry, Bureau of Health discontinued from sale in December management and prevention of attacks Workforce, HRSA, 5600 Fishers Lane, 2004. FDA moved the product to the of angioedema of all types (cutaneous, 15N–116, Rockville, Maryland 20857; ‘‘Discontinued Drug Product List’’ abdominal, and laryngeal) in males and 301–945–3505; or KCarter@hrsa.gov. section of the Orange Book at that time. females, the Agency has determined that SUPPLEMENTARY INFORMATION: In a letter dated October 17, 2011, DANOCRINE (danazol) continues to Sanofi-Aventis requested the ACTPCMD provides advice and have a favorable benefit-risk profile. recommendations to the Secretary of withdrawal of the DANOCRINE Accordingly, the Agency will application. On July 19, 2013, the HHS (Secretary) on policy, program continue to list DANOCRINE (danazol) development, and other matters of Agency issued a Federal Register notice Capsules, 50 mg, 100 mg, and 200 mg, withdrawing NDA 017557, the significance concerning the activities in the ‘‘Discontinued Drug Product List’’ under section 747 of Title VII of the application for DANOCRINE, effective section of the Orange Book. All August 19, 2013. Public Health Service (PHS) Act, as it approved ANDAs have removed the existed upon the enactment of Section After reviewing our records and based fibrocystic breast disease indication 749 of the PHS Act in 1998. ACTPCMD on the information we have at this time, from their labeling. In addition, FDA prepares an annual report describing the FDA has determined that under will continue to approve ANDAs that activities of the Committee, including § 314.161 DANOCRINE (danazol) refer to DANOCRINE (danazol) Capsules findings and recommendations made by Capsules, 50 mg, 100 mg, and 200 mg, were not withdrawn from sale for as long as they meet relevant legal and the Committee concerning the activities reasons of safety or effectiveness, except regulatory requirements, but FDA will under section 747, as well as training with respect to the indication for not accept or approve ANDAs that refer programs in oral health and dentistry. fibrocystic breast disease. Fibrocystic to this drug product and propose to The annual report is submitted to the breast disease refers to mastalgia or include the fibrocystic breast disease Secretary and Chairman and ranking breast pain caused by benign indication. members of the Senate Committee on proliferative breast tissue. The term Dated: August 16, 2018. Health, Education, Labor and Pensions, fibrocystic breast disease is no longer Leslie Kux, and the House of Representatives used, in part because it is not accurate Associate Commissioner for Policy. Committee on Energy and Commerce. to describe the condition as a disease [FR Doc. 2018–18081 Filed 8–21–18; 8:45 am] The Committee also develops, when it is in fact the result of normal publishes, and implements performance BILLING CODE 4164–01–P physiologic changes. measures and guidelines for DANOCRINE (danazol) has been longitudinal evaluations of programs associated with two serious adverse DEPARTMENT OF HEALTH AND authorized under Title VII, Part C, of the reactions: hepatocellular injury (i.e., HUMAN SERVICES PHS Act, and recommends hepatocellular injury, hepatocellular appropriation levels for programs under jaundice, and hepatic failure) and an Meeting of the Advisory Committee on this Part. increased risk of rhabdomyolysis in Training in Primary Care Medicine and During the September 10–11, 2018, patients taking danazol and statins. Dentistry meeting, ACTPCMD will have follow-up These two adverse reactions were not discussions on PHS Act section 747 and yet recognized when DANOCRINE AGENCY: Health Resources and Service oral health training programs, and (danazol) was originally approved for Administration (HRSA), Department of finalize its recommendations on funding fibrocystic breast disease in 1980. Both Health and Human Services (HHS). and appropriation levels to be included of these adverse reactions were added to ACTION: Notice of meeting. in its 16th report. In addition, the the safety labeling for the product Committee will complete the 16th several years after the product was SUMMARY: In accordance with the report and a pending report on initially approved. In addition, Federal Advisory Committee Act, this promoting clinical trainee and faculty androgenic adverse effects and a notice announces that the Advisory well-being and mitigating burnout. contraindication for use in women who Committee on Training in Primary Care Agenda items are subject to change as amozie on DSK3GDR082PROD with NOTICES1 are pregnant or attempting to become Medicine and Dentistry (ACTPCMD) priorities dictate. pregnant limit the utility of will hold a public meeting. Information Members of the public will have the DANOCRINE (danazol) for the about ACTPCMD and the agenda for this opportunity to provide comments. fibrocystic breast disease indication. meeting can be found on the ACTPCMD Public participants may submit written The Agency conducted a review of the website at: https://www.hrsa.gov/ statements in advance of the scheduled benefit-risk profile for each indication of advisory-committees/primarycare- meeting. Oral comments will be DANOCRINE (danazol). For the dentist/index.html. honored in the order they are requested VerDate Sep<11>2014 16:34 Aug 21, 2018 Jkt 244001 PO 00000 Frm 00057 Fmt 4703 Sfmt 4703 E:\FR\FM\22AUN1.SGM 22AUN1


Document Created: 2018-08-22 00:39:00
Document Modified: 2018-08-22 00:39:00
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.
ContactStacy Kane, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 6236, Silver Spring, MD 20993-0002, 301-796-8363.
FR Citation83 FR 42514 
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