[Federal Register Volume 83, Number 163 (Wednesday, August 22, 2018)]
[Notices]
[Pages 42514-42515]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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100 Milligrams, and 200 Milligrams, Were Not Withdrawn From Sale for 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Breast Disease, Which Was Withdrawn From Sale for Reasons of Safety or 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mg, and 200 mg, were not withdrawn from sale for reasons of safety or 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breast disease that was withdrawn for reasons of safety or 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