[Federal Register Volume 79, Number 46 (Monday, March 10, 2014)]
[Notices]
[Pages 13310-13311]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-05062]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2014-N-0199]


MK Laboratories, Inc., et al.; Proposal To Withdraw Approval of 
Three Abbreviated New Drug Applications for Propoxyphene Products; 
Opportunity for a Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration's (FDA) Center for Drug 
Evaluation and Research (CDER) is proposing to withdraw approval of 
three abbreviated new drug applications (ANDAs) for propoxyphene drug 
products from multiple sources and is announcing an opportunity for 
holders of those ANDAs to request a hearing on this proposal.

DATES: Submit written requests for a hearing by April 9, 2014; submit 
data and information in support of the hearing request by May 9, 2014.

ADDRESSES: Requests for a hearing, supporting data, and other comments 
are to be identified with Docket No. FDA-2014-N-0199 and submitted to 
the Division of Dockets Management, Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: David Joy, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 51, Rm. 6254, Silver Spring, MD 20993-0002, 301-796-3601.

SUPPLEMENTARY INFORMATION: Propoxyphene is an opioid pain relief 
medication first approved by FDA in 1957. It has been marketed as a 
single active ingredient drug product and in combination with other 
active ingredients such as acetaminophen. It has been marketed under 
brand names such as Darvon and Darvocet and in generic forms.
    After receiving clinical data and other information showing that 
propoxyphene puts patients at risk of potentially serious and even 
fatal heart rhythm abnormalities, FDA determined that the risks of 
propoxyphene outweigh its benefits. On November 18, 2010, FDA asked 
Xanodyne Pharmaceuticals, Inc. (Xanodyne), the maker of Darvon and 
Darvocet, and manufacturers of then marketed generic propoxyphene drug 
products to voluntarily withdraw their products from the U.S. market. 
In a separate notice published elsewhere in this issue of the Federal 
Register, FDA is withdrawing approval of 8 NDAs and 46 ANDAs from 
multiple sources, whose application holders have agreed in writing to 
permit FDA to withdraw approval of the applications and have waived 
their opportunity for a hearing.
    Although the holders of the approved applications listed in Table 1 
are believed to have discontinued marketing these products prior to 
November 2010, FDA has not received correspondence from these 
application holders requesting that the Agency withdraw approval of the 
identified applications. Hence, in accordance with section 505(e) of 
the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(e)), 
we hereby notify the application holders listed in Table 1 of their 
opportunity to request a hearing on CDER's proposal to withdraw 
approval of the listed applications.

 Table 1--Propoxyphene Drug Product Applications for Which FDA Proposes
                          To Withdraw Approval
------------------------------------------------------------------------
                                                         Applicant or
         Application No.                 Drug               holder
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ANDA 083544.....................  Kesso-Gesic         MK Laboratories
                                   (propoxyphene       Inc., 424
                                   hydrochloride       Grasmere Ave.,
                                   (HCl)) Capsules,    Fairfield, CT
                                   65 milligrams       06430.
                                   (mg).
ANDA 084551.....................  Propoxyphene HCl    Whiteworth Towne
                                   Capsules, 65 mg.    Paulsen Inc.
ANDA 084553.....................  Compound 65         Alra Labs, 3850
                                   (aspirin,           Clearview Ct.,
                                   caffeine, and       Gurnee, IL 60031.
                                   propoxyphene HCl)
                                   Capsules, 389 mg/
                                   32.4 mg/65 mg.
------------------------------------------------------------------------

I. Safety Concern

    NDAs 010996 and 010997 for propoxyphene HCl alone and in 
combination with aspirin and caffeine, both held by Xanodyne, were 
initially approved in 1957 solely on the basis of safety. The 1962 
amendments to the FD&C Act required that drugs be shown to be effective 
as well as safe. To implement the 1962 amendments, FDA initiated the 
Drug Efficacy Study Implementation (DESI) review to evaluate the 
effectiveness of drugs that had been previously approved on safety 
grounds alone. In its DESI review of propoxyphene HCl; propoxyphene HCl 
with aspirin; and propoxyphene HCl with aspirin, phenacetin, and 
caffeine, FDA concluded that these drugs were effective for the relief 
of mild to moderate pain (34 FR 6264, April 8, 1969).

[[Page 13311]]

    In January 2009, FDA held a joint meeting of the Anesthetic and 
Life Support Drugs Advisory Committee and the Drug Safety and Risk 
Management Advisory Committee to address the safety and efficacy of 
propoxyphene and propoxyphene combination products for the treatment of 
mild to moderate pain. The committee members voted 14 to 12 against the 
continued marketing of propoxyphene products but noted that additional 
information about the drug's cardiac effects would be relevant in 
weighing its risks and benefits. Using authority under the Food and 
Drug Administration Amendments Act of 2007 (Pub. L. 110-85), FDA 
required Xanodyne to conduct a safety study of the effects of 
propoxyphene on the heart at higher than recommended doses.
    Before proceeding with the cardiac safety study, the company first 
conducted a study on healthy volunteers to determine an appropriate 
dose. In this study, the healthy volunteers in one group were given a 
total daily dose of 600 mg of propoxyphene (the maximum approved dose), 
and volunteers in the second group were given a total daily dose of 900 
mg (a dose higher than recommended in product labeling). The results 
showed that there were significant changes to the electrical activity 
of the heart (prolonged PR interval, widened QRS complex, and prolonged 
QT interval), at both the 600 and 900 mg doses. These changes, which 
can be seen on an electrocardiogram, can increase the risk for serious 
abnormal heart rhythms. In light of these new scientific findings, CDER 
determined the postmarketing safety signals for this drug have taken on 
new importance, and the overall balance of risk and benefit can no 
longer be considered favorable. Memoranda explaining CDER's 
determination are available on FDA's Web site and will be placed in 
Docket No. FDA-2014-N-0199 (Refs. 1 and 2).
    On November 19, 2010, FDA issued a Drug Safety Communication 
recommending against the continued prescription and use of propoxyphene 
drug products. This recommendation was based on all available data, 
including the new data showing that when propoxyphene is taken at 
therapeutic doses, it can cause significant changes to the electrical 
activity of the heart. FDA has concluded that this safety risk 
outweighs propoxyphene's benefits for pain relief at recommended doses. 
Based on this information, FDA asked the manufacturers of currently 
marketed propoxyphene products to voluntarily remove their products 
from the market.
    Therefore, based on all available data, notice is given to the 
holders of the approved applications listed in Table 1 and to all other 
interested persons that the Director of CDER proposes to issue an 
order, under section 505(e) of the FD&C Act, withdrawing approval of 
the applications, amendments, and supplements upon the grounds that 
scientific data show the listed drugs are unsafe under the conditions 
of use for which they were approved.

II. Hearing Procedures

    In accordance with section 505(e) of the FD&C Act, the applicants 
are hereby provided an opportunity to request a hearing to show why 
approval of the applications listed in Table 1 should not be withdrawn 
and an opportunity to raise, for administrative determination, all 
issues relating to the legal status of the drug products covered by 
these applications.
    An applicant who decides to seek a hearing must file the following: 
(1) A written notice of participation and request for hearing (see 
DATES) and (2) the data, information, and analyses relied on to 
demonstrate that there is a genuine and substantial issue of fact that 
requires a hearing to resolve (see DATES). Any other interested person 
may also submit comments on this notice. The procedures and 
requirements governing this notice of opportunity for a hearing, notice 
of participation and request for a hearing, the information and 
analyses to justify a hearing, other comments, and a grant or denial of 
a hearing are contained in Sec.  314.200 (21 CFR 314.200) and in 21 CFR 
part 12.
    The failure of an applicant to file a timely written notice of 
participation and request for a hearing, as required by Sec.  314.200, 
constitutes an election by that applicant not to avail itself of the 
opportunity for a hearing concerning CDER's proposal to withdraw 
approval of the applications and constitutes a waiver of any 
contentions concerning the legal status of the drug products. FDA will 
then withdraw approval of the applications, and the drug products may 
not thereafter be lawfully introduced or delivered for introduction 
into interstate commerce. Any new drug product introduced or delivered 
for introduction into interstate commerce without an approved 
application is subject to regulatory action at any time.
    A request for a hearing may not rest upon mere allegations or 
denials, but must present specific facts showing that there is a 
genuine and substantial issue of fact that requires a hearing. If a 
request for a hearing is not complete or is not supported, the 
Commissioner of Food and Drugs will enter summary judgment against the 
person who requests the hearing, making findings and conclusions, and 
denying a hearing.
    All submissions under this notice of opportunity for a hearing must 
be filed in four copies. Except for data and information prohibited 
from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 1905, the 
submissions may be seen in the Division of Dockets Management (see 
ADDRESSES) between 9 a.m. and 4 p.m., Monday through Friday, and will 
be posted to the docket at http://www.regulations.gov.
    This notice is issued under section 505(e) of the FD&C Act and 
under the authority delegated to the Director of CDER by the 
Commissioner of Food and Drugs.

III. References

    FDA has placed the following references on display in the Division 
of Dockets Management (see ADDRESSES). They may be seen by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday, and are 
available electronically at http://www.regulations.gov.

    1. Memorandum to Dr. Woodcock: Recommendation on a Regulatory 
Decision for Propoxyphene-Containing Products (November 18, 2010, 
Hertz and Avigan); http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM234349.pdf.
    2. Memorandum to Dr. Woodcock on Propoxyphene-Containing 
Products (November 18, 2010, Rappaport); http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM234340.pdf.


    Dated: March 4, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-05062 Filed 3-7-14; 8:45 am]
BILLING CODE 4160-01-P