[Federal Register Volume 65, Number 227 (Friday, November 24, 2000)]
[Notices]
[Pages 70573-70575]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-29998]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 00N-1609]


Digoxin Products for Oral Use; Reaffirmation of New Drug Status 
and Conditions for Marketing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is reaffirming its 
determination that digoxin products for oral use (tablets and elixir) 
are new drugs and announcing the conditions for marketing the products. 
Manufacturers who wish to begin to market or to continue marketing 
digoxin products for oral use must submit new drug applications (NDA's) 
or abbreviated new drug applications (ANDA's). Elsewhere in this issue 
of the Federal Register, FDA is publishing a proposed rule to revoke 
the regulations that establishes conditions for marketing digoxin 
products for oral use.

DATES: This notice is effective November 24, 2000.

ADDRESSES: All communications in response to this notice should be 
identified with Docket No. 00N-1609 and directed to the appropriate 
office listed as follows:
    Applications under section 505(j) of the Federal Food, Drug, and 
Cosmetic Act (the act) (21 U.S.C. 355(j)): Office of Generic Drugs, 
Center for Drug Evaluation and Research, Food and Drug Administration, 
7500 Standish Pl., rm. E150, Rockville, MD 20855.
    Applications under section 505(b) of the act: Central Document 
Room, Center for Drug Evaluation and Research, Food and Drug 
Administration, 12229 Wilkins Ave., Rockville, MD 20852.
    Requests for an opinion on the applicability of this notice to a 
specific product: Division of Prescription Drug Compliance and 
Surveillance (HFD-330), Center for Drug Evaluation and Research, Food 
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT: Mary E. Catchings, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    Digoxin is a member of a group of drugs known as cardiac 
glycosides. The cardiac or digitalis glycosides are a closely related 
group of drugs having in common specific effects on the myocardium. 
These drugs are found in several plants and animals. The term digitalis 
is used to designate the whole group.
    Since ancient times, squill (Urginea (Scilla) maritima) and 
foxglove (Digitalis purpurea) and other natural sources of cardiac 
glycosides have been used for their effects on the heart. Digoxin, 
which is extracted from the leaves of Digitalis lanata, was reportedly 
discovered and developed in 1930 at the Wellcome Chemical Works at 
Dartford. According to Burroughs Wellcome (now Glaxo Wellcome), the 
company has manufactured and marketed a digoxin product in the United 
States since 1934.
    Digoxin has been used in the treatment of certain cardiac disorders 
for many years and labeled for use in heart failure, atrial 
fibrillation, atrial flutter, and paroxysmal atrial tachycardia. 
Digoxin is available for oral and intravenous administration.
    Digoxin products for parenteral use and digoxin solution in 
capsules have previously been classified as new drugs (July 27, 1972, 
and July 26, 1982, respectively) and are subjects of approved 
applications. This notice addresses digoxin tablets and elixir.
    Because of bioavailability problems found to exist with digoxin 
tablets, FDA has sought, over the years, to provide a systematic 
regulatory approach to ensure the uniformity of all marketed, oral 
digoxin products. Since 1968, digoxin tablets (and related drugs) have 
been covered by a number of compliance programs.
    In April 1970, FDA began a program to systematically test marketed 
lots of digoxin tablets. FDA took this action after the agency became 
aware of an apparent potency problem with this cardiac glycoside. As a 
result of this testing program, from April to November 1970, there were 
79 recalls of digoxin products. In October 1970, FDA instituted a 
voluntary certification program in which participating manufacturers 
agreed not to release new lots of digoxin tablets until samples of the 
lots were tested by FDA and found to meet the United States 
Pharmacopeia (USP) requirements for potency and content uniformity.
    Later, studies showed evidence of clinically significant 
differences in bioavailability between some batches of digoxin tablets 
made by different manufacturers, and even between some batches made by 
the same manufacturer. Because of these problems and because available 
data showed a general correlation between bioavailability and 
dissolution, the USP monograph for digoxin tablets was revised to 
include a requirement for dissolution.
    In the Federal Register of January 22, 1974 (39 FR 2471), FDA 
issued a regulation (21 CFR 130.51; now Sec. 310.500 (21 CFR 310.500)) 
establishing conditions for marketing digoxin products for oral use 
(tablets and elixir). The regulation: (1) Declared all digoxin products 
for oral use (tablets and elixir) to be new drugs, (2) required

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submission of ANDA's and bioavailability tests for all oral digoxin 
products, (3) required a mandatory FDA certification program for 
digoxin tablets based on dissolution testing by the National Center for 
Drug Analysis, (4) required a recall of any previously marketed batch 
of digoxin tablets found to fail USP dissolution specifications, and 
(5) set forth a labeling requirement for all oral digoxin products. The 
regulation announced the agency's intentions to initiate procedures to 
monitor digoxin product formulations to ensure that products requiring 
reformulations complied with in vitro test requirements and possessed 
uniform batch-to-batch bioavailability.
    Because of the narrow margin between therapeutic and toxic levels 
of digoxin and the potential for serious risk to cardiac patients using 
digoxin products that may vary in bioavailability, the agency 
determined that immediate implementation of the corrective procedures 
detailed in the regulation was necessary and made Sec. 310.500 
effective on the date of publication in the Federal Register. Even 
though the regulation was effective immediately, FDA accepted comments 
on Sec. 310.500 for 30 days, until February 21, 1974.
    As a result of the comments submitted, FDA published notices in the 
Federal Register of March 8, 1974 (39 FR 9184 and 9219), that stayed 
the time for submission of ANDA's, stayed the requirement that labeling 
of digoxin products conform to Sec. 310.500(e), and announced a public 
meeting to discuss the labeling of digoxin. The notices stated that the 
stay for submission of ANDA's would be lifted 30 days after a final 
decision on labeling revisions had been reached.
    The submitted comments concerning the labeling requirements were 
reviewed by the agency's Cardiovascular and Renal Advisory Committee 
and discussed at a public meeting. Later, FDA published a proposed 
regulation in the Federal Register of April 28, 1976 (41 FR 17755), to 
revise the labeling for digoxin products set out in Sec. 310.500(e). 
FDA also proposed to lift the stay only insofar as it affected the 
labeling requirement. The agency believed that revised labeling was 
necessary because the labeling then being used for digoxin tablets 
contained dosage information suitable for the older, less bioavailable 
formulations that the agency had removed from the market through the 
digoxin certification program. Continued use of such older labeling 
constituted a potential health hazard. The agency concluded that 
revision of the labeling was necessary as soon as practicable to 
protect the public health. Revisions were needed to correct dosage and 
other recommendations for use and warn against the use of such products 
in the treatment of obesity.
    FDA published a final regulation in the Federal Register of 
September 30, 1976 (41 FR 43135), that amended Sec. 310.500(e) by 
revising the required labeling for digoxin products for oral use. The 
rule lifted the stay for revised labeling. The requirement for 
submission of ANDA's was stayed pending resolution of the agency's ANDA 
policy.
    This notice reaffirms FDA's determination of new drug status for 
digoxin products for oral use and announces the conditions for 
marketing the products.

II. Legal Status

    Digoxin products for oral use, as set forth in Sec. 310.500, are 
new drugs as defined in section 201(p) of the act (21 U.S.C. 321(p)), 
and subject to the requirements of section 505 of the act. As discussed 
above, FDA based its determination of new drug status on new 
information that emerged about the bioavailability of digoxin products 
for oral use. Studies had shown significant variation in 
bioavailability of the products that occurred in batches from a single 
manufacturer as well as in batches produced by different manufacturers. 
Because variations in bioavailability can adversely affect the safety 
and effectiveness of the products, FDA concluded that the products 
could not be considered generally recognized as safe and effective and 
are new drugs requiring approved applications for marketing.
    At the time that Sec. 310.500 was published, FDA had not approved 
any NDA's for digoxin products for oral use. Since FDA stayed the 
requirement in Sec. 310.500 for submission of ANDA's, FDA has regulated 
digoxin products for oral use under the remaining requirements in 
Sec. 310.500.
    In September 1993, Glaxo Wellcome (then Burroughs Wellcome) 
submitted to the agency an NDA (NDA 20-405) for Lanoxin (digoxin) 
Tablets under section 505(b) of the act. The submission included safety 
and effectiveness data on the drug product. In addition to published 
studies from the literature, the submission included two original 
studies sponsored by Glaxo Wellcome. These were double-blind, placebo-
controlled studies of Lanoxin Tablets in treating congestive heart 
failure patients taking angiotensin converting enzyme (ACE) inhibitors 
and/or diuretics.
    Based on its review of NDA 20-405 for Lanoxin Tablets, FDA 
concluded that the application was approvable. The agency determined 
that the issue of labeling, including appropriate indications, for the 
drug product should be presented to the Cardiovascular and Renal Drugs 
Advisory Committee. During this time, the agency began a systematic 
review of the labeling for cardiac drugs in general.
    In May 1996, the advisory committee addressed the issue of labeling 
for Lanoxin (digoxin) Tablets. The committee recommended that digoxin 
be indicated for resting and ambulatory heart rate control in atrial 
fibrillation and that use in atrial flutter be excluded. The committee 
recommended that the indication for heart failure should state that 
most clinical trial data came from trials where digoxin was used in 
combination with diuretics and ACE inhibitors. The committee also 
considered preliminary results of The Digitalis Investigation Group 
(DIG) clinical trial conducted by the National Heart, Lung, and Blood 
Institute of the National Institutes of Health and the Department of 
Veterans Affairs Cooperative Studies Program. The DIG trial was a 
randomized, double-blind, placebo-controlled multicenter trial to 
evaluate the effects of digoxin (Lanoxin) on mortality from any cause 
and on hospitalization for heart failure over a 3- to 5-year period in 
patients with heart failure and normal sinus rhythm. The committee 
recommended that the final results of the DIG trial be submitted to the 
Lanoxin Tablets NDA and be incorporated into the labeling.
    Glaxo Wellcome submitted the results of the DIG trial to the agency 
in April 1997. The results of the trial showed that digoxin did not 
affect mortality adversely.
    Based on the review of NDA 20-405 for Lanoxin Tablets and the 
recommendations of the Cardiovascular and Renal Drugs Advisory 
Committee, FDA approved NDA 20-405 for the following indications:
    Heart Failure: LANOXIN is indicated for the treatment of mild to 
moderate heart failure. LANOXIN increases left ventricular ejection 
fraction and improves heart failure symptoms as evidenced by exercise 
capacity and heart failure-related hospitalizations and emergency care, 
while having no effect on mortality. Where possible, LANOXIN should be 
used with a diuretic and an angiotensin-converting enzyme inhibitor, 
but an optimal order for starting these three drugs cannot be 
specified. [Glaxo Wellcome received 3 years of exclusivity for this 
indication.]
    Atrial Fibrillation: LANOXIN is indicated for the control of 
ventricular

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response rate in patients with chronic atrial fibrillation.
    Because of the approval of NDA 20-405, digoxin tablets are now 
eligible for ANDA's under section 505 of the act. Therefore, by this 
notice, FDA is lifting the stay for submitting ANDA's for digoxin 
products for oral use.
    This notice reaffirms FDA's previous determination that digoxin 
products for oral use are new drugs requiring approved applications for 
marketing. Because the new drug status of digoxin has already been 
established by notice-and-comment rulemaking, the agency is not 
providing a formal procedure for the submission of claims that a 
particular digoxin product for oral use is not subject to the new drug 
provision of the act. (Cf. 62 FR 43535, August 14, 1997 (oral 
levothyroxine sodium; determination of new drug status).)

III. Conditions for Approval and Marketing

    On September 30, 1997, FDA approved NDA 20-405 for Lanoxin Tablets 
(62.5, 125, 187.5, 250, 375, and 500 micrograms) held by Glaxo Wellcome 
Inc. for the indications listed above.
    Approval of an NDA under section 505(b) of the act and Sec. 314.50 
(21 CFR 314.50) or an ANDA under section 505(j) of the act and 
Sec. 314.94 (21 CFR 314.94) is required as a condition for marketing 
all digoxin products for oral use. Such an ANDA should use Glaxo's NDA 
20-405 as the reference listed drug.
    Elsewhere in this issue of the Federal Register, FDA is publishing 
a proposed rule to revoke Sec. 310.500, thus eliminating the conditions 
for marketing digoxin products for oral use established by that 
regulation.
    Inquiries regarding procedures for obtaining approval of NDA's 
should be directed to the Division of Cardio-Renal Drug Products (HFD-
110), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, Maryland 20857, 301-594-
5300.
    Inquiries regarding procedures for obtaining approval of ANDA's 
should be directed to the Office of Generic Drugs (HFD-600), Center for 
Drug Evaluation and Research, Food and Drug Administration, 7500 
Standish Pl., Rockville, Maryland 20855, 301-827-5845.
    This notice is issued under the Federal Food, Drug, and Cosmetic 
Act (secs. 502, 505 (21 U.S.C. 352, 355).

    Dated: November 15, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-29998 Filed 11-22-00; 8:45 am]
BILLING CODE 4160-01-F