[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