[Federal Register Volume 61, Number 69 (Tuesday, April 9, 1996)]
[Rules and Regulations]
[Pages 15700-15703]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-8761]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 341
[Docket No. 76N-052G]
RIN 0910-AA01
Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug
Products for Over-the-Counter Human Use; Products Containing
Diphenhydramine Citrate or Diphenhydramine Hydrochloride; Enforcement
Policy
AGENCY: Food and Drug Administration, HHS.
-ACTION: Final rule; enforcement policy.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final
rule, and a statement of its enforcement policy, providing for the use
of diphenhydramine citrate or diphenhydramine hydrochloride as an
antitussive and an antihistamine for treating concurrent symptoms in
either single-ingredient or combination drug products. The agency will
include the permitted combination products that may include
diphenhydramine citrate or diphenhydramine hydrochloride in the final
monograph for over-the-counter (OTC) cold, cough, allergy,
bronchodilator, and antiasthmatic (cough-cold) combination drug
products. The OTC marketing of combination drug products containing
diphenhydramine citrate or diphenhydramine hydrochloride is being
permitted pending completion under the OTC drug review of the final
monograph for OTC cough-cold combination drug products. This final rule
is part of the ongoing review of OTC drug products conducted by FDA.
EFFECTIVE DATE: April 9, 1996.
ADDRESSES: Written comments to the Dockets Management Branch (HFA-305),
Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville,
MD 20857.
FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug
Evaluation and Research (HFD-105), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2304.
[[Page 15701]]
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of February 23, 1995 (60 FR 10286), FDA
proposed to amend the tentative final monograph for OTC cough-cold
combination drug products to classify combination drug products
containing the ingredients diphenhydramine citrate or diphenhydramine
hydrochloride. As part of that proposal, FDA discussed the use of a
single dose of diphenhydramine citrate or diphenhydramine hydrochloride
as an antitussive and antihistamine for treating concurrent symptoms
either in an OTC cough-cold single-ingredient or combination drug
product. The agency proposed specific labeling for drug products
containing diphenhydramine citrate or diphenhydramine hydrochloride for
concurrent antitussive and antihistamine use. At that time, the agency
did not allow marketing to occur because this was a new concept. The
agency stated that it wanted to receive public comment on the proposed
new concept and on the proposed labeling approach before marketing of
such products began. The agency added that it would issue a notice of
enforcement policy at a later date to state whether marketing may begin
prior to the issuance of the final monograph for OTC cough-cold
combination drug products.
In response to the proposed amendment, two drug manufacturers
submitted comments. Copies of the comments received are on public
display in the Dockets Management Branch (address above).
After carefully reviewing the comments received, the agency is
issuing a final rule containing the required labeling of drug products
containing diphenhydramine citrate or diphenhydramine hydrochloride for
concurrent antitussive and antihistamine use either as a single
ingredient product or as a single ingredient in combination with other
active ingredients. The agency is allowing the marketing of combination
products prior to the completion of the final monograph for OTC cough-
cold combination drug products, subject to the risk that the agency may
in the final monograph adopt a different position that could require
relabeling, recall, or other regulatory action. Marketing of any such
product with labeling not in accord with the final monograph may result
in regulatory action against the product, the manufacturer, or both.
II. The Agency's Conclusions on the Comments
1. One comment requested that the agency allow a broader dosage
range for a single-ingredient drug product containing diphenhydramine
hydrochloride for concurrent use as both an antitussive and an
antihistamine. The comment requested a dose of 25 milligrams (mg) every
4 to 6 hours (h), not to exceed 150 mg in 24 h, instead of restricting
the dose to every 4 h. The comment stated that the shorter antitussive
dosing interval (every 4 h) would limit other ingredients in a
combination product with a broader dosing interval (every 4 to 6 h).
The comment questioned whether restricting these combination products
to a 4-h dosing interval would increase the number of consumer
exposures to diphenhydramine over a 24-h period. The comment added that
a dosing regimen of 25 mg every 4 to 6 h, not to exceed 150 in 24 h,
would reduce exposure to both diphenhydramine and other ingredients in
the combination on a faster timing that may be consistent with a safe
yet satisfactory level of effectiveness.
When the agency included diphenhydramine citrate and
diphenhydramine hydrochloride in the OTC antitussive drug products
monograph (59 FR 29172 at 29174, June 3, 1994), the agency concluded
that diphenhydramine hydrochloride is generally recognized as safe and
effective in an antitussive dosage of 25 mg every 4 h, not to exceed
150 mg in 24 h. The agency stated that the available clinical data and
marketing history of products containing diphenhydramine citrate or
diphenhydramine hydrochloride for antitussive use do not support a
broader dosage range (4 to 6 h). The comment did not submit any data to
show that 25 mg diphenhydramine hydrochloride is effective over a 6-h
period. Without any supporting data, the agency has no basis to
establish such a dosage. While the proposed every 4 to 6 h dosage may
potentially be safer, there is no evidence that it is effective.
Therefore, in this final rule, the agency is including the following
adult dosage for diphenhydramine hydrochloride drug products for
concurrent antitussive and antihistamine use: 25 mg every 4 h, not to
exceed 150 mg in 24 h.
2. Both comments requested that marketing of diphenhydramine in the
same product as both an antitussive and antihistamine be allowed prior
to the issuance of the final monograph for OTC cough-cold combination
drug products. One comment noted that an OTC drug product in which
diphenhydramine citrate or diphenhydramine hydrochloride serves both as
the antitussive and antihistamine component for treating concurrent
symptoms would reduce the number of ingredients in the product. The
comment stated that allowing marketing of such a product would be
consistent with FDA's policy to expose the user of OTC drug products to
the smallest number of ingredients possible at the lowest possible
dosage consistent with a satisfactory level of effectiveness. The
comment added that permitting an antitussive indication on currently
marketed OTC drug products labeled with an antihistamine-only
indication would not be a safety concern.
The agency agrees with the comments and is permitting the OTC
marketing of such products pending completion under the OTC drug review
of a final monograph covering OTC cough-cold combination drug products.
The labeling required for these products appears in new Sec. 341.70 (21
CFR 341.70) of the cough-cold drug products monograph.
Specifically, when diphenhydramine citrate or diphenhydramine
hydrochloride is labeled for concurrent use, the statement of identity
is ``antihistamine/cough suppressant'' or ``antihistamine/antitussive
(cough suppressant).'' The indications are combined from
Secs. 341.72(b) and 341.74(b) (21 CFR 341.72(b) and 341.74(b)). The
warnings are combined from Sec. 341.72(c)(1), (c)(2), (c)(4), and
(c)(6) and Sec. 341.74(c)(1), (c)(2), (c)(3), and (c)(4). The warnings
for diphenhydramine for antitussive use in Sec. 341.74(c)(4) encompass
all of the same warnings for diphenhydramine for antihistamine use in
Sec. 341.72(c)(1), (c)(2), (c)(4), and (c)(6). In addition, the
labeling must include the required warnings for antitussive use in
Sec. 341.74(c)(1), (c)(2), and (c)(3), as applicable (depending on the
ages for which the product is labeled). Thus, when diphenhydramine
citrate or diphenhydramine hydrochloride as a single ingredient is
labeled for both antihistamine and antitussive use, all of the warnings
in Sec. 341.74 of the antitussive monograph must be used. At this time,
diphenhydramine citrate or diphenhydramine hydrochloride may only be
marketed for concurrent antitussive and antihistamine use in the
permitted combinations of active ingredients proposed in
Sec. 341.40(d), (e), and (f). (See 60 FR 10286 at 10292.) The agency
will discuss the other permitted combinations proposed in Sec. 341.40
in the final rule for OTC cough-cold combination drug products.
[[Page 15702]]
The agency recognizes there are other ingredients such as menthol
in the final monograph for OTC antitussive drug products (52 FR 30042,
August 12, 1987), and in the proposed rule for OTC oral health care
drug products (56 FR 48302, September 24, 1991), that may be used for
treating concurrent symptoms. The agency will address menthol for
treating concurrent symptoms in either a single-ingredient or
combination drug product in the final monograph for OTC cough-cold
combination drug products in a future issue of the Federal Register and
is reserving Sec. 341.70(b) for this ingredient at this time.
The agency proposed new combinations as well as single ingredients
with diphenhydramine labeled as both an antihistamine and antitussive
(60 FR 10286). The agency added Sec. 341.70 for labeling for
diphenhydramine-containing drug products for concurrent antitussive and
antihistamine use under the heading: Labeling of drug products
containing diphenhydramine citrate or diphenhydramine hydrochloride for
concurrent antitussive and antihistamine use either as a single
ingredient or as a single ingredient in combination with other active
ingredients. In order to provide a general heading for diphenhydramine,
menthol, and other OTC cough-cold ingredients that may be used for
treating concurrent symptoms (in either a single-ingredient or
combination drug product), the agency is revising the heading proposed
in Sec. 341.70 to read: Labeling of OTC drug products containing
ingredients that are used for treating concurrent symptoms (in either a
single-ingredient or combination drug product). The agency is placing
the labeling information for diphenhydramine citrate and
diphenhydramine hydrochloride in Sec. 341.70(a) and is reserving
Sec. 341.70(b) for menthol.
3. One comment requested monograph status for the combination of a
drug recognized as both an antitussive and an antihistamine (such as
diphenhydramine) with another oral antitussive (such as
dextromethorphan) and antihistamine when there is some advantage over
the active ingredients alone. The agency intends to address this matter
in the final monograph for OTC cough-cold combination drug products.
No comments were received in response to the agency's request for
specific comment on the economic impact of the proposed rule.
III. Analysis of Impacts
FDA has examined the impacts of this final rule and notice of
enforcement policy under Executive Order 12866 and the Regulatory
Flexibility Act (Pub. L. 96-354). Executive Order 12866 directs
agencies to assess all costs and benefits of available regulatory
alternatives and, when regulation is necessary, to select regulatory
approaches that maximize net benefits (including potential economic,
environmental, public health and safety, and other advantages;
distributive impacts; and equity). The agency believes that the final
rule for OTC cough-cold combination products containing diphenhydramine
citrate or diphenhydramine hydrochloride for concurrent antitussive and
antihistamine use is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the rule is
not a significant regulatory action as defined by the Executive Order
and, thus, is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. This final rule and notice of enforcement policy
allow the use of diphenhydramine citrate or diphenhydramine
hydrochloride as an active ingredient for concurrent antitussive and
antihistamine use in OTC cough-cold drug products.
The agency's enforcement policy, which is set out in Sec. 330.13
(21 CFR 330.13), relating to OTC marketing of drug products containing
certain ingredients that are under consideration in FDA's review of OTC
drug products, makes it clear that FDA may by notice in the Federal
Register permit interim marketing of these products. Manufacturers may
choose to market such products at their option. Accordingly, the agency
certifies that this final rule and notice of enforcement policy will
not have a significant economic impact on a substantial number of small
entities. Therefore, under the Regulatory Flexibility Act, no further
analysis is required.
IV. Paperwork Reduction Act of 1995
FDA concludes that the labeling requirements in this document are
not subject to review by the Office of Management and Budget because
they do not constitute a ``collection of information'' under the
Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the
labeling is a ``public disclosure of information originally supplied by
the Federal government to the recipient for the purpose of disclosure
to the public'' (5 CFR 1320.3(c)(2)).
V. Environmental Impact
The agency has determined under 21 CFR 25.24(c)(6) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
VI. Enforcement Status
The agency advises that any OTC drug product containing
diphenhydramine citrate or diphenhydramine hydrochloride intended for
concurrent use as an antitussive and antihistamine in either a single-
ingredient or combination drug product may be marketed pending
completion of the final monograph, subject to the risk that the agency
may, in the final monograph, adopt a different position that could
require relabeling, recall, or other regulatory action. Marketing of
such products with labeling not in accord with the labeling required by
Sec. 341.70 may result in regulatory action against the product, the
marketer, or both.
VII. Opportunity for Comments
Interested persons may submit written comments to the Dockets
Management Branch (address above). Such comments will be considered in
determining whether further amendments to or revisions of this
enforcement policy are warranted. Three copies of all comments are to
be submitted, except that individuals may submit one copy. Comments are
to be identified with the docket number found in brackets in the
heading of this document. Received comments may be seen in the Dockets
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.
List of Subjects in 21 CFR Part 341
Labeling, Over-the-counter drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
341 is amended as follows:
PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC
DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
1. The authority citation for 21 CFR part 341 continues to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353,
355, 360, 371).
[[Page 15703]]
2. New Sec. 341.70 is added to subpart C to read as follows:
Sec. 341.70 Labeling of OTC drug products containing ingredients that
are used for treating concurrent symptoms (in either a single-
ingredient or combination drug product).
The statements of identity, indications, warnings, and directions
for use, respectively, applicable to each ingredient in the product may
be combined to eliminate duplicative words or phrases so that the
resulting information is clear and understandable.
(a) For products containing diphenhydramine citrate and
diphenhydramine hydrochloride identified in Sec. 341.14(a)(5) and
(a)(6). The labeling of the product contains the established name of
the drug, if any, and identifies the product as an ``antihistamine/
cough suppressant'' or ``antihistamine/antitussive (cough
suppressant).'' The indications shall be combined from Secs. 341.72(b)
and 341.74(b). The warnings shall be combined from Secs. 341.72(c)(1),
(c)(2), (c)(4), and (c)(6) and 341.74(c)(1), (c)(2), (c)(3), and
(c)(4). Alternatively, all of the warnings in Sec. 341.74(c) shall be
used. The directions for OTC labeling shall follow
Secs. 341.74(d)(1)(iv) or (d)(1)(v), as applicable. The directions for
professional labeling shall follow Sec. 341.90(j) or (k), as
applicable.
(b) (Reserved)
Dated: March 28, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-8761 Filed 4-8-96; 8:45 am]
BILLING CODE 4160-01-F