[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