[Federal Register Volume 59, Number 106 (Friday, June 3, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-13586]
[[Page Unknown]]
[Federal Register: June 3, 1994]
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Part VIII
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
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21 CFR Part 341
Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products
for Over-the-Counter Human Use; Final Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 341
[Docket No. 89P-0040]
RIN 0905-AA06
Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug
Products for Over-the-Counter Human Use; Amendment of Final Monograph
for OTC Antitussive Drug Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
amending the final monograph for over-the-counter (OTC) antitussive
drug products to include the ingredients diphenhydramine citrate and
diphenhydramine hydrochloride. OTC antitussive drug products are used
to relieve cough. This final rule addresses only single-ingredient
antitussive drug products containing one of these ingredients. In a
future issue of the Federal Register, the agency will propose to amend
the tentative final monograph for OTC cold, cough, allergy,
bronchodilator, and antiasthmatic combination drug products to address
combination cough-cold drug products containing diphenhydramine citrate
or diphenhydramine hydrochloride. This final rule is part of the
ongoing review of OTC drug products conducted by FDA.
EFFECTIVE DATE: June 5, 1995.
FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug
Evaluation and Research (HFD-810), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5000.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of August 12, 1987 (52 FR 30042), FDA
issued a final monograph for OTC antitussive drug products in part 341
(21 CFR part 341) that lists in Sec. 341.14 (21 CFR 341.14) the active
ingredients that are generally recognized as safe and effective for use
in these products. Diphenhydramine citrate and diphenhydramine
hydrochloride were not included in Sec. 341.14 at that time.
Subsequently, two manufacturers petitioned the agency to amend the
final monograph for OTC antitussive drug products to include
diphenhydramine citrate and diphenhydramine hydrochloride as monograph
active ingredients (Refs. 1 and 2). The petitions are on display in the
Dockets Management Branch (HFA-305), Food and Drug Administration, rm.
1-23, 12420 Parklawn Dr., Rockville, MD 20857.
In the Federal Register of December 9, 1992 (57 FR 58378), the
agency discussed these petitions and proposed that diphenhydramine
citrate and diphenhydramine hydrochloride be generally recognized as
safe and effective for OTC antitussive use. The agency previously
determined that diphenhydramine citrate is bioequivalent and
therapeutically equivalent to diphenhydramine hydrochloride (54 FR 6814
at 6824, February 14, 1989). The agency proposed specific warnings and
directions for these ingredients for OTC antitussive use. The agency
advised in its proposed rule (57 FR 58378 at 58380) that any final rule
resulting from this proposed rule would be effective 12 months after
the final rule's date of publication in the Federal Register.
The agency invited written comments by February 8, 1993, on the
proposed rule and the agency's economic impact determination for the
proposal. In response to the proposed rule, the agency received two
comments from manufacturers. Copies of the comments are on public
display in the Dockets Management Branch (address above).
References
(1) Comment No. CP2, Docket No. 89P-0040, Dockets Management
Branch.
(2) Comment No. CP3, Docket No. 89P-0040, Dockets Management
Branch.
II. The Agency's Conclusions on the Comments
1. Two comments requested that the agency's proposed OTC
antitussive dosage for diphenhydramine hydrochloride (25 milligrams
(mg) every 4 hours (h), not to exceed 150 mg in 24 h) be expanded to a
range of 25 to 50 mg every 4 to 6 h, not to exceed 300 mg in 24 h. One
of the comments also requested a corresponding expansion of the OTC
antitussive dosage for diphenhydramine citrate, i.e., a dosage of 38 to
76 mg every 4 to 6 h, not to exceed 456 mg in 24 h.
To support an expanded dosage range for antitussive use, one of the
comments provided pharmacokinetic data for diphenhydramine
hydrochloride dosed at 25 mg every 4 h and 50 mg every 6 h. The data
included the following steady state concentrations (Css), minimum
concentrations at steady state (Css min), and maximum
concentrations at steady state (Css max) in nanograms/milliliter
(ng/mL) for both dosages; and the areas under the curve (AUC) for both
dosages in ng x h/mL:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Diphenhydramine Hydrochloride Pharmacokinetic Data
---------------------------------------------------------------------------------------------------------------------------------------------------------
(Css max) (Css min) (Css) (AUC)
--------------------------------------------------------------------------------------------------------------------------------------------------------
25 mg every 4 h 55 ng/mL 27.5 ng/mL 40 ng/mL 160 ng x h/mL
50 mg 312 ng x h/mL 85 ng/mL 30 ng/mL 52 ng/mL
--------------------------------------------------------------------------------------------------------------------------------------------------------
The comment pointed out that the two Css min concentrations are
comparable. The comment stated that the 50 mg every 6 h dosing regimen
is as efficacious as the 25 mg every 4 h regimen because the 50 mg dose
does not fall below the minimum effective concentration. The comment
added that further substantiation is provided by the Css and AUC
data, which fall within the minimum effective concentration levels.
The other comment stated that the potential for conflict between
the different dosages for antitussive and antihistamine use of
diphenhydramine would be eliminated by accepting the broader
antihistamine dosage (e.g., for diphenhydramine hydrochloride, 25 to 50
mg every 4 to 6 h, not to exceed 300 mg in 24 h) for products intended
for both uses. The comment added that this approach would reduce the
potential for consumer confusion. The comment argued that it would not
be in the consumer's interest to establish a lower dose for
diphenhydramine in products that will not meet consumer expectations of
the antihistamine effect. The comment contended that, based on the
established safety of diphenhydramine citrate and diphenhydramine
hydrochloride for both antitussive and antihistamine use, monograph
status for four uses, and potential use for more than one indication in
a cough-cold product, the broader dosage range (e.g., for
diphenhydramine hydrochloride, 25 to 50 mg every 4 to 6 h) should be
permitted to provide maximum effectiveness. Both comments concluded
that diphenhydramine hydrochloride has been found safe for a variety of
OTC uses at dosages of 25 to 50 mg every 4 to 6 h and, thus, safety is
not an issue at this dosage range.
In the Federal Register of September 9, 1976 (41 FR 38312 at
38341), the Advisory Review Panel on OTC Cold, Cough, Allergy,
Bronchodilator, and Antiasthmatic Drug Products based its 25 mg every 4
h recommendation for diphenhydramine hydrochloride for antitussive use
on data demonstrating effectiveness and acceptable tolerability at this
dosage. All approved applications for diphenhydramine hydrochloride as
an OTC antitussive are for a dosage of 25 mg every 4 h, based on
supporting clinical data. No clinical data have been received by the
agency to support the safety or increased effectiveness of higher
dosages of diphenhydramine hydrochloride or diphenhydramine citrate for
OTC antitussive use either under the OTC drug review or an approved
application. One comment submitted pharmacokinetic data concerning
diphenhydramine at both the 25 mg every 4 h dose and the 50 mg every 6
h dose showing that Css min for both regimens were similar. It is
therefore likely that dosing at 50 mg every 6 h is effective. That
regimen, however, produces higher Css max and almost twice the
drug exposure, with increased potential adverse effects such as
sedation, but with no evidence of greater effectiveness than the every
4 h regimen. In conclusion, the agency cannot consider to be generally
recognized as safe and effective an antitussive dosage (25 to 50 mg
every 4 to 6 h for diphenhydramine hydrochloride) that is not supported
by clinical data. Therefore, based on the Panel's recommended dosage
and the approved application labeling for OTC antitussive drug products
containing diphenhydramine hydrochloride, the agency is establishing
the monograph antitussive dosage of diphenhydramine hydrochloride as
follows:
Adults and children 12 years of age and over: oral dosage is 25
milligrams every 4 hours, not to exceed 150 milligrams in 24 hours,
or as directed by a doctor. Children 6 to under 12 years of age:
oral dosage is 12.5 milligrams every 4 hours, not to exceed 75
milligrams in 24 hours, or as directed by a doctor. Children under 6
years of age: consult a doctor.
The monograph antitussive dosage of diphenhydramine citrate is as
follows:
Adults and children 12 years of age and over: oral dosage is 38
milligrams every 4 hours, not to exceed 228 milligrams in 24 hours,
or as directed by a doctor. Children 6 to under 12 years of age:
oral dosage is 19 milligrams every 4 hours, not to exceed 114
milligrams in 24 hours, or as directed by a doctor. Children under 6
years of age: consult a doctor.
With respect to the comment's discussion of a single ingredient
drug product containing diphenhydramine for concurrent use as both an
antihistamine and an antitussive, this issue will be addressed in an
amendment to the OTC cough-cold combinations tentative final monograph
in a future issue of the Federal Register.
2. One comment discussed ``multiuse'' labeling of OTC drug products
that contain diphenhydramine. The comment described this as labeling a
product with some or all of the proven pharmacologic activities of the
drug whether or not the conditions to be treated are related. As an
example, the comment stated that a product containing diphenhydramine
could be labeled for both antitussive and antihistamine use. If this
occurred, the statement of identity could be expressed as ``cough
suppressant/antihistamine.'' The comment stated that the product's
labeling could describe each use separately under the product's
``Indications,'' with accompanying warnings and directions for both
uses. The comment contended that there is no legal restriction that
prevents ``multiuse'' labeling whether or not the conditions to be
treated are related. The comment discussed several aspects of
``multiuse'' labeling.
This final rule addresses only single-ingredient diphenhydramine
citrate and diphenhydramine hydrochloride drug products for antitussive
use. The agency acknowledges that ``multiuse'' labeling is possible for
products containing diphenhydramine but is not aware of any such
products having been or currently being in the marketplace. The agency
intends to address ``multiuse'' labeling in a future issue of the
Federal Register in an amendment to the tentative final monograph for
OTC cough-cold combination drug products. The agency will discuss: (1)
Concurrent use of diphenhydramine as an antitussive and as an
antihistamine for concurrent symptoms, and (2) different uses of
diphenhydramine with separate full labeling for different,
nonconcurrent symptoms. Manufacturers may not introduce diphenhydramine
products having ``multiuse'' labeling into the OTC marketplace until
the agency's proposal on how this should be done appears in a future
issue of the Federal Register.
3. One comment contended that an agency statement in the proposed
rule appeared to be inconsistent with the agency's general provisions
and administrative procedures for marketing OTC combination drug
products under 21 CFR 330.13(b)(2) and Compliance Policy Guide
7132b.16. The agency statement said: ``Until the agency amends the
tentative final monograph for OTC cough-cold combination drug products,
no cough-cold combination drug product containing diphenhydramine
citrate or diphenhydramine hydrochloride labeled for antitussive use
can be marketed OTC unless it is the subject of an approved NDA or
ANDA'' (57 FR 58378 at 58380). The comment stated that, because FDA
recognizes diphenhydramine as both an OTC antihistamine and an OTC
antitussive, marketing of diphenhydramine for both claims in
combination drug products should be allowed under the provisions of the
tentative final monograph for OTC cough-cold combination drug products.
The comment listed a number of examples where an antitussive can be
combined with an antihistamine and stated that diphenhydramine should
be able to perform both functions in the product. The comment contended
that this approach should be acceptable provided that all of the
labeled uses are for Category I combinations.
This final rule does not address combination drug products
containing diphenhydramine citrate or diphenhydramine hydrochloride as
an antitussive active ingredient. There are a number of issues that
need to be resolved before diphenhydramine can be used to perform both
functions (antitussive and antihistamine) in a single product. These
include, among others, a difference in the monograph directions for use
(amount of drug to be taken and time interval for taking the drug) and
different warnings related to the individual uses. The agency intends
to discuss these matters in a future issue of the Federal Register, as
noted above. At this time, the agency reaffirms its position stated
above that any OTC cough-cold combination drug product containing
diphenhydramine citrate or diphenhydramine hydrochloride labeled for
antitussive use can only be marketed if it is the subject of an
approved application.
No comments were received in response to the agency's request for
specific comment on the economic impact of this rulemaking. FDA has
examined the impacts of this final rule 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
this final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the final
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. Currently marketed OTC single ingredient
diphenhydramine drug products already meet the conditions of the final
monograph. Other manufacturers will be able to enter the OTC
marketplace without having to obtain an approved application.
Accordingly, the agency certifies that the final rule 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.
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.
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).
2. Section 341.14 is amended by adding new paragraphs (a)(5) and
(a)(6) to read as follows:
Sec. 341.14 Antitussive active ingredients.
* * * * *
(a) * * *
(5) Diphenhydramine citrate.
(6) Diphenhydramine hydrochloride.
* * * * *
3. Section 341.74 is amended by adding new paragraphs (c)(4)(vii),
(c)(4)(viii), (c)(4)(ix), (d)(1)(iv), and (d)(1)(v) to read as follows:
Sec. 341.74 Labeling of antitussive drug products.
* * * * *
(c) * * *
(4) * * *
(vii) For products containing diphenhydramine citrate or
diphenhydramine hydrochloride identified in Sec. 341.14(a)(5) and
(a)(6). ``May cause excitability especially in children.''
(viii) For products containing diphenhydramine citrate or
diphenhydramine hydrochloride identified in Sec. 341.14(a)(5) and
(a)(6) when labeled only for children under 12 years of age--(A) ``Do
not give this product to children who have a breathing problem such as
chronic bronchitis, or who have glaucoma, without first consulting the
child's doctor.''
(B) ``May cause marked drowsiness. Sedatives and tranquilizers may
increase the drowsiness effect. Do not give this product to children
who are taking sedatives or tranquilizers, without first consulting the
child's doctor.''
(ix) For products containing diphenhydramine citrate or
diphenhydramine hydrochloride identified in Sec. 341.14(a)(5) and
(a)(6) when labeled for use in adults and children under 12 years of
age--(A) ``Do not take this product, unless directed by a doctor, if
you have a breathing problem such as emphysema or chronic bronchitis,
or if you have glaucoma or difficulty in urination due to enlargement
of the prostate gland.''
(B) ``May cause marked drowsiness; alcohol, sedatives, and
tranquilizers may increase the drowsiness effect. Avoid alcoholic
beverages while taking this product. Do not take this product if you
are taking sedatives or tranquilizers, without first consulting your
doctor. Use caution when driving a motor vehicle or operating
machinery.''
* * * * *
(d) * * *
(1) * * *
(iv) For products containing diphenhydramine citrate identified in
Sec. 341.14(a)(5). ``Adults and children 12 years of age and over: oral
dosage is 38 milligrams every 4 hours, not to exceed 228 milligrams in
24 hours, or as directed by a doctor. Children 6 to under 12 years of
age: oral dosage is 19 milligrams every 4 hours, not to exceed 114
milligrams in 24 hours, or as directed by a doctor. Children under 6
years of age: consult a doctor.''
(v) For products containing diphenhydramine hydrochloride
identified in Sec. 341.14(a)(6). ``Adults and children 12 years of age
and over: oral dosage is 25 milligrams every 4 hours, not to exceed 150
milligrams in 24 hours, or as directed by a doctor. Children 6 to under
12 years of age: oral dosage is 12.5 milligrams every 4 hours, not to
exceed 75 milligrams in 24 hours, or as directed by a doctor. Children
under 6 years of age: consult a doctor.''
* * * * *
4. Section 341.90 is amended by adding new paragraphs (r) and (s)
to read as follows:
Sec. 341.90 Professional labeling.
* * * * *
(r) For products containing diphenhydramine citrate identified in
Sec. 341.14(a)(5). ``Children 2 to under 6 years of age: oral dosage is
9.5 milligrams every 4 hours, not to exceed 57 milligrams in 24
hours.''
(s) For products containing diphenhydramine hydrochloride
identified in Sec. 341.14(a)(6). ``Children 2 to under 6 years of age:
oral dosage is 6.25 milligrams every 4 hours, not to exceed 37.5
milligrams in 24 hours.''
Dated: May 16, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-13586 Filed 6-2-94; 8:45 am]
BILLING CODE 4160-01-F