[Federal Register Volume 60, Number 36 (Thursday, February 23, 1995)]
[Proposed Rules]
[Pages 10286-10293]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4464]
[[Page 10285]]
_______________________________________________________________________
Part VI
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Part 341
Human Drugs: Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic
Drug Products for Over-the-Counter Human Use; Amendment of the
Tentative Final Monograph for Combination Drug Products; Proposed Rule
Federal Register / Vol. 60, No. 36 / Thursday, February 23, 1995 /
Proposed Rules
[[Page 10286]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 341
[Docket No. 76N-052G]
RIN 0905-AA06
Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug
Products for Over-the-Counter Human Use; Amendment of the Tentative
Final Monograph for Combination Drug Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of proposed rulemaking.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the tentative final monograph for over-the-counter (OTC) cold, cough,
allergy, bronchodilator, and antiasthmatic combination drug products to
classify combination drug products containing the ingredients
diphenhydramine citrate or diphenhydramine hydrochloride. The agency
recently amended the final monograph for OTC antitussive drug products
(products used to relieve cough) to include the ingredients
diphenhydramine citrate and diphenhydramine hydrochloride. The agency
also previously included diphenhydramine citrate and diphenhydramine
hydrochloride in the final monograph for OTC antihistamine drug
products. This proposal is part of the ongoing review of OTC drug
products conducted by FDA.
DATES: Written comments or objections by May 9, 1995; written comments
on the agency's economic impact determination by May 9, 1995.
ADDRESSES: Written comments or objections to the Dockets Management
Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420
Parklawn Dr., Rockville, MD 20857.
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 September 9, 1976 (41 FR 38312), FDA
published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance
notice of proposed rulemaking to establish a monograph for OTC cold,
cough, allergy, bronchodilator, and antiasthmatic drug products. In
that notice, the Advisory Review Panel on OTC Cold, Cough, Allergy,
Bronchodilator, and Antiasthmatic Drug Products (the Panel) discussed
OTC cough-cold combination drug products, including combinations
containing an oral antitussive and/or an antihistamine (41 FR 38312 at
38327). The Panel considered combinations containing the ingredient
diphenhydramine hydrochloride. (Diphenhydramine citrate was not
submitted for the Panel's consideration.) The Panel recommended that
diphenhydramine hydrochloride be Category I (generally recognized as
safe and effective) as both an oral antitussive and an antihistamine.
However, the Panel recommended a Category II classification (not
generally recognized as safe and effective or misbranded) for any
combination containing an oral antitussive ingredient and an
antihistamine if the antitussive ingredient is also a Category I
antihistamine or if the antihistamine is also a Category I antitussive.
Diphenhydramine hydrochloride was the only ingredient that the Panel
classified in Category I for both antitussive and antihistamine use.
In the Federal Register of August 12, 1988 (53 FR 30522), FDA
published the tentative final monograph for OTC cold, cough, allergy,
bronchodilator, and antiasthmatic combination drug products. FDA did
not include specific combinations for OTC cough-cold drug products
containing diphenhydramine citrate or diphenhydramine hydrochloride for
OTC oral antitussive use in that tentative final monograph. At that
time, these ingredients were not included in the final monograph for
OTC antitussive drug products because adequate data to support
monograph status were not publicly available. Subsequently, data were
submitted to the rulemaking for OTC antitussive drug products (see
discussion below).
In the tentative final monograph, the agency discussed combinations
containing a drug recognized as both an antitussive and an
antihistamine combined with another oral antitussive and/or
antihistamine (53 FR 30522 at 30539). The agency proposed that such
combinations be Category III (available data are insufficient to
classify as safe and effective, and further testing is required).
In the Federal Register of December 9, 1992 (57 FR 58378), the
agency proposed that diphenhydramine citrate and diphenhydramine
hydrochloride be included in the final monograph for OTC antitussive
drug products as single ingredients. This action was taken because the
data needed to support monograph status had been made publicly
available. The proposal was recently finalized in the Federal Register
of June 3, 1994 (59 FR 29172). In that final rule, the agency stated
that it would address the following matters in a future issue of the
Federal Register: (1) OTC cough-cold combination drug products
containing diphenhydramine citrate or diphenhydramine hydrochloride for
antitussive use, (2) concurrent antitussive and antihistamine use of
diphenhydramine ingredients (either in an OTC cough-cold single-
ingredient or combination drug product) for concurrent symptoms, and
(3) ``multiuse'' labeling for OTC drug products containing an
ingredient that may be used separately for more than one indication for
nonconcurrent symptoms--with full, separate labeling for each
indication. The first two subjects are addressed in this proposed rule.
The third will be addressed in a future issue of the Federal Register.
Labeling issues relating to that topic are broader than
diphenhydramine, applying to other OTC drug ingredients that have more
than one pharmacologic activity and that are included or proposed for
inclusion in more than one OTC drug monograph. For example, sodium
bicarbonate has a number of drug uses.
II. The Agency's Proposals for OTC Cough-Cold Combination Drug
Products Containing Diphenhydramine Citrate or Diphenhydramine
Hydrochloride for Antitussive Use
In this proposed rule, the agency has considered all OTC cough-cold
combination products classified in the tentative final monograph for
OTC cough-cold combination drug products (53 FR 30522) that could
include diphenhydramine as an oral antitussive or as an antihistamine.
The agency is proposing only a few changes in the classification of
these combinations when diphenhydramine is included in the combination
as an antitussive or an antihistamine (see section III). The following
table lists the combinations that were considered:
[[Page 10287]]
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Table 1
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Cough-Cold Combinations Considered in the Tentative Final Monograph That
Contain an Antihistamine or an Antitussive
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A. Combinations containing an oral antitussive, but not an antihistamine
1. Analgesic-antipyretic(s) and oral antitussive
2. Analgesic-antipyretic(s) and oral antitussive and oral nasal
decongestant
3. Oral antitussive and expectorant (if labeled for nonproductive
cough)
4. Oral antitussive and oral nasal decongestant
5. Oral antitussive and expectorant and oral nasal decongestant
(if labeled for nonproductive cough)
6. Oral antitussive and anesthetic/analgesic (if available only in
a solid dosage form)
7. Oral nasal decongestant and oral antitussive and anesthetic/
analgesic (if available only in a solid dosage form)
8. Oral antitussive and oral demulcent (if available in a solid
dosage form)
9. Oral nasal decongestant and oral antitussive and oral demulcent
(if available only in a solid dosage form)
10. Oral antitussive and anesthetic/analgesic and oral demulcent
(if available only in a solid dosage form)
11. Oral nasal decongestant and oral antitussive and anesthetic/
analgesic and oral demulcent (if available only in a solid dosage
form)
12. Oral antitussive and debriding agent/oral wound cleanser
13. Oral antitussive and astringent
14. Oral bronchodilator and oral antitussive (if labeled for cough
associated with asthma)
15. Oral antitussive and bronchodilator used as an antitussive (if
labeled for productive cough)
16. Oral antitussive and expectorant (if labeled for productive
cough)
17. Oral antitussive and expectorant and oral nasal decongestant
(if labeled for productive cough)
18. Analgesic-antipyretic(s) and oral antitussive and expectorant
and oral nasal decongestant
B. Combinations containing an antihistamine, but not an oral
antitussive.
1. Analgesic-antipyretic(s) and antihistamine
2. Analgesic-antipyretic(s) and antihistamine and oral nasal
decongestant
3. Antihistamine and oral nasal decongestant
4. Antihistamine and debriding agent/oral wound cleanser
5. Antihistamine and astringent
6. Antihistamine and expectorant
7. Oral bronchodilator and antihistamine
8. Antihistamine and anticholinergic
9. Anticholinergic and antihistamine and oral nasal decongestant
10. Combinations containing an antihistamine for the relief of
symptoms of allergic rhinitis and an additional antihistamine
which is added exclusively for sedation, and the product contains
labeling which represents the additional antihistamine as a sleep-
aid
11. Combinations containing an antihistamine with a sleep- aid
claim
12. Antihistamine and oral anesthetic/analgesic
13. Antihistamine and oral demulcent
14. Antihistamine and nasal decongestant (administered topically
as spray or drops)
C. Combinations containing both an oral antitussive and an
antihistamine.
1. Antihistamine and oral antitussive (if labeled ``May cause
marked drowsiness'')
2. Analgesic-antipyretic(s) and oral antitussive and oral nasal
decongestant and antihistamine
3. Antihistamine and oral antitussive and oral nasal decongestant
4. Antihistamine (if antihistamine is also a Category I
antitussive) and oral antitussive
5. Oral antitussive (if antitussive is also a Category I
antihistamine) and antihistamine
------------------------------------------------------------------------
A. OTC cough-cold combinations containing: (1) An oral antitussive, but
no antihistamine and (2) an antihistamine, but no antitussive.
1. Comparison of Category I Antitussive Combinations With Category II
and III Antihistamine-containing Combinations.
The agency has compared all of the Category I combinations
containing an oral antitussive, but not an antihistamine (in Table 1,
A.1. through A.11.), with all of the Category II and III combinations
containing an antihistamine, but not an oral antitussive (in Table 1,
B.4. through B.14.). The agency compared the classes of ingredients
included with an oral antitussive in Category I and the classes
included with an antihistamine in Categories II and III to determine
which combinations similar to the Category II and III antihistamine
combinations were included in the Category I antitussive combinations.
The following table lists these combinations:
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Table 2
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Category I Oral Antitussive Corresponding Category II or III
Combination Antihistamine Combination
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Oral antitussive and an expectorant Antihistamine and expectorant
Oral antitussive and an expectorant None
and a nasal decongestant (if
labeled for nonproductive cough)
Oral antitussive and an anestehetic/ Antihistamine and an anesthetic/
analgesic in a solid dosage form analgesic in a solid dosage form
Oral antitussive and an demulcent in Antihistamine and a demulcent
a solid dosage form
Oral nasal decongestant and an oral None
antitussive and an anesthetic/
analgesic in a solid dosage form
Oral nasal decongestant and an oral None
antitussive and a demulcent in
solid dosage
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[[Page 10288]] (a) Combination drug products containing an
expectorant and an oral antitussive that is also an antihistamine. The
Panel recommended a Category I classification for combinations
containing an oral antitussive and an expectorant that is labeled for
nonproductive cough (41 FR 38312 at 38328). The agency concurred in the
tentative final monograph for OTC cough-cold combination drug products
(53 FR 30522 at 30556). However, the Panel recommended a Category II
classification for combinations containing an antihistamine and an
expectorant. In this combination, the anticholinergic effect (drying
action) of the antihistamine would produce the opposite effect of the
secretory action of the expectorant ingredient. Thus, the combination
would be medically irrational (41 FR 38312 at 38326). The agency
concurred with the Panel in the OTC cough-cold combinations tentative
final monograph (53 FR 30522 at 30556). Because diphenhydramine is an
antihistamine as well as an antitussive, it would have anticholinergic
effects whether it is included in a combination as an oral antitussive
or as an antihistamine. Accordingly, the agency is proposing a Category
II classification for all combinations containing an expectorant and an
oral antitussive if the antitussive is also an antihistamine. The
agency is revising proposed Sec. 341.40(g) and (i) to replace the
phrase ``Any single oral antitussive active ingredient identified in
Sec. 341.14(a) * * *'' with the phrase ``Any single oral antitussive
active ingredient identified in Sec. 341.14(a)(1) through (a)(4) * *
*.'' This revision specifically excludes combinations containing
diphenhydramine citrate or diphenhydramine hydrochloride as an
antitussive.
(b) Combination drug products containing an anesthetic/analgesic
and/or a demulcent (in a solid dosage form) and an oral antitussive
that is also an antihistamine. The Cough-Cold Panel reviewed data
relating to combination drug products containing cough-cold and oral
health care active ingredients with claims for relief of sore throat
(41 FR 38312 at 38325). The Panel established specific criteria for the
treatment of symptoms with combination products and based its Category
I recommendations on whether the combination is rational concurrent
therapy for a significant and existing population. The Panel determined
that products containing an antitussive or a nasal decongestant
combined with an oral anesthetic/analgesic in a lozenge dosage form are
rational and recommended a Category I classification for these
combinations. The agency concurred with the Panel in the tentative
final monograph for OTC cough-cold combination drug products. However,
the agency determined that such a combination could be rational only if
the combination drug product were in a solid dosage form so that the
anesthetic/analgesic ingredient or the demulcent ingredient may exert
its topical effect and the antitussive can be ingested (53 FR 30522 at
30536 and 30537).
The Panel did not discuss combinations containing an antihistamine
with an anesthetic/analgesic or a demulcent. However, the agency
considered such combinations in the OTC cough-cold combinations
tentative final monograph (53 FR 30522 at 30537). The agency stated
that the combination of an antihistamine and an oral anesthetic/
analgesic or an oral demulcent could be rational if the combination
drug product is in a solid dosage form. In addition, the symptoms of
allergic rhinitis and minor throat irritation that may result from the
nasal congestion that often occurs with allergic rhinitis and
subsequent breathing through the mouth could be treated concurrently
with such combinations. However, the agency also stated that it was
unaware of any currently marketed drug product that contains such a
combination and that no data were submitted to demonstrate a
significant target population with concurrent symptoms that would
benefit from such a combination. Therefore, the agency proposed a
Category III classification for the combination of an antihistamine
with an oral anesthetic/analgesic or an oral demulcent. The agency has
since determined that data do exist to support a target population for
such combinations based on epidemiological data accepted by the Panel
(41 FR 38312 at 38325). The agency believes that a Category I
classification is appropriate for combinations containing an oral
antitussive (which is also an antihistamine, although antihistamine
claims cannot be made for these combinations) with an oral anesthetic/
analgesic or an oral demulcent if in a solid dosage form. Thus, the
agency is proposing to include diphenhydramine citrate and
diphenhydramine hydrochloride in combinations specified in
Sec. 341.40(j), (q), (u), (w), (x), and (z). At this time, sufficient
data have not been provided to support a suitable target population
with concurrent symptoms of sufficient duration to justify an
antihistamine claim for any of these combination drug products.
Therefore, any of these combinations that contain diphenhydramine
citrate or diphenhydramine hydrochloride as the antitussive cannot also
make antihistamine claims.
2. Category II and III Combinations Containing an Antitussive.
The agency has considered all OTC cough-cold combinations
containing an oral antitussive, but no antihistamine, that were placed
in Category II or III in the OTC cough-cold combinations tentative
final monograph (combinations in Table 1 under A.1. through A.18.). The
agency has determined that these combinations would be categorized in
the same manner if diphenhydramine were used as the antitussive. The
agency is not aware of any data or information that would support
reclassification of any of these combinations because they contain
diphenhydramine rather than any other monograph oral antitussive
ingredient.
3. Combinations Containing an Antihistamine With no Corresponding
Category I Antitussive Combination.
The agency considered all antihistamine combinations (not including
an oral antitussive) that did not have a corresponding Category I
antitussive combination (not including an antihistamine), e.g., an
antihistamine and an anticholinergic. The agency is not changing the
classification of any of these combinations because they do not contain
an antitussive component. Thus, these combinations are not pertinent to
combinations that include an antitussive that is also an antihistamine.
B. OTC cough-cold combinations containing: (1) An oral antitussive and
an antihistamine if the antitussive is also a antihistamine or (2) an
antihistamine and an oral antitussive if the antihistamine is also an
antitussive.
The Panel recommended a Category II classification for combinations
containing: (1) An oral antitussive and an antihistamine if the
antitussive is also a Category I antihistamine, and (2) an
antihistamine and an oral antitussive if the antihistamine is also a
Category I antitussive (41 FR 38312 at 38326). Such combinations
include diphenhydramine and dextromethorphan or diphenhydramine and
chlorpheniramine. The Panel stated that the combinations are not safe
because the side effects of two drugs having the same action may
combine. For example, the drowsiness effect of each ingredient may be
additive and result in an unacceptable level of
[[Page 10289]] drowsiness for the combination drug product.
In the proposed rule for OTC cough-cold combination drug products
(53 FR 30522 at 30539), FDA did not include any specific OTC cough-cold
combination drug products containing diphenhydramine citrate or
diphenhydramine hydrochloride as oral antitussive active ingredients.
These ingredients were not included in the final monograph for OTC
antitussive drug products because of a lack of publicly available data
that would support the antitussive effectiveness of diphenhydramine.
(See the Federal Register of October 19, 1983, 48 FR 48576.) However,
the agency did discuss combinations containing a drug that is both an
antitussive and an antihistamine (such as diphenhydramine) combined
with another oral antitussive or antihistamine (53 FR 30522 at 30539).
The agency considered such products to be combinations containing two
ingredients from the same pharmacologic group and proposed a Category
III classification based on the agency's ``General Guidelines for OTC
Drug Combination Products'' (Ref. 1). Under the guidelines, Category I
active ingredients from the same therapeutic category that have the
same mechanism of action should not ordinarily be combined unless there
is some advantage over the single ingredient in terms of enhanced
effectiveness, safety, patient acceptance, or quality of formulation.
However, the guidelines also state that such ingredients may be
combined in selected circumstances to treat the same symptoms or
conditions if the combination meets the OTC drug combination policy in
all respects, the combination offers some advantage over the active
ingredients used alone, and the combination is, on a benefit-risk
basis, equal to or better than each of the active ingredients used
alone at its therapeutic dose.
Accordingly, the agency is proposing to place combinations
containing a drug recognized as both an antitussive and an
antihistamine with another oral antitussive and antihistamine in
Category III. At the present time, this proposal only involves
combinations containing diphenhydramine citrate or diphenhydramine
hydrochloride with any monograph antihistamine in Sec. 341.12 or any
monograph antitussive in Sec. 341.14. The agency is revising proposed
Sec. 341.40(d), (e), and (f) to replace the phrase ``Any single
antihistamine active ingredient identified in Sec. 341.12 * * *'' with
the phrase ``Any single antihistamine active ingredient identified in
Sec. 341.12(a) through (e) and (h) through (m) * * *.'' This revision
specifically excludes combinations containing diphenhydramine citrate
or diphenhydramine hydrochloride as an antihistamine with an
antitussive.
The agency is also revising proposed Sec. 341.40(d), (e), and (f)
to replace the phrase ``any single oral antitussive active ingredient
identified in Sec. 341.14(a) * * *'' with the phrase ``any single oral
antitussive active ingredient identified in Sec. 341.14(a)(1) through
(a)(4) * * *.'' This revision specifically excludes combinations
containing diphenhydramine citrate or diphenhydramine hydrochloride as
an antitussive with an antihistamine.
The agency has also considered combinations containing a dose of
diphenhydramine as the oral antitussive component and an additional
dose of diphenhydramine as the antihistamine. The agency concludes that
such a combination would contain too large a dose of diphenhydramine to
be safe. Thus, the agency is proposing that such a combination be
Category II.
The use of a single dose of diphenhydramine as an antitussive and
antihistamine for treating concurrent symptoms in either a single-
ingredient or combination drug product is discussed in section III.
Reference
(1) Food and Drug Administration ``General Guidelines for OTC
Drug Combination Products, September 1976,'' Docket No. 78D-0322,
Dockets Management Branch.
III. Use of a Single Dose of Diphenhydramine Citrate or
Diphenhydramine Hydrochloride as an Antitussive and Antihistamine
for Treating Concurrent Symptoms (in Either a Single-Ingredient or
Combination Drug Product)
In the Federal Register of December 9, 1992 (57 FR 58378), the
agency proposed to amend the final monograph for OTC antitussive drug
products to add diphenhydramine citrate and diphenhydramine
hydrochloride. In response, one comment stated that a single-ingredient
drug product containing diphenhydramine hydrochloride for concurrent
use as both an antihistamine and an antitussive should be labeled with
a broader dosing range (e.g., diphenhydramine hydrochloride, 25 to 50
milligrams (mg) every 4 to 6 hours, not to exceed 300 mg in 24 hours)
to eliminate confusion to consumers (Ref. 1). The comment also
contended that the broader dosage range should be permitted to provide
the maximum antihistamine effectiveness for consumers. In addition, the
comment stated that the labeling of products for concurrent
antihistamine/antitussive use should include the appropriate warnings
for both indications.
The Panel believed that the interests of consumers are best served
by exposing 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 (41 FR 38312 at 38322). Thus, 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. For example, a Category I combination drug
product containing diphenhydramine as an antihistamine and antitussive
combined with a nasal decongestant would contain only two ingredients.
Such a combination would contain one less ingredient than a similar
combination product containing three different ingredients for the same
therapeutic uses. Similarly, an antihistamine-antitussive combination
could contain only diphenhydramine to serve both functions.
In a final rule that amended the OTC antitussive monograph to
include diphenhydramine citrate and diphenhydramine hydrochloride (59
FR 29172), the agency determined that the available clinical data and
marketing history of products containing these ingredients for
antitussive use do not support a broader dosage range. The agency
concluded that it could not generally recognize as safe and effective
an antitussive dosage (25 to 50 mg every 4 to 6 hours for
diphenhydramine hydrochloride) that is not supported by clinical data.
The dosage for diphenhydramine hydrochloride in Sec. 341.74(d)(1)(v) of
the antitussive monograph (21 CFR 341.74(d)(1)(v)) reads:
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 dosage for diphenhydramine citrate in Sec. 341.74(d)(1)(iv) of the
antitussive monograph (21 CFR 341.74(d)(1)(iv)) reads:
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 [[Page 10290]] 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.
The dosage for diphenhydramine hydrochloride in Sec. 341.72(d)(7) of
the antihistamine monograph (21 CFR 341.72(d)(7)) reads:
Adults and children 12 years of age and over: oral dosage is 25
to 50 milligrams every 4 to 6 hours, not to exceed 300 milligrams in
24 hours, or as directed by a doctor. Children 6 to under 12 years
of age: oral dosage is 12.5 to 25 milligrams every 4 to 6 hours, not
to exceed 150 milligrams in 24 hours, or as directed by a doctor.
Children under 6 years of age: consult a doctor.
The dosage for diphenhydramine citrate in Sec. 341.72(d)(6) of the
antihistamine monograph (21 CFR 341.72(d)(6)) reads:
Adults and children 12 years of age and over: oral dosage is 38
to 76 milligrams every 4 to 6 hours, not to exceed 456 milligrams in
24 hours, or as directed by a doctor. Children 6 to under 12 years
of age: oral dosage is 19 to 38 milligrams every 4 to 6 hours, not
to exceed 228 milligrams in 24 hours, or as directed by a doctor.
Children under 6 years of age: consult a doctor.
The agency believes that an OTC drug product containing
diphenhydramine citrate or diphenhydramine hydrochloride that is
labeled both as an antitussive and an antihistamine should conform to
the same labeling restrictions that apply to combination drug products
containing a different antitussive and antihistamine ingredient. In the
tentative final monograph for OTC cough-cold combination drug products,
the agency proposed that when there is a difference in the directions
established for the individual ingredients in a combination drug
product, e.g., when the time intervals or age limitations for
administration of the individual ingredients differ, the directions for
the combination product may not exceed any maximum dosage limits
established for the individual ingredients in the applicable OTC drug
monograph (53 FR 30522 at 30554). Therefore, when diphenhydramine
citrate or diphenhydramine hydrochloride is labeled for both
antitussive and antihistamine use, the limiting factor for directions
for use for both the dosage amount and dosing interval for OTC labeling
is the antitussive dosage in Sec. 341.74(d)(1)(iv) and (d)(1)(v).
However, the limiting factor for directions for use for professional
labeling is the antihistamine dosage in Sec. 341.90(j) and (k) (21 CFR
341.90(j) and (k)), respectively. As noted above, the Panel believed
that the interests of consumers are best served by exposing 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 (41 FR 38312 at 38322).
The comment also questioned how the statements of identity,
indications, and warnings required for both OTC antitussive and
antihistamine drug products could be combined when the product contains
diphenhydramine for concurrent antitussive and antihistamine use. The
agency has determined that the labeling of such products should conform
to the labeling requirements for combination drug products containing
an antitussive and an antihistamine. The proposed labeling section for
OTC cough-cold combinations (Sec. 341.85) states that the statements of
identity, indications, and warnings may be combined to eliminate
duplicative wording or phrases so that the resulting information is
clear and understandable (53 FR 30522 at 30562).
When applied to diphenhydramine for concurrent use, the statement
of identity would be ``antihistamine/cough suppressant'' or
``antihistamine/antitussive (cough suppressant).'' The indications
would be combined from Secs. 341.72(b) and 341.74(b). The warnings
would be 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 product
would need to have 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, an easy rule to follow
when using diphenhydramine citrate or diphenhydramine hydrochloride as
a single ingredient for both antihistamine and antitussive use is to
follow all of the warnings in Sec. 341.74(c) of the antitussive
monograph. This example illustrates how a single uniform warning
results when the duplicative words or phrases from the respective
warnings are eliminated.
Accordingly, the agency is proposing the following labeling for
drug products that contain diphenhydramine citrate or diphenhydramine
hydrochloride for concurrent antitussive and antihistamine use:
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 statements
of identity, indications, and warnings required for antitussive and
antihistamine use may be combined to eliminate duplicative words or
phrases so that the resulting information is clear and understandable.
The directions for OTC labeling shall follow Sec. 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.
The agency notes that allowing the use of diphenhydramine in the
same product as both an antitussive and antihistamine for treating
concurrent symptoms is a new concept. Therefore, the agency would like
to receive public comment on the proposed new concept and on the
proposed labeling approach before marketing begins. Although the agency
is proposing in this amendment to the cough-cold combination tentative
final monograph to allow the use of diphenhydramine in the same product
as both an antitussive and an antihistamine, OTC marketing may not
begin at this time. The agency is providing a short comment period of
75 days and plans to 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.
Reference
(1) Comment No. C0001, Docket No. 89P-0040, Dockets Management
Branch.
IV. Summary of the Agency's Proposals for OTC Cough-Cold
Combinations Containing Diphenhydramine as an Antitussive
The agency has reviewed all combinations containing an oral
antitussive and/or an antihistamine that were classified as Category I,
II, or III in the tentative final monograph for OTC cough-cold
combination drug products (53 FR 30522 at 30556 and 30557), to clarify
the use of diphenhydramine citrate and diphenhydramine hydrochloride as
antitussive active ingredients in these combinations. For the
convenience of the reader, the following table is included as a summary
of the proposed classification changes by the agency of combinations
containing an antitussive in the tentative final monograph for OTC
cough-cold combination drug products (53 FR 30522 at 30556 and 30557)
and the proposed classification by the agency of these combinations
when the antitussive or the antihistamine active ingredient is either
diphenhydramine citrate or diphenhydramine hydrochloride. Table 3
includes only [[Page 10291]] the proposed changes in classification
made in Sec. 341.40 of the cough-cold combination drug products
tentative final monograph. All other combination classifications remain
the same:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Table 3
---------------------------------------------------------------------------------------------------------------------------------------------------------
Tentative Final Monograph Proposed New Proposed Classification for
Cold-Cough Combinations Classification Dephenhydramine-Containing Combinations
--------------------------------------------------------------------------------------------------------------------------------------------------------
Oral antitussive and expectorant (if labeled for
nonproductive cough) I II
Oral antitussive and expectorant and oral nasal
decongestant (if labeled for nonproductive cough) I II
Oral antitussive and bronchdilator used as an
antitussive (if labeled for productive cough) III II
Oral antitussive and expectorant (if labeled for
productive cough) III II
Oral antitussive and expectorant and oral nasal
decongestant (if labeled for productive cough) III II
Analgesic-antipyretic(s) and oral antitussive and
expectorant and oral nasal decongestant III II
Antihistamine and oral antitussive (if labeled ``May
cause marked drowsiness'') I III
Analgesic-antipyretic(s) and oral antitussive and oral
nasal decongestant and antihistamine I III
Antihistamine and oral antitussive and oral nasal
decongestant I III
--------------------------------------------------------------------------------------------------------------------------------------------------------
1. The agency is revising proposed Sec. 341.40(d), (e), and (f) to
replace the phrase ``Any single antihistamine active ingredient
identified in Sec. 341.12 * * *'' with the phrase ``any single
antihistamine active ingredient identified in Sec. 341.12(a) through
(e) and (h) through (m) * * *'' to exclude the ingredients
diphenhydramine citrate and diphenhydramine hydrochloride. (See section
II.B.)
2. The agency is revising Sec. 341.40(d) through (g) and (i) to
replace the phrase ``Any single oral antitussive active ingredient
identified in Sec. 341.14(a) * * *'' with the phrase ``Any single oral
antitussive active ingredient identified in Sec. 341.14(a)(1) through
(a)(4) * * *'' to exclude the ingredients diphenhydramine citrate and
diphenhydramine hydrochloride. (See sections II.A.(i) and II.B.)
3. The agency is proposing to include diphenhydramine citrate and
diphenhydramine hydrochloride in combinations specified in
Sec. 341.40(h), (j), (k), (q), (u), (w), (x), and (z). (See section
II.A.(ii).)
4. The agency is proposing in Sec. 341.40(d), (e), and (f) the use
of diphenhydramine citrate in Secs. 341.12(f) and 341.14(a)(5) or
diphenhydramine hydrochloride in Secs. 341.12(g) and 341.14(a)(6) as
both the antihistamine and the antitussive active ingredient provided
that the product is labeled according to Sec. 341.70.
5. The agency is revising Sec. 341.40(f) and (k) to include the
specific section numbers for allowed internal analgesic ingredients.
6. In the oral health care tentative final monograph published on
September 24, 1991 (56 FR 48302), the agency redesignated the active
anesthetic/analgesic ingredients previously proposed in Sec. 356.10 as
Sec. 356.12. Accordingly, the agency is revising Sec. 341.40(j), (q),
(x), and (z) to replace the phrase ``any single oral anesthetic/
analgesic active ingredient identified in Sec. 356.10 * * *'' with the
phrase ``any single oral anesthetic/analgesic active ingredient
identified in Sec. 356.12 * * *''.
7. The agency is proposing to add to Sec. 341.70 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 product or as a single ingredient in combination with other
active ingredients. (See section III.)
V. Effective Date
The agency advises that any final rule resulting from this proposed
rule will be effective 12 months after its date of publication in the
Federal Register. On or after that date, any OTC drug product that is
not in compliance may not be initially introduced or initially
delivered for introduction into interstate commerce unless it is the
subject of an approved application. Further, any OTC drug product
subject to the rule that is repackaged or relabeled after the effective
date of the rule must be in compliance with the rule regardless of the
date that the product was initially introduced or initially delivered
for introduction into interstate commerce. Manufacturers are encouraged
to comply voluntarily with the rule at the earliest possible date.
VI. Analysis of Impacts
FDA has examined the impacts of the proposed 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 proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the
[[Page 10292]] proposed rule is not a significant regulatory action as
defined by the Executive Order and so 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 proposed rule clarifies the use of
diphenhydramine citrate or diphenhydramine hydrochloride as an
antitussive active ingredient in OTC cough-cold combination drug
products and proposes marketing of either a single-ingredient or a
combination drug product containing one of these ingredients for
concurrent antitussive and antihistamine use. Manufacturers may market
such products at their option when marketing is allowed to begin. (See
marketing discussion in section III.) Accordingly, the agency certifies
that the proposed 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 invites public comment regarding any substantial or
significant economic impact that this rulemaking would have on OTC
cough-cold combination drug products. Comments regarding the impact of
this rulemaking on these drug products should be accompanied by
appropriate documentation.
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.
VII. Request for Comments
Interested persons may, on or before May 9, 1995, submit to the
Dockets Management Branch (address above) written comments or
objections. Three copies of all comments or objections are to be
submitted, except that individuals may submit one copy. Comments and
objections are to be identified with the docket number found in
brackets in the heading of this document and may be accompanied by a
supporting memorandum or brief. Comments and objections may be seen in
the office above 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, it is
proposed that 21 CFR part 341 (as proposed in the Federal Register of
August 12, 1988 (53 FR 30522)) be 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 341.40 is amended by revising paragraphs (d) through
(k), (q), (u), (w), (x), and (z) to read as follows:
Sec. 341.40 Permitted combinations of active ingredients.
* * * * *
(d) Any single antihistamine active ingredient identified in
Sec. 341.12(a) through (e) and (h) through (m) may be combined with any
single oral antitussive active ingredient identified in
Sec. 341.14(a)(1) through (a)(4) provided that the product is labeled
according to Sec. 341.85(c)(5). Diphenhydramine citrate in
Secs. 341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in
Secs. 341.12(g) and 341.14(a)(6) may be both the antihistamine and the
antitussive active ingredient provided that the product is labeled
according to Sec. 341.70.
(e) Any single antihistamine active ingredient identified in
Sec. 341.12(a) through (e) and (h) through (m) may be combined with any
single oral antitussive active ingredient identified in
Sec. 341.14(a)(1) through (a)(4) and any single oral nasal decongestant
active ingredient identified in Sec. 341.20(a). Diphenhydramine citrate
in Secs. 341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in
Secs. 341.12(g) and 341.14(a)(6) may be both the antihistamine and the
antitussive active ingredient provided that the product is labeled
according to Sec. 341.70.
(f) Any single antihistamine active ingredient identified in
Sec. 341.12(a) through (e) and (h) through (m) may be combined with any
single oral antitussive active ingredient identified in
Sec. 341.14(a)(1) through (a)(4) and any single oral nasal decongestant
active ingredient identified in Sec. 341.20(a) and any single
analgesic-antipyretic active ingredients identified in Sec. 343.10 of
this chapter, or any combination of acetaminophen with other analgesic-
antipyretic active ingredients identified in Sec. 343.20(a) of this
chapter, or any aspirin and antacid combination identified in
Sec. 343.20(b)(3). Diphenhydramine citrate in Secs. 341.12(f) and
341.14(a)(5) or diphenhydramine hydrochloride in Secs. 341.12(g) and
341.14(a)(6) may be both the antihistamine and the antitussive active
ingredient provided that the product is labeled according to
Sec. 341.70.
(g) Any single oral antitussive active ingredient identified in
Sec. 341.14(a)(1) through (a)(4) may be combined with any single
expectorant active ingredient identified in Sec. 341.18.
(h) Any single oral antitussive active ingredient identified in
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral
nasal decongestant active ingredient identified in Sec. 341.20(a)
provided the product contains only the labeling claims identified in
this paragraph.
(i) Any single oral antitussive drug ingredient identified in
Sec. 341.14(a)(1) through (a)(4) may be combined with any single oral
nasal decongestant active ingredient identified in Sec. 341.20(a) and
any single expectorant active ingredient identified in Sec. 341.18.
(j) Any single oral antitussive active ingredient identified in
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral
anesthetic/analgesic active ingredient identified in Sec. 356.12 of
this chapter provided that the product is available in a solid dosage
form to be dissolved in the mouth and swallowed and provided the
product contains only the labeling claims identified in this paragraph.
(k) Any single oral antitussive drug ingredient identified in
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral
nasal decongestant active ingredient identified in Sec. 341.20(a) and
any single analgesic-antipyretic active ingredients identified in
Sec. 343.10 of this chapter, or any combination of acetaminophen with
other analgesic-antipyretic active ingredients identified in
Sec. 343.20(a) of this chapter, or any aspirin and antacid combination
identified in Sec. 343.20(b)(3) provided the product contains only the
labeling claims identified in this paragraph and provided the product
contains only the labeling claims identified in this paragraph.
* * * * *
(q) Any single oral nasal decongestant active ingredient identified
in Sec. 341.20(a) may be combined with any single oral antitussive
active ingredient identified in Sec. 341.14(a)(1) through (a)(6) and
any single oral anesthetic/analgesic active ingredient identified in
Sec. 356.12 of this chapter provided that the product is available in a
solid dosage form to be dissolved in the mouth and swallowed and
provided the [[Page 10293]] product contains only the labeling claims
identified in this paragraph.
* * * * *
(u) Any single oral antitussive active ingredient identified in
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral
demulcent active ingredient identified in Sec. 356.18 of this chapter
provided that the product is available in a solid dosage form to be
dissolved in the mouth and swallowed and provided the product contains
only the labeling claims identified in this paragraph.
* * * * *
(w) Any single oral antitussive active ingredient identified in
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral
nasal decongestant active ingredient identified in Sec. 341.20(a) and
any single oral demulcent active ingredient identified in Sec. 356.18
of this chapter provided that the product is available in a solid
dosage form to be dissolved in the mouth and swallowed and provided the
product contains only the labeling claims identified in this paragraph.
(x) Any single oral antitussive active ingredient identified in
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral
anesthetic/analgesic active ingredient identified in Sec. 356.12 of
this chapter and any single oral demulcent active ingredient identified
in Sec. 356.18 of this chapter provided that the product is available
in a solid dosage form to be dissolved in the mouth and swallowed and
provided the product contains only the labeling claims identified in
this paragraph.
* * * * *
(z) Any single oral antitussive active ingredient identified in
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral
nasal decongestant active ingredient identified in Sec. 341.20(a) and
any single oral anesthetic/analgesic active ingredient identified in
Sec. 356.12 of this chapter and any single oral demulcent active
ingredient identified in Sec. 356.18 of this chapter provided that the
product is available in a solid dosage form to be dissolved in the
mouth and swallowed and provided the product contains only the labeling
claims identified in this paragraph.
3. New Sec. 341.70 is added to subpart C to read as follows:
Sec. 341.70 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 statements of identity, indications, and warnings required for
antitussive and antihistamine use may be combined to eliminate
duplicative words or phrases so that the resulting information is clear
and understandable. The directions for OTC labeling shall follow
Sec. 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.
Dated: January 31, 1995.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 95-4464 Filed 2-22-95; 8:45 am]
BILLING CODE 4160-01-F
