Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use; Amendment of the Tentative Final Monograph for Combination Drug Products

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

-------------------------------------------------------------------------

Cough-Cold Combinations Considered in the Tentative Final Monograph That

Contain an Antihistamine or an Antitussive

-------------------------------------------------------------------------

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

-------------------------------------------------------------------------

Category I Oral Antitussive Corresponding Category II or III

Combination Antihistamine Combination

------------------------------------------------------------------------

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