10286 Federal Register / Vol. 60, No. 36 / Thursday, February 23, 1995 / Proposed Rules

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.

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 § 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 coughcold 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:
Federal Register / Vol. 60, No. 36 / Thursday, February 23, 1995 / Proposed Rules 10287

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:

Table 2

Category I Oral Antitussive Combination Corresponding Category II or III Antihistamine Combination

Oral antitussive and an expectorant Antihistamine and expectorant

Oral antitussive and an expectorant and a nasal decongestant (if labeled

for nonproductive cough)

None

Oral antitussive and an anestehetic/analgesic in a solid dosage form Antihistamine and an anesthetic/analgesic in a solid dosage form

Oral antitussive and an demulcent in a solid dosage form Antihistamine and a demulcent

Oral nasal decongestant and an oral antitussive and an anesthetic/analgesic in a solid dosage formNone

Oral nasal decongestant and an oral antitussive and a demulcent in solid

dosage

None
10288 Federal Register / Vol. 60, No. 36 / Thursday, February 23, 1995 / Proposed Rules

(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

§ 341.40(g) and (i) to replace the phrase

‘‘Any single oral antitussive active

ingredient identified in § 341.14(a) * *

*’’ with the phrase ‘‘Any single oral

antitussive active ingredient identified

in § 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 § 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
Federal Register / Vol. 60, No. 36 / Thursday, February 23, 1995 / Proposed Rules 10289

drowsiness for the combination drug

product.

In the proposed rule for OTC coughcold 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

§ 341.12 or any monograph antitussive

in § 341.14. The agency is revising

proposed § 341.40(d), (e), and (f) to

replace the phrase ‘‘Any single

antihistamine active ingredient

identified in § 341.12 * * *’’ with the

phrase ‘‘Any single antihistamine active

ingredient identified in § 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

§ 341.40(d), (e), and (f) to replace the

phrase ‘‘any single oral antitussive

active ingredient identified in

§ 341.14(a) * * *’’ with the phrase ‘‘any

single oral antitussive active ingredient

identified in § 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

§ 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 § 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
10290 Federal Register / Vol. 60, No. 36 / Thursday, February 23, 1995 / Proposed Rules

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 § 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 § 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

§ 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

§ 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 (§ 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

§§ 341.72(b) and 341.74(b). The

warnings would be combined from

§ 341.72(c)(1), (c)(2), (c)(4), and (c)(6)

and § 341.74(c)(1), (c)(2), (c)(3), and

(c)(4). The warnings for

diphenhydramine for antitussive use in

§ 341.74(c)(4) encompass all of the same

warnings for diphenhydramine for

antihistamine use in § 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

§ 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 § 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

§ 341.74(d)(1)(iv) or (d)(1)(v), as

applicable. The directions for

professional labeling shall follow

§ 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
Federal Register / Vol. 60, No. 36 / Thursday, February 23, 1995 / Proposed Rules 10291

the proposed changes in classification

made in § 341.40 of the cough-cold

combination drug products tentative

final monograph. All other combination

classifications remain the same:

Table 3

Cold-Cough Combinations Tentative Final Monograph Proposed Classification

New Proposed Classification for

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

§ 341.40(d), (e), and (f) to replace the

phrase ‘‘Any single antihistamine active

ingredient identified in § 341.12 * * *’’

with the phrase ‘‘any single

antihistamine active ingredient

identified in § 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 § 341.40(d)

through (g) and (i) to replace the phrase

‘‘Any single oral antitussive active

ingredient identified in § 341.14(a) * *

*’’ with the phrase ‘‘Any single oral

antitussive active ingredient identified

in § 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 § 341.40(h),

(j), (k), (q), (u), (w), (x), and (z). (See

section II.A.(ii).)

4. The agency is proposing in

§ 341.40(d), (e), and (f) the use of

diphenhydramine citrate in §§ 341.12(f)

and 341.14(a)(5) or diphenhydramine

hydrochloride in §§ 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 § 341.70.

5. The agency is revising § 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 § 356.10 as

§ 356.12. Accordingly, the agency is

revising § 341.40(j), (q), (x), and (z) to

replace the phrase ‘‘any single oral

anesthetic/analgesic active ingredient

identified in § 356.10 * * *’’ with the

phrase ‘‘any single oral anesthetic/

analgesic active ingredient identified in

§ 356.12 * * *’’.

7. The agency is proposing to add to

§ 341.70 labeling for diphenhydraminecontaining 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
10292 Federal Register / Vol. 60, No. 36 / Thursday, February 23, 1995 / Proposed Rules

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:

§ 341.40 Permitted combinations of active

ingredients.

* * * * *

(d) Any single antihistamine active

ingredient identified in § 341.12(a)

through (e) and (h) through (m) may be

combined with any single oral

antitussive active ingredient identified

in § 341.14(a)(1) through (a)(4) provided

that the product is labeled according to

§ 341.85(c)(5). Diphenhydramine citrate

in §§ 341.12(f) and 341.14(a)(5) or

diphenhydramine hydrochloride in

§§ 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

§ 341.70.

(e) Any single antihistamine active

ingredient identified in § 341.12(a)

through (e) and (h) through (m) may be

combined with any single oral

antitussive active ingredient identified

in § 341.14(a)(1) through (a)(4) and any

single oral nasal decongestant active

ingredient identified in § 341.20(a).

Diphenhydramine citrate in §§ 341.12(f)

and 341.14(a)(5) or diphenhydramine

hydrochloride in §§ 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 § 341.70.

(f) Any single antihistamine active

ingredient identified in § 341.12(a)

through (e) and (h) through (m) may be

combined with any single oral

antitussive active ingredient identified

in § 341.14(a)(1) through (a)(4) and any

single oral nasal decongestant active

ingredient identified in § 341.20(a) and

any single analgesic-antipyretic active

ingredients identified in § 343.10 of this

chapter, or any combination of

acetaminophen with other analgesicantipyretic active ingredients identified

in § 343.20(a) of this chapter, or any

aspirin and antacid combination

identified in § 343.20(b)(3).

Diphenhydramine citrate in §§ 341.12(f)

and 341.14(a)(5) or diphenhydramine

hydrochloride in §§ 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 § 341.70.

(g) Any single oral antitussive active

ingredient identified in § 341.14(a)(1)

through (a)(4) may be combined with

any single expectorant active ingredient

identified in § 341.18.

(h) Any single oral antitussive active

ingredient identified in § 341.14(a)(1)

through (a)(6) may be combined with

any single oral nasal decongestant active

ingredient identified in § 341.20(a)

provided the product contains only the

labeling claims identified in this

paragraph.

(i) Any single oral antitussive drug

ingredient identified in § 341.14(a)(1)

through (a)(4) may be combined with

any single oral nasal decongestant active

ingredient identified in § 341.20(a) and

any single expectorant active ingredient

identified in § 341.18.

(j) Any single oral antitussive active

ingredient identified in § 341.14(a)(1)

through (a)(6) may be combined with

any single oral anesthetic/analgesic

active ingredient identified in § 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 § 341.14(a)(1)

through (a)(6) may be combined with

any single oral nasal decongestant active

ingredient identified in § 341.20(a) and

any single analgesic-antipyretic active

ingredients identified in § 343.10 of this

chapter, or any combination of

acetaminophen with other analgesicantipyretic active ingredients identified

in § 343.20(a) of this chapter, or any

aspirin and antacid combination

identified in § 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

§ 341.20(a) may be combined with any

single oral antitussive active ingredient

identified in § 341.14(a)(1) through

(a)(6) and any single oral anesthetic/

analgesic active ingredient identified in

§ 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
Federal Register / Vol. 60, No. 36 / Thursday, February 23, 1995 / Proposed Rules 10293

product contains only the labeling

claims identified in this paragraph.

* * * * *

(u) Any single oral antitussive active

ingredient identified in § 341.14(a)(1)

through (a)(6) may be combined with

any single oral demulcent active

ingredient identified in § 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 § 341.14(a)(1)

through (a)(6) may be combined with

any single oral nasal decongestant active

ingredient identified in § 341.20(a) and

any single oral demulcent active

ingredient identified in § 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 § 341.14(a)(1)

through (a)(6) may be combined with

any single oral anesthetic/analgesic

active ingredient identified in § 356.12

of this chapter and any single oral

demulcent active ingredient identified

in § 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 § 341.14(a)(1)

through (a)(6) may be combined with

any single oral nasal decongestant active

ingredient identified in § 341.20(a) and

any single oral anesthetic/analgesic

active ingredient identified in § 356.12

of this chapter and any single oral

demulcent active ingredient identified

in § 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 § 341.70 is added to subpart C

to read as follows:

§ 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 § 341.74(d)(1)(iv) or (d)(1)(v), as

applicable. The directions for

professional labeling shall follow

§ 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